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Bioactivity and Potential Health Benefits of Licorice
Abstract
Licorice is an herbal plant named for its unique sweet flavor. It is widely used in the food and tobacco industries as a sweetener. Licorice is also used in traditional Chinese medicine (TCM) and complementary medicine. Because the use of licorice has long been a part of TCM, the details of its therapeutic applications have been thoroughly established. In modern science, licorice is of interest because of its broad range of applications. Extracts of and compounds isolated from licorice have been well studied and biologically characterized. In this review, we discuss the nutraceutical and functional activities of licorice as well as those of the extracts of and the isolated compounds from licorice, including agents with anti-inflammatory activity, cell-protective abilities and chemopreventive effects. The side effects of licorice are also enumerated. A comparison of the activities of licorice described by modern science and TCM is also presented, revealing the correspondence of certain characteristics.
... The medicinal plant Glycyrrhiza uralensis Fisch is widely used to treat multiple diseases, and its efficacy is largely attributed to liquiritin and glycyrrhizic acid [51,52]. Glycyrrhizic acid is a triterpenoide glycoside with multiple anti-cancer-related pharmacological activities [53], while liquiritin is a flavonoid that can be utilized to prevent inflammation and relieve pain [54]. ...
... Glycyrrhizic acid is a triterpenoide glycoside with multiple anti-cancer-related pharmacological activities [53], while liquiritin is a flavonoid that can be utilized to prevent inflammation and relieve pain [54]. An interesting phenomenon about G. uralensis is that wild plants produced significantly more liquiritin and glycyrrhizic acid than cultivated plants [51,52]. Comparative multi-omics analyses between the wild and cultivated G. uralensis revealed that the bacteria genus Lysobacter was remarkably more abundant in the cultivated plant rhizosphere than the wild plant rhizosphere, and that the expression of some key genes involved in liquiritin and glycyrrhizic acid biosynthesis were strongly negatively correlated with the abundance of Lysobacter [51,52]. ...
... An interesting phenomenon about G. uralensis is that wild plants produced significantly more liquiritin and glycyrrhizic acid than cultivated plants [51,52]. Comparative multi-omics analyses between the wild and cultivated G. uralensis revealed that the bacteria genus Lysobacter was remarkably more abundant in the cultivated plant rhizosphere than the wild plant rhizosphere, and that the expression of some key genes involved in liquiritin and glycyrrhizic acid biosynthesis were strongly negatively correlated with the abundance of Lysobacter [51,52]. In addition, the bacteria genus Rhodoplanes was found to be positively correlated with the accumulation of both liquiritin and glycyrrhizic acid, as well as be more abundant in the rhizosphere of wild G. uralensis compared to cultivated plants [51,52]. ...
An important trend in global agriculture is to utilize
plant probiotics, which are microbes that can promote
plant growth and/or increase plant resistance to stress
conditions, to reduce the use of chemical fertilizers
and pesticides while maintaining or increasing yield. Te global market size of plant probiotics for crops
was valued at USD 5.27 billion in 2021 and is projected
to reach 15.71 billion by 2029. Probiotic-induced plant
growth promotion commonly involves improvements
in nutrient acquisition and the modulation of phytohormone homeostasis, whereas the potential contributions of other cellular processes, such as the biogenesis
of ribosomes, which translates mRNAs into proteins
and accordingly has an essential role in the control of cell
growth, have received little attention. In addition, unlike
the apparent efects on plant growth, the efects of probiotics
on plant secondary metabolites at the omics level, which are
important for the quality of plant-based foods, are generally unclear.
... The medicinal plant Glycyrrhiza uralensis Fisch is widely used to treat multiple diseases, and its efficacy is largely attributed to liquiritin and glycyrrhizic acid [51,52]. Glycyrrhizic acid is a triterpenoide glycoside with multiple anti-cancer-related pharmacological activities [53], while liquiritin is a flavonoid that can be utilized to prevent inflammation and relieve pain [54]. ...
... Glycyrrhizic acid is a triterpenoide glycoside with multiple anti-cancer-related pharmacological activities [53], while liquiritin is a flavonoid that can be utilized to prevent inflammation and relieve pain [54]. An interesting phenomenon about G. uralensis is that wild plants produced significantly more liquiritin and glycyrrhizic acid than cultivated plants [51,52]. Comparative multi-omics analyses between the wild and cultivated G. uralensis revealed that the bacteria genus Lysobacter was remarkably more abundant in the cultivated plant rhizosphere than the wild plant rhizosphere, and that the expression of some key genes involved in liquiritin and glycyrrhizic acid biosynthesis were strongly negatively correlated with the abundance of Lysobacter [51,52]. ...
... An interesting phenomenon about G. uralensis is that wild plants produced significantly more liquiritin and glycyrrhizic acid than cultivated plants [51,52]. Comparative multi-omics analyses between the wild and cultivated G. uralensis revealed that the bacteria genus Lysobacter was remarkably more abundant in the cultivated plant rhizosphere than the wild plant rhizosphere, and that the expression of some key genes involved in liquiritin and glycyrrhizic acid biosynthesis were strongly negatively correlated with the abundance of Lysobacter [51,52]. In addition, the bacteria genus Rhodoplanes was found to be positively correlated with the accumulation of both liquiritin and glycyrrhizic acid, as well as be more abundant in the rhizosphere of wild G. uralensis compared to cultivated plants [51,52]. ...
Medicinal plants are rich in secondary metabolites with beneficial pharmacological effects. The production of plant secondary metabolites is subjected to the influences by environmental factors including the plant-associated microbiome, which is crucial to the host’s fitness and survival. As a result, research interests are increasing in exploiting microbial capacities for enhancing plant production of pharmacological metabolites. A growing body of recent research provides accumulating evidence in support of developing microbe-based tools for achieving this objective. This mini review presents brief summaries of recent studies on medicinal plants that demonstrate microbe-augmented production of pharmacological terpenoids, polyphenols, and alkaloids, followed by discussions on some key questions beyond the promising observations. Explicit molecular insights into the underlying mechanisms will enhance microbial applications for metabolic fortification in medicinal plants.
... and serves as a key marker for its agricultural evaluation, It exhibits antiviral [9], antibacterial [10], anti-inflammatory [11], and anticancer [12,13] properties. Therefore, licorice has been used in the pharmaceutical and food industries [14]. ...
Licorice (Glycyrrhiza spp.) is a medicinal plant belonging to the Fabaceae family. In Korean Pharmacopoeia, three species of G. uralensis, G. glabra, and G. inflata are listed as licorice. Recently, G. korshinskyi has been registered in the Korean Pharmacopoeia, but there is no comprehensive monograph covering its agronomic characteristics. This research evaluated the agronomic characteristics of G. korshinskyi through growth characteristics, character correlations analysis, and principal component analysis (PCA) using 50 lines. We evaluated growth characteristics of the stem, root, stolon (rhizome), the emergence rate, and glycyrrhizin content. Correlation analysis showed that plant height and root diameter strong positively correlated with root weight and glycyrrhizin content. PCA was useful for understanding the agronomic characteristics of G. korshinskyi, with plant height, root diameter, root weight, stolon diameter, glycyrrhizin content, stolon length, stolon number, and stolon weight as key factors. Cluster analysis grouped G. korshinskyi lines into three groups. Group III contained nine lines with a high plant height, leaf length, leaf width, root diameter, root weight, and glycyrrhizin content. In conclusion, this research evaluated the agronomic characteristics of G. korshinskyi resources through growth traits, correlation analysis, and principal component analysis. This research establishes a foundation for future breeding programs and functional studies.
... Licorice compounds have also shown promise as inhibitors of COVID-19 (Kim et al., 2023). Beyond medicinal applications, licorice and its extracts have found use in industries like food, tobacco, and household chemicals (Kao et al., 2014). ...
Introduction
Licorice stands out as an exceptional medicinal resource with a long history of application, attributed to its substantial pharmacological potential. The basic helix-loop-helix (bHLH) transcription factors (TFs) gene family, being the second-largest in plants, is vital for plant development and adapting to environmental shifts. Despite this, the comprehensive characteristics of licorice bHLH gene family are not well-documented.
Results
In this study, a detailed and thorough genome-wide identification and expression analysis of Glycyrrhiza uralensis bHLH gene family was carried out, resulting in the identification of 139 licorice bHLH members. Our duplication analysis highlighted the significant contribution of segmental duplications to the expansion of G. uralensis bHLH genes, with GubHLH genes experiencing negative selection throughout evolution. It was discovered that GubHLH64 and GubHLH38 could be importantly linked to the licorice trichome initiation and anthocyanin biosynthesis and GubHLH64 was also involved in the abiotic stress response. Additionally, certain subfamily III (d+e) GubHLH members could be implicated in the licorice drought response. GubHLH108, GubHLH109, and GubHLH116 were suggested to form a tightly related cluster, initiating transcriptional responses via JA signaling pathway.
Discussion
In summary, our findings furnish a foundational understanding for future investigations of GubHLH gene functions and regulation mechanisms, shedding light on the potential applications of licorice in medicine and agriculture.
... The saponin present in Q. saponaria is ecologically and industrially relevant due to its bioactive and pharmacological properties, such as hypolipidemic, anti-inflammatory, expectorant, and androgenic activities, making it widely used in the food and pharmaceutical industries. Saponins act as natural detergents, and have been studied for their physicochemical properties (e.g., as surfactants) and biological properties (e.g., as biocides and antibacterial agents), serving as key components in applications such as encapsulation agents, stabilizers for bioactive compounds, and foaming agents in beverages and processed foods [25][26][27]. In the agricultural industry, saponins play an important role as biocontrol agents due to their insecticidal, antimicrobial, and plant growth-promoting properties. ...
The use of living organisms to treat human by-products, such as residual sludge, has gained interest in the last years. Fungi have been used for bioremediation and improving plant performance in contaminated soils. We investigated the impact of the mycorrhizal fungus (MF) Gigaspora roseae and the saprophytic fungus (SF) Coriolopsis rigida on the survival and growth of Quillaja saponaria seedlings cultivated in a sandy substrate supplemented with residual sludge. Q. saponaria is a sclerophyllous tree endemic to Chile, known for its high content of saponins. We inoculated plants with the MF, the SF, and a combination of both (MF + SF). Following inoculation, varying doses of liquid residual sludge equivalent to 0, 75, and 100% of the substrate’s field capacity were applied. After 11 months, we found a positive influence of the utilized microorganisms on the growth of Q. saponaria. Particularly, inoculation with the SF resulted in higher plant growth, mycorrhizal colonization percentage, and higher enzymatic activity, especially after the application of the sludge. This increase was more evident with higher doses of the applied sludge. These results highlight the potential of combined microorganism and residual sludge application as a sustainable strategy for enhancing plant growth and reducing waste.
... Influenced adipogenesis in maturing preadipocytes and induced lipolysis in mature adipocytes [53] Neuroprotective PC12 cells (in vitro) 0.5 mg/mL 0.5 mg/mL Inhibited apoptosis Mitochondrial Bax/Bcl-2 protein levels Activate the PI3K/Akt pathways [54] Liquiritin Neuroprotective B65 cells (in vitro) 1-100 μM Dependent on dose Upregulated the expression of functional glucose-6phosphate dehydrogenase and antioxidants 48 Isoliquiritin Cytoprotective PC12 cells (in vitro) 1-20 μmol/L 20 μmol/L Corticosterone mediated cell damage by decreasing oxidative stress, catalase, and malondialdehyde [55] Licochalcone A Anti-inflammatory Chondrocytes (in vitro) 5-10 μM Dosedependent Suppressed the production of MMP1, MMP3, and MMP13 in chondrocytes stimulated by IL-1β [56] Anticancer ...
Oxidative stress is a critical factor in the pathogenesis of various diseases, including cancers, neurodegenerative disorders, and inflammatory conditions. Glycyrrhiza glabra L., commonly known as licorice, has been utilized in traditional medicine systems for its therapeutic benefits, particularly its rejuvenating properties. This review provides a detailed examination of the ethnopharmacological applications, global distribution, and phytochemical composition of G. glabra . Furthermore, the key bioactive molecules of G. glabra , such as glycyrrhizin, glycyrrhizinic acid, and isoliquiritin, are highlighted for their roles in counteracting oxidative stress. These phytomolecules have been shown to exert significant effects through mechanisms such as modulation of antioxidant enzyme activities and inhibition of free radical production. Comprehensive literature searches were performed across major scientific databases, including PubMed, Web of Science, PMC, Google Scholar, Springer, ScienceDirect, and Research Gate, to synthesize information on G. glabra . The review explores how these phytomolecules contribute to the mitigation of oxidative stress-related disorders, including cancer, neurodegenerative diseases, and inflammatory conditions. By synthesizing data from experimental studies, this review underscores the therapeutic potential of G. glabra in managing oxidative stress-induced conditions. It also identifies gaps in the current understanding of its molecular mechanisms and suggests the need for further research, to enhance its application in therapeutic settings. Future studies shall focus on elucidating the synergistic effects of bioactive compounds of G. glabra and their integration into clinical practice and integrative research to fully exploit its medicinal benefits.
... Although liquorice abuse can be harmful, its low toxicity in normal consumption render Glycyrrhiza glabra a healthy food source [32]. Furthermore liquorice is being largely utilized as a sweetener during food and beverage preparation and as important ingredient in cosmetics, pharmacology and tobacco industry [43][44][45][46]. ...
... Liquorice, a herb commonly utilised in Eastern medicinal practices and recognised for its low toxicity, is endorsed by the US Food and Drug Administration (FDA) as a food supplement, finding its way into numerous products. As highlighted previously, the principal active compound in liquorice is glycyrrhizic acid, which undergoes a prompt transformation into 18βGA within the human body, manifesting a variety of effects including antioxidant, anti-inflammatory, and antisenescence, as referenced in numerous studies [34,[53][54][55]. The results depicted in the present work establishes the capability of 18βGA to counteract CSE-induced expression of oxidative stress, inflammatory status, and senescence markers in vitro in BCiNS1.1 cells. ...
... К сапонинам солодки относят 18-β-глицерретиновую кислоту и ее тритерпеновый гликозид -глицерризовую кислоту. Для этих соединений была показана гепатопротекторная функция, позитивное действие на ткани головного мозга при ишемии, противовоспалительный эффект при вирусных и бактериальных инвазиях, ингибирование репликации вирусов, в частности ВИЧ-1, Эпштейн-Барра, гепатита В [6] и COVID-19 [7]. ...
Корень солодки традиционно используется в медицине благодаря содержанию в нем сапонинов и флавоноидов. Листья солодки в качестве фармакопейного сырья не используются, хотя в последнее время ведется изучение их химического состава и биологической активности, что позволяет оценить возможности использования этого сырья как лекарственного. Активный сбор солодки может поставить под угрозу ее естественные популяции, поэтому актуальной задачей является культивирование клеток этого растения в системах in vitro и изучение состава метаболитов культур клеток. В нашем исследовании материалом для получения каллусной культуры листьев солодки были растения из коллекции Ботанического сада Уральского Отделения РАН. Для подбора оптимальных условий выращивания каллусов проведено сравнение 9 комбинаций фитогормонов. Лучший рост каллусов был обнаружен на среде Мурасиге-Скуга с сочетанием фитогормонов 1 мг/л БАП и 10 мг/л НУК. В этих условиях флавоноиды накапливались в каллусе в количестве, сопоставимом с их содержанием в интактных листьях и корнях. Содержание фенольных соединений было сравнимо с их количеством в корнях. Этанольные экстракты, полученные из каллусной культуры, обладали выраженной антиоксидантной активностью, сравнимой с экстрактами из интактного растения и стандартами рутином, галловой и аскорбиновой кислотами. При оценке влияния экстрактов на культуры животных клеток в МТТ-тесте показано, что все полученные экстракты повышали метаболическую активность как нормальных клеток человека, так и линии HeLa. При этом экстракт, полученный из листьев, проявлял максимальный эффект, а из каллуса – минимальный и незначительно отличался от экстракта корня. Таким образом, каллусы из листовых эксплантов могут рассматриваться как новое сырье для получения БАД с антиоксидантной активностью.
... However, p-Stat1 Tyr701 was not involved in Nrf2-induced ferroptosis or Crizotinib-induced hepatotoxicity. The other functions of p-Stat1 Tyr701 under Crizotinib treatment warrant further investigation Licorice, a cornerstone of traditional Chinese medicine, is celebrated for its hepatoprotective and detoxifying virtues, attributed to its bioactive constituents such as triterpenes (GL and GA), and flavonoids (ISL and LQ) [61,62]. GA, derived from licorice root, emerges as a pivotal compound, underpinning the herb's biological activities, including anti-inflammatory, immunomodulatory, antitumor, and antioxidative properties [63][64][65]. ...
Crizotinib carries an FDA hepatotoxicity warning, yet analysis of the FAERS database suggests that the severity of its hepatotoxicity risks, including progression to hepatitis and liver failure, might be underreported. However, the underlying mechanism remains poorly understood, and effective intervention strategies are lacking. Here, mRNA-sequencing analysis, along with KEGG and GO analyses, revealed that DEGs linked to Crizotinib-induced hepatotoxicity predominantly associate with the ferroptosis pathway which was identified as the principal mechanism behind Crizotinib-induced hepatocyte death. Furthermore, we found that ferroptosis inhibitors, namely Ferrostatin-1 and Deferoxamine mesylate, significantly reduced Crizotinib-induced hepatotoxicity and ferroptosis in both in vivo and in vitro settings. We have also discovered that overexpression of AAV8-mediated Nrf2 could mitigate Crizotinib-induced hepatotoxicity and ferroptosis in vivo by restoring the imbalance in glutathione metabolism, iron homeostasis, and lipid peroxidation. Additionally, both Stat1 deficiency and the Stat1 inhibitor NSC118218 were found to reduce Crizotinib-induced ferroptosis. Mechanistically, Crizotinib induces the phosphorylation of Stat1 at Ser727 but not Tyr701, promoting the transcriptional inhibition of Nrf2 expression after its entry into the nucleus to promote ferroptosis. Meanwhile, we found that MgIG and GA protected against hepatotoxicity to counteract ferroptosis without affecting or compromising the anti-cancer activity of Crizotinib, with a mechanism potentially related to the Stat1/Nrf2 pathway. Overall, our findings identify that the phosphorylation activation of Stat1 Ser727, rather than Tyr701, promotes ferroptosis through transcriptional inhibition of Nrf2, and highlight MgIG and GA as potential therapeutic approaches to enhance the safety of Crizotinib-based cancer therapy.
... Licorice saponins include 18-β-glycerretinic acid and its triterpene glycoside, glycerritic acid. These compounds have been shown to have a hepatoprotective function, a positive effect on brain tissue during ischemia, an anti-inflammatory effect during viral and bacterial invasions, and inhibition of the replication of viruses, in particular HIV-1, Epstein-Barr, hepatitis B [6], and COVID-19 [7]. ...
Licorice root is traditionally used in medicine due to its content of saponins and flavonoids. Licorice leaves are not used as pharmacopoeial raw materials, although their chemical composition and biological activity have been studied recently, which makes it possible to evaluate the possibilities of using this raw material as a medicinal one. Active harvesting of licorice can jeopardize its natural populations, so urgent tasks are to cultivate cells of this plant in systems in vitro and to study the composition of cell culture metabolites. In our study, the material for obtaining a callus culture of licorice leaves was plants from the collection of the Botanical Garden of the Ural Branch of the Russian Academy of Sciences. To select optimal conditions for growing calli, nine combinations of phytohormones were compared. The best growth of calli was found on Murashige–Skoog medium with a combination of phytohormones 1 mg/L BAP and 10 mg/L NAA. Under these conditions, flavonoids accumulated in callus in quantities comparable to their content in intact leaves and roots. The content of phenolic compounds was comparable to their amount in the roots. Ethanol extracts obtained from callus culture had pronounced antioxidant activity comparable to extracts from the intact plant and standards of rutin, gallic, and ascorbic acids. When assessing the effect of extracts on animal cell cultures in the MTT test, it was shown that all obtained extracts increased the metabolic activity of both normal human cells and the HeLa line. At the same time, the extract obtained from the leaves showed the maximum effect, while that from the callus showed the minimum and differed slightly from the root extract. Thus, calli from leaf explants can be considered as a new raw material for obtaining dietary supplements with antioxidant activity.
... It was demonstrated that non-cytotoxic and non-mutagenic plant extracts may be as potent as synthetic whitening agents (Baurin et al. 2002;Batubara et al. 2010;Kamakshi 2012;Almeda et al. 2015). The most important of these is licorice root (Glycyrrhiza glabra), which contains isoflavonoids and chalcone as active ingredients (Nerya et al. 2003;Kao et al. 2014). Extracts of oregano (Origanum vulgare, whitening agent: origanoside, a glycosylated phenolic compound) and Chinese skullcap (Scutellaria baicalensis, whitening agent: baicalein, a flavone), as well as white mulberry (Morus alba) containing chalcones and stilbenoids, and citrus (Citrus) fruits containing flavones and flavonelles species also show interesting whitening properties (Lee et al. 2002;Jeong et al. 2009;Kang et al. 2013). ...
This study investigated the effect of some herbal extracts, such as licorice root, white mulberry leaf, green tea leaf, and grape seed, with a combination of bacterial nanocellulose and some bioactive materials, such as ascorbic acid, niacinamide, hexylresorcinol, and alpha-arbutin, on treatment of hyperpigmentation. The effect of the prepared emulsions on hyperpigmentation was revealed by analyzing their tyrosinase inhibition properties, their ability to stop melanin production, or their properties of whitening the brown spot on the skin. In addition to the physicochemical properties of the 5 different emulsions obtained, tyrosinase, collagenase, and elastase enzyme activities, antioxidant properties, cytotoxicity, and microbiological analyzes were performed by cell-culture modelling. Finally, a dermocosmetic facial serum was designed that is compatible with skin pH, is homogeneously mixed, has good spreading properties, does not cause any microbiological growth, does not inhibit elastase activity while stimulating collagenase activity, reduces melanin production by inhibiting the tyrosinase enzyme, and does not have any toxic effects.
... Its roots and rhizomes have the effects of tonifying qi, detoxifying, relieving pain, strengthening the spleen and stomach, relieving tussis, and promoting expectoration; they are widely used in TCM and are an indispensable part of TCM formulations [2,6] . With the advancement of modern science and technology, hundreds of compounds have been isolated from licorice, including triterpenoid saponins, flavonoids, polysaccharides, coumarins, amino acids, and alkaloids, which have been shown to exert a wide range of pharmacological effects, including anti-inflammatory, antioxidant, antiviral, antitumor, hepatoprotective, and neuroprotective effects [7][8][9] . The increasing potential applications of licorice in modern pharmaceutical and other industries necessitate a deeper understanding of its active ingredients and mechanisms. ...
Licorice, a perennial herb of Leguminosa, is one of the oldest and most widely used herbal medicines worldwide. Its distinct sweet flavor and rich medicinal value make it an integral component of traditional Chinese medicine (TCM) formulations, which continue to be widely employed. The main chemical constituents of licorice include triterpenoid saponins, flavonoids, and polysaccharides. Experimental and clinical studies have demonstrated that various extracts and pure compounds derived from licorice exhibit a wide range of pharmacological properties including anti-inflammatory, antioxidant, antimicrobial, antiviral, antitumor, immune-regulatory, and neuroprotective activities. The bioactive constituents of licorice offer therapeutic benefits for cardiovascular and cerebrovascular diseases, diabetes mellitus, and liver disorders. This comprehensive review discusses the primary chemical constituents of licorice and their pharmacological activities, describes in vivo and in vitro models employed for studying licorice, and its potential targets and mechanisms of action. Furthermore, we discuss the toxicological profile, side effects, dosage recommendations, and clinical applications of licorice. This review aims to establish a foundation for further research on the safe and effective utilization of licorice while facilitating an in-depth exploration of its properties and fostering the development of novel therapeutic agents.
Graphical abstract: http://links.lww.com/AHM/A102
... This could be the underlying mechanism for the increased absorption and pharmacokinetic features of liquiritigenin and isoliquiritigenin after the oral administration of the GR extract. GR contains at least 400 different chemical constituents, including triterpenoid saponins, flavanones, coumarins, and their glycosides (Fujii et al. 2014;Kao et al. 2014). Furthermore, over 25% of the GR components have been identified as active constituents through oral bioavailability, virtual screening, and drug-likeness (Liu et al. 2013). ...
... Subsequently, molecular docking was employed to confirm the inhibitory effect on PTP1B, and cell experiments further validated the antiinflammatory effects. We also compared the anti-inflammatory efficacy of Baikal skullcap with that of recognized anti-inflammatory drug glycyrrhiza [22]. The workflow is shown in Figure 1. ...
Type 2 diabetes mellitus (T2DM) is marked by persistent hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction, imposing substantial health burdens and elevating the risk of systemic complications and cardiovascular diseases. While the pathogenesis of diabetes remains elusive, a cyclical relationship between insulin resistance and inflammation is acknowledged, wherein inflammation exacerbates insulin resistance, perpetuating a deleterious cycle. Consequently, anti-inflammatory interventions offer a therapeutic avenue for T2DM management. In this study, a herb called Baikal skullcap, renowned for its repertoire of bioactive compounds with anti-inflammatory potential, is posited as a promising source for novel T2DM therapeutic strategies. Our study probed the anti-diabetic properties of compounds from Baikal skullcap via network pharmacology, molecular docking, and cellular assays, concentrating on their dual modulatory effects on diabetes through Protein Tyrosine Phosphatase 1B (PTP1B) enzyme inhibition and anti-inflammatory actions. We identified the major compounds in Baikal skullcap using liquid chromatography–mass spectrometry (LC–MS), highlighting six flavonoids, including the well-studied baicalein, as potent inhibitors of PTP1B. Furthermore, cellular experiments revealed that baicalin and baicalein exhibited enhanced anti-inflammatory responses compared to the active constituents of licorice, a known anti-inflammatory agent in TCM. Our findings confirmed that baicalin and baicalein mitigate diabetes via two distinct pathways: PTP1B inhibition and anti-inflammatory effects. Additionally, we have identified six flavonoid molecules with substantial potential for drug development, thereby augmenting the T2DM pharmacotherapeutic arsenal and promoting the integration of herb-derived treatments into modern pharmacology.
... The antioxidant properties of licorice are attributed to its several constituents, including glycyrrhizic acid, 18β-glycyrrhetinic acid, glabridin, and liquiritin [16]. The aforementioned components can elicit immunological responses and augment the activity of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase [17,18]. ...
Background: Bacterin-based vaccination may be a stressful condition, leading to harmful effects, such as high lipid peroxidation and telomere shortening. This study aimed to reduce these probable side effects via the administration of different concentrations of licorice (because of its anti-oxidative and anti-aging properties). Materials and Methods: Japanese quails as animal models were reared for 42 days under standard conditions. The birds were divided into eight groups, including a control group, licorice treatments (licorice 0.02%, Licorice 0.04%, and licorice 0.08% groups), and Salmonella bacterin treatments (bacterin, bacterin+licorice 0.02%, bacterin+licorice 0.04%, and bacterin+licorice 0.08% groups). The Salmonella enterica bacterin-based vaccine was injected twice on days 14 and 28. Serum lipid peroxidation and telomere length of immune cells in all experimental groups were measured. Results: Lipid peroxidation and telomere shortening enhanced following bacterin vaccination. Licorice at doses of 0.04%, 0.08%, or both reduced the lipid peroxidation and telomere shortening in non-vaccinated and vaccinated birds, while the dose of 0.02% was not effective. Conclusion: This study confirmed the side effects of high lipid peroxidation and telomere attrition for S. enterica bacterin-based vaccination. Also, the improving properties of licorice for these side effects were considered to be effective.
... (Md.K. Hasan) . and qi (energy), clear heat, remove toxicity, expectorant, and relieve cough ( Lin et al., 2019b ;Kao et al., 2014 ). ...
... By decreasing IKB kinase complex activation, licochalcone A prevents TNF-from activating nuclear factor kappa B (NF-KB) [67]. Licorice includes extractable flavonoids that can decrease eosinophilic lung inflammation, Ig levels, IL-3, IL-5, and IL-13 levels and boost INF-gamma activity [68]. ...
More than 30 species of the Glycyrrhiza genus can be found all over the world. It was the herb that was most frequently advised in Ancient Egypt, Rome, Greece, East China, and the West as of the Former Han era. Glycyrrhiza glabra is the scientific name for licorice, a plant that belongs to the Leguminosae family. Commonly used is the ayurvedic herb G. glabra. Licorice root extracts have a variety of beneficial effects, including the treatment of TB, pulmonary, hepatic, and immune system problems as well as throat infections. Traditional therapies, on the other hand, are becoming more well-liked for a range of ailments. Screening is essential to find new chemicals from medicinal plants that may treat chronic illnesses including cancer, cardiovascular, respiratory, and hepatoprotective, among others.
... However, the leaves from the plant Glycyrrhiza uralensis (GU) have not been employed for green Mn 2 O 3 NP synthesis. A perennial herb belonging to the genus Glycyrrhiza, licorice is mostly found in China [26]. Licorice is widely used in various industries, including food, tobacco, cosmetics, health care, and pharmaceuticals [27]. ...
In this study, we evaluated the antiproliferative and apoptotic properties of Pluronic-F127-containing manganese oxide nanoparticles (PF-127-coated Mn2O3 NPs) derived from the leaf extract of Glycyrrhiza uralensis (GU) on breast adenocarcinoma, MCF7, and MDA-MB-231 cell lines. The leaf extract of GU contains bioactive molecules that act as a reducing or capping agent to form Mn2O3 NPs. Various analytical techniques were used to characterize the physiochemical properties of PF-127-coated Mn2O3 NPs, including spectroscopy (ultralight-Vis, Fourier transform infrared, photoluminescence), electron microscopy (field emission scanning electron microscopy and transmission electron microscopy), X-ray diffraction (XRD), electron diffracted X-ray spectroscopy (EDAX), and dynamic light scattering. The average crystallite size of Mn2O3 NPs was estimated to be 80 nm, and the NPs had a cubic crystalline structure. PF127-encapsulated Mn2O3 NPs significantly reduce MDA-MB-231 and MCF-7 cell proliferation, while increasing endogenous ROS and lowering mitochondrial matrix protein levels. DAPI, EtBr/AO dual staining, and Annexin-V-FITC-based flow cytometry analysis revealed that PF127-coated Mn2O3 NP-treated breast cancer cells exhibit nuclear damage and apoptotic cell death, resulting in cell cycle arrest in the S phase. Furthermore, PF127-encapsulated Mn2O3 NPs show strong antimicrobial efficacy against various strains. As a result, we can conclude that PF127-coated Mn2O3 NPs may be effective as future anticancer agents and treatment options for breast cancer.
... The Glycyrrhiza genus is used around the world for food and medicinal purposes [26]. The Generally Recognized as Safe (GRAS) status of licorice allows its application in a plethora of foods at typical concentrations. ...
... and G. inflate Batalin) is the triterpenoids glycyrrhizic acid (glycyrrhizin) and the main product of its metabolism is a pentacyclic triterpene compound, the aglycone 18--glycyrrhetinic acid, 22,23 which is a key bioactive constituent of licorice. [28][29][30][31] In this study, we attempted to use a biological reduction approach to create stable silver nanoparticles (AgNPs) from 18--glycyrrhetinic acid. Using Box-Behnken Design (BBD) of RSM, this study sought to optimize a number of experimental parameters critical to the eco-friendly synthesis of AgNPs of 18--glycyrrhetinic acid. ...
Using 18-beta-glycyrrhetinic acid, a well-known component of licorice (Glycyrrhiza glabra Lin.), the current study offers a unique rapid ecological & simple approach of biologically synthesizing of silver nanoparticles (AgNPs). To synthesise stable silver nanoparticles via a biological reduction technique, a methanolic stock solution of 18-β-glycyrrhetinic acid was produced and used as capping and reducing agent. The approach was methodically optimized using response surface analysis (RSA) based Box-Behnken design (BBD), taking into account influence of parameters like as silver nitrate (AgNO3) concentration, incubation time and temperature on response. RSA was utilized to determine the association among factors and the responses by mathematical modelling with a quadratic polynomial model. AgNO3 (1mM), 55°C, and 5 hours incubation were optimal. 18-β-glycyrrhetinic acid methanolic stock solution can convert silver ions (Ag+) into silver nanoparticles (AgNPs) in 5 hours at 55°C. Biosynthesized and optimized AgNPs have an SPR absorption peak at 419 nm in their UV spectra. 18-β-glycyrrhetinic acid reduced and capped silver ions according to FTIR spectroscopy. XRD showed AgNPs’ crystallinity. SEM revealed spherical elemental silver with particle size of 100 nm. Average particle size, PDI & Zeta were 83.36 nm, 0.462 and -35.4mV, respectively, at 100% intensity. Silver nanoparticles (GAAgNPs) are stable. DPPH experiment showed substantial antioxidant activity in GAAgNPs compared to ascorbic acid. At 10 μg/mL, AgNPs showed utmost region of inhibition of 15 and 14 mm against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. Finally, the synthesized AgNPs and their quality components have strong antioxidant and antibacterial activity, indicating that this research can be used to formulate useful biomedical goods.
... Glycyrrhiza glabra (licorice) belongs to the Fabaceae family. This species is native to Mediterranean areas, but it is also present in India, China, and Iran [25]. Licorice has a long story in traditional medicines and folk remedies to treat gastrointestinal problems, dyspepsia, inflammation, and arthritis. ...
Objective:
Plant-derived estrogens (phytoestrogens) with structural similarity to primary female sex hormones could be suitable replacements for sex hormones. Therefore, the effects of the licorice root extract and Linum usitatissimum oil on biochemical and hormonal indices in the serum and uterine stereological changes in ovariectomized rats were evaluated.
Design:
In this study, 70 adult female rats were randomly divided into seven groups including 1) control group, 2) sham-operated group, 3) ovariectomized (OVX) group, 4) OVX rats that received 1 mg/kg estradiol for 8 weeks at the day of post-operation, 5) OVX rats which received 2.0 mg/kg body wt Linum usitatissimum oil for 8 weeks at the day of post-operation, 6) OVX rats which received 2.0 mg/kg body wt licorice extract for 8 weeks at the day of post-operation, and 7) OVX rats which received 2.0 mg/kg body wt Linum usitatissimum oil + 2.0 mg/kg body wt licorice extract for 8 weeks at the day of post-operation. After eight weeks, alkaline phosphatase activity, as well as calcium, estradiol, and progesterone concentrations were assessed and tissue samples of the uterus were serologically examined.
Results:
The results indicated that after 8 weeks of OVX the alkaline phosphatase activity (Mean = 637.7 IU/L) increased and the calcium (Mean = 7.09 mg/dl), estradiol (5.30 pmol/L), and progesterone (Mean = 3.53 nmol/L) reduced compared to other groups. Moreover, stereological changes in the uterus in ovariectomy groups were seen compared to the other groups. The treatment with Linum usitatissimum oil and licorice extract had a significant therapeutic effect on biochemical factors and stereological changes compared to the ovariectomized group.
Conclusion:
The results of this study showed that the combination of Linum usitatissimum oil with licorice extract showed the high potential of hormone replacement therapy in the reduction of OVX complications.
... The aglycone of both natural products (1d and 10) belongs to the oleanane-type of triterpenoids under the name of glycyrrhetinic acid (1e; Figure 1). The plant G. uralensis has widely been used in traditional Chinese medicine for treating health disorders, e.g., diabetes [54], hepatitis [55][56][57], bronchitis [58], or AIDS [59]. It also showed a potential therapeutic effect on SARS-CoV-2 [60]. ...
Saponins represent important natural derivatives of plant triterpenoids that are secondary plant metabolites. Saponins, also named glycoconjugates, are available both as natural and synthetic products. This review is focused on saponins of the oleanane, ursane, and lupane types of triterpenoids that include several plant triterpenoids displaying various important pharmacological effects. Additional convenient structural modifications of naturally-occurring plant products often result in enhancing the pharmacological effects of the parent natural structures. This is an important objective for all semisynthetic modifications of the reviewed plant products, and it is included in this review paper as well. The period covered by this review (2019–2022) is relatively short, mainly due to the existence of previously published review papers in recent years.
Glycyrrhiza glabra L. (licorice) root is one of the oldest medicines of natural origin. Licorice has various pharmacological effects, among others: anti-inflammatory, antioxidant and phytoestrogenic. The aim of the study was to determine the effect of the use of an ethanolic extract of licorice root and the powdered licorice root on the skeletal system in rats with estrogen deficiency induced by bilateral ovariectomy. The experiments were carried out on mature rats divided into seven groups: sham-operated control rats, ovariectomized control rats, and OVX rats treated with: estradiol, Glycyrrhiza glabra L. root extract at doses of 5, 10 and 20 mg/kg p.o. and powdered licorice root at a dose of 90 mg/kg p.o. The tested substances were administered orally for 4 weeks once daily. Bone composition, mineralization, histomorphometric parameters, and mechanical properties were examined. Estrogen deficiency induced osteoporotic changes, including worsening of bone mechanical properties in OVX rats. Administration of licorice extracts or licorice powdered root did not counteract the skeletal changes induced by estrogen deficiency in rats.
Glycyrrhiza uralensis, Glycyrrhiza glabra, and Glycyrrhiza inflata are significant medicinal plants in traditional Chinese medicine. They also contribute to ecological protection and restoration in the arid and semi-arid regions of Northwest China. This study employed the MaxEnt model to predict the potential habitats of these three species in China under climate change, and examined the relationship between their distribution and desert ecosystems. The results indicated that (1) G. uralensis has a broad distribution, primarily in Northeast, North, and Northwest China. Glycyrrhiza glabra and G. inflata are predominantly found in the northwest provinces. (2) Under current climate conditions, the distribution of the most suitable habitats for these species closely mirrors that of deserts. However, future climate change is expected to reduce the spatial range of all three species. (3) These three species are effective psammophytes, capable of thriving in desert margins and other highly suitable habitats on a large scale. This research offers a theoretical basis for the conservation of plant resources, the restoration and protection of desertified areas, and the advancement of deserticulture.
The formulation of a herbal facewash tablet incorporating liquorice (Glycyrrhizaglabra) and neem (Azadirachta indica) aims to provide a natural, effective, and convenient skin care solution. Both liquorice and neem are renowned for their therapeutic properties, with antinflammatory and antioxidant benefits, while neem is known for its antimicrobial, antiinflammatory, and purifying effects. In this study, herbal extracts of liquorice and neem we combined to create a tablet-based facewash, which promises gentle yet effective cleansing, while nourishing and protecting the skin. The tablets were developed using herbal extracts, binders and excipients, ensuring ease of use and minimal environmental impact. Key quality parameters, including tablet hardness, pH,and cleansing efficiency, were evaluated. The product’s dermatological safety and effectiveness in cleansing and removing impurities were also tested. The results suggest that the liquorice and neem-based herbal facewash tablet is a promising, eco-friendly alternative to liquid facewash products, offering a natural approach to skincare with potential benefits for acne-prone and sensitive skin types.
The liver is the largest, important organ and the site for essential biochemical reactions in the human body. It has the function to detoxify toxic substances and synthesize useful biomolecules. Liver diseases related complications represent a significant source of morbidity and mortality worldwide, creating a substantial economic burden. Oxidative stress, excessive inflammation, and dysregulated energy metabolism significantly contributed to liver diseases. Therefore, discovery of novel therapeutic drugs for the treatment of liver diseases are urgently required. For centuries, flavonoids and their preparations which have the beneficial health effects in chronic diseases have been used to treat various human illnesses. Flavonoids mainly include flavones, isoflavones, flavanols, dihydroflavones, dihydroflavonols, anthocyanins and chalcones. The primary objective of this review is to assess the efficacy and safety of flavonoids, mainly from a clinical point of view and considering clinically relevant end-points. We summarized the recent progress in the research of hepatoprotective and molecular mechanisms of different flavonoids bioactive ingredients and also outlined the networks of underlying molecular signaling pathways. Further pharmacology and toxicology research will contribute to the development of natural products in flavonoids and their derivatives as medicines with alluring prospect in the clinical application.
Myocardial ischemia/reperfusion injury (MI/RI) generates reactive oxygen species (ROS) and initiates inflammatory responses. Traditional therapies targeting specific cytokines or ROS often prove inadequate. An innovative drug delivery system (DDS) is developed using neutrophil decoys (NDs) that encapsulate 18β‐glycyrrhetinic acid (GA) within a hydrolyzable oxalate polymer (HOP) and neutrophil membrane vesicles (NMVs). These NDs are responsive to hydrogen peroxide (H2O2), enabling controlled GA release. Additionally, NDs adsorb inflammatory factors, thereby reducing inflammation. They exhibit enhanced adhesion to inflamed endothelial cells (ECs) and improved penetration. Once internalized by cardiomyocytes through clathrin‐mediated endocytosis, NDs protect against ROS‐induced damage and inhibit HMGB1 translocation. In vivo studies show that NDs preferentially accumulate in injured myocardium, reducing infarct size, mitigating adverse remodeling, and enhancing cardiac function, all while maintaining favorable biosafety profiles. This neutrophil‐based system offers a promising targeted therapy for MI/RI by addressing both inflammation and ROS, holding potential for future clinical applications.
Acute kidney injury (AKI) is a major public health problem worldwide that still lacks effective treatments. Recent studies have suggested that ferroptosis is a key mediator of AKI due to its activation of lipid peroxidation. Therefore, we hypothesized that antiferroptosis agents might be a novel potential therapeutic strategy for AKI. Herein, we demonstrated that liquiritigenin (LG), an active ingredient of liquorice, improves renal function by inhibiting vitamin K epoxide reductase complex subunit 1 (VKORC1)-mediated ferroptosis, both in vivo and in vitro. In a folic acid-induced murine AKI model, after a single pre-treatment intravenous injection, LG markedly alleviated the loss of renal function through suppressing ferroptosis induced by iron accumulation. LG prevented mitochondrial morphological changes and upregulated glutathione and glutathione peroxidase 4 levels, while downregulating malonaldehyde and divalent iron levels. An in vitro RNA-sequence analysis suggested that the protective role of LG may involve upregulation of VKORC1. Moreover, knockdown of VKORC1 diminished the renal protective and antiferroptosis roles of LG. Collectively, our findings demonstrated that LG protected against AKI by inhibiting VKORC1-mediated ferroptosis. This suggests that inhibiting ferroptosis might be a novel therapeutic approach in the future.
A functional fermented milk drink with plant extracts for prevention and recovery was studied. The data of classical fermentation were used, in particular, the peculiarities of the preparation of phytoextracts for the development of a functional fermented milk drink. The recipe was developed and the influence of licorice root extract concentration and the type of bacterial starter on the physical, chemical and organoleptic characteristics and biological activity of the biobeverage was studied. The specifics of fermentation were taken into account when developing a technological scheme for the pilot production of a functional fermented milk drink with licorice root phytoextract.
Licorice is a well-known Chinese medicinal plant that is widely used to treat multiple diseases and process food; however, wild licorice is now facing depletion. Therefore, there is an urgent need to identify and protect licorice germplasm diversity. In this study, metabolomic and transcriptomic analyses were conducted to investigate the biodiversity and potential medicinal value of the rare wild Glycyrrhiza squamulose. A total of 182 differentially accumulated metabolites and 395 differentially expressed genes were identified by comparing Glycyrrhiza uralensis and Glycyrrhiza squamulose. The molecular weights of the chemical component of G. squamulose were comparable with those of G. uralensis, suggesting that G. squamulose may have medicinal value. Differentially accumulated metabolites (DAMs), mainly flavonoids such as kaempferol-3-O-galactoside, kaempferol-3-O-(6ʺmalonyl) glucoside, and hispidulin-7-O-glucoside, showed potential vitality in G. squamulose. Comparative transcriptomics with G. uralensis showed that among the 395 differentially expressed genes (DEGs), 69 were enriched in the isoflavonoid biosynthesis pathway. Multiomics analysis showed that the distinction in flavonoid biosynthesis between G. squamulose and G. uralensis was strongly associated with the expression levels of IF7GT and CYP93C. In addition to identifying similarities and differences between G. squamulose and G. uralensis, this study provides a theoretical basis to protect and investigate rare species such as G. squamulose.
Pesticide spraying serves as a prevalent segment in crop production for substantial economic and ecological benefits. Nevertheless, the existing pesticide formulations are often plagued by droplets rebounding during the spraying process, and the controlled‐release, photolysis protection, and non‐targeted bio‐friendliness are not inadequately considered. Herein, by combining spinosad (SSD, a model pesticide) with glycyrrhizic acid (GL) as an attractive building block, a supramolecular co‐assembly strategy is employed to elaborate pesticide formulations (GL‐SSD) simultaneously featuring high deposition, controlled‐release, and environmental friendliness. The resulting spherical GL‐SSD nanoparticles (NPs) have an average diameter of 207 nm and show an improved 5.2‐fold photostability compared with commercial spinosad suspension (SSD SC). Upon impacting on hydrophobic surfaces of polytetrafluoroethylene film and cabbage leaf, the droplets of GL‐SSD NPs exhibit superior affinity to the micro/nano structure of the surface. Consequently, the droplet rebounding is inhibited effectively, ensuring high deposition efficiency of droplets on surfaces. In addition, the release of SSD from GL‐SSD NPs can be controlled by pH variation. Indoor toxicity and pot experiments demonstrate that GL‐SSD NPs possess good control efficacy against Plutella xylostella. The work offers an alternative approach for the development of multi‐functional and sustainable pesticide formulations with promising potentials in actual agriculture production.
Zhigancao decoction is a traditional prescription for treating irregular pulse and palpitations in China. As the monarch drug of Zhigancao decoction, the bioactive molecules of licorice against heart diseases remain elusive. We established the HRESIMS-guided method leading to the isolation of three novel bicyclic peptides, glycnsisitins A–C (1–3), with distinctive C–C and C–O–C side-chain-to-side-chain linkages from the roots of Glycyrrhiza uralensis (Licorice). Glycnsisitin A demonstrated stronger cardioprotective activity than glycnsisitins B and C in an in vitro model of doxorubicin (DOX)-induced cardiomyocyte injury. Glycnsisitin A treatment not only reduced the mortality of heart failure (HF) mice in a dose-dependent manner but also significantly attenuated DOX-induced cardiac dysfunction and myocardial fibrosis. Gene set enrichment analysis (GSEA) of the differentially expressed genes indicated that the cardioprotective effect of glycnsisitin A was mainly attributed to its ability to maintain iron homeostasis in the myocardium. Mechanistically, glycnsisitin A interacted with transferrin and facilitated its binding to the transferrin receptor (TFRC), which caused increased uptake of iron in cardiomyocytes. These findings highlight the key role of bicyclic peptides as bioactive molecules of Zhigancao decoction for the treatment of HF, and glycnsisitin A constitutes a promising therapeutic agent for the treatment of HF.
Licorice from Glycyrrhiza uralensis roots is used in foods and medicines. Although we are aware that licorice roots and leaves have distinct material compositions, the specific reasons for these differences remain unknown. Comparison of the metabolomes and transcriptomes between the leaves and roots revealed flavonoids and triterpenoid saponins were significantly different. Isoflavones were enriched in roots because of upregulation of genes encoding chalcone isomerase and flavone synthase, which are involved in isoflavone synthesis. Six triterpenoid saponins were significantly enriched only in the roots. The leaves did not accumulate glycyrrhetinic acid because of low expression levels of genes involved in its synthesis. A gene encoding a UDP glycosyltransferase, which likely catalyzes the key step in the transformation of glycyrrhetinic acid to glycyrrhizin, was screened. Our results provide information about the differences in flavonoid and triterpenoid synthesis between roots and leaves, and highlight targets for genetic engineering.
Licorice, has a long history in China, where it has various uses, including as a medicine, which is often widely consumed as a food ingredient. Licorice is rich in various...
Licorice is a famous medicine-food herb for treating cardiovascular diseases in many compound prescriptions. Angiotensin-converting enzyme (ACE) is a key target of cardiovascular diseases. Despite its significance, there is limited scientific investigation regarding the ACE inhibitory effects of licorice. In this study, we used an activity-guided approach with an aggregation-induced emission (AIE) fluorescent probe to identify compounds with ACE-inhibitory activity in licorice. Nine components of licorice were found to have ACE inhibitory activity, in which 46 compounds were identified by using UPLC-QTOF-MS. Seven active compounds were found in this study. Among them, licochalcone B had best ACE inhibitory activity (IC50 = 0.24 μM). Finally, an UPLC-Q-MS method was established to quantify the five major active compounds in three batches of licorice. The findings of this study offer valuable insights into the potential of licorice as a source of ACE inhibitors and its relevance in the development of related products.
Cleft lip and/or palate anomalies (CL ± P) are the most frequent birth defects affecting the orofacial region in humans. Although their etiology remains unclear, the involvement of environmental and genetic risk factors is known. This observational study aimed to investigate how the use of crude drugs with estrogen activity influenced an animal model's ability to prevent CL ± P. A/J mice were randomly divided into six experimental groups. Five of these groups consumed a drink containing crude drug licorice root extract, with the following weights attributed to each group: 3 g in group I, 6 g in group II, 7.5 g in group III, 9 g in group IV, and 12 g in group V, whereas a control group consumed tap water. The effect of licorice extract was examined for fetal mortality and fetal orofacial cleft development compared to the control group. The rates for fetal mortality were 11.28%, 7.41%, 9.18%, 4.94%, and 7.90% in groups I, II, III, IV, and V, respectively, compared to 13.51% in the control group. There were no significant differences in the mean weight of alive fetuses in all five groups compared to the control group (0.63 ± 0.12). Group IV showed the lowest orafacial cleft occurrence of 3.20% (8 fetuses) with statistical significance (p = 0.0048) out of 268 live fetuses, whereas the control group had the occurrence of 8.75% (42 fetuses) among 480 live fetuses. Our study showed that the dried licorice root extract may reduce orofacial birth defects in experimental animal studies.
Background and objectives:
Entecavir (ETV) has disadvantages, such as poor improvement in liver function, during the treatment of Chronic hepatitis B (CHB). Thus ETV is often used in clinical therapy with glycyrrhizic acid (GA) preparations. However, due to the lack of reliable and direct clinical studies, it remains controversial whether glycyrrhizic acid preparations have the best efficacy in CHB. Therefore, we aimed to compare and rank the different GA preparations in the treatment of CHB using network meta-analysis (NMA).
Methods:
We systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Science, China national knowledge internet (CNKI), Wanfang, VIP, and SinoMed databases as of August 4, 2022. Literature was screened according to predefined inclusion and exclusion criteria to extract meaningful information. A Bayesian approach was used for random effects model network meta-analysis, and Stata 17 software was used for data analysis.
Results:
From 1074 papers, we included 53 relevant randomized clinical trials (RCTs). For the primary outcome, we used the overall effective rate in assessing the effectiveness of treatment for CHB (31 RCTs including 3007 patients): CGI, CGT, DGC and MgIGI significantly reduced the incidence of overall response compared to controls (RRs range from 1.16 to 1.24); SUCRA results showed that MgIGI was the best (SUCRA 0.923). In terms of secondary outcomes, we assessed the effect of treatment for CHB according to the level of reduction in ALT and AST: for ALT (37 RCTs including 3752 patients), CGI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to controls (MD range from 14.65 to 20.41); SUCRA results showed that CGI was the best (SUCRA 0.87); for AST, GI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to the control group (MD range from 17.46 to 24.42); SUCRA results showed that MgIGI was the best (SUCRA 0.871).
Conclusion:
In this study, we verified that the combination of GA and Entecavir is more effective than entecavir monotherapy in the treatment of hepatitis B. MgIGI and CGI showed clinically significant effects on liver function recovery compared with other GA preparations. MgIGI appeared to be the best choice among all GA preparations for the treatment of CHB. Our study provides some references for the treatment of CHB.
Nerve inflammation is linked to the development of various neurological disorders. This study aimed to examine whether Glycyrrhizae Radix effectively influences the duration of the pentobarbital-induced loss of righting reflex, which may increase in a mouse model of lipopolysaccharide (LPS)-induced nerve inflammation and diazepam-induced γ-aminobutyric acid receptor hypersensitivity. Furthermore, we examined the anti-inflammatory effects of Glycyrrhizae Radix extract on LPS-stimulated BV2 microglial cells, in vitro. Treatment with Glycyrrhizae Radix significantly decreased the duration of pentobarbital-induced loss of righting reflex in the mouse model. Furthermore, treatment with Glycyrrhizae Radix significantly attenuated the LPS-induced increases in interleukin-1β, interleukin-6, and tumor necrosis factor-alpha at the mRNA level, and it significantly reduced the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus 24 h after LPS treatment. Treatment with Glycyrrhizae Radix also suppressed the release of nitric oxide, interleukin-1β, interleukin-6, and tumor necrosis factor protein in culture supernatants of LPS-stimulated BV2 cells. In addition, glycyrrhizic acid and liquiritin, active ingredients of Glycyrrhizae Radix extract, reduced the duration of pentobarbital-induced loss of righting reflex. These findings suggest that Glycyrrhizae Radix, as well as its active ingredients, glycyrrhizic acid and liquiritin, may be effective therapeutic agents for the treatment of nerve inflammation-induced neurological disorders.
Drought adaptation of plants is closely related to resistance and tolerance to drought stress as well as the ability to recover after the elimination of the stress. Glycyrrhiza uralensis Fisch is a commonly applied herb whose growth and development are greatly affected by drought. Here, we provide the first comprehensive analysis of the transcriptomic, epigenetic, and metabolic responses of G. uralensis to drought stress and rewatering. The hyper-/hypomethylation of genes may lead to up-/downregulated gene expression, and epigenetic changes can be regarded as an important regulatory mechanism of G. uralensis under drought stress and rewatering. Moreover, integrated transcriptome and metabolome analysis revealed that genes and metabolites involved in pathways of antioxidation, osmoregulation, phenylpropanoid biosynthesis, and flavonoid biosynthesis may regulate the drought adaptation of G. uralensis. This work provides crucial insights into the drought adaptation of G. uralensis and offers epigenetic resources for cultivating G. uralensis with high drought adaptation.
Acute colitis is characterised by an unpredictable onset and causes intestinal flora imbalance together with microbial migration, which leads to complex parenteral diseases. Dexamethasone, a classic drug, has side effects, so it is necessary to use natural products without side effects to prevent enteritis. Glycyrrhiza polysaccharide (GPS) is an α-d-pyranoid polysaccharide with anti-inflammatory effects; however, its anti-inflammatory mechanism in the colon remains unknown. This study investigated whether GPS reduces the lipopolysaccharide (LPS)-induced inflammatory response in acute colitis. The results revealed that GPS attenuated the upregulation of tumour necrosis factor-α, interleukin (IL)-1β, and IL-6 in the serum and colon tissues and significantly reduced the malondialdehyde content in colon tissues. In addition, the 400 mg/kg GPS group showed higher relative expressions of occludin, claudin-1, and zona occludens-1 in colon tissues and lower concentrations of diamine oxidase, D-lactate, and endotoxin in the serum than the LPS group did, indicating that GPS improved the physical and chemical barrier functions of colon tissues. GPS increased the abundance of beneficial bacteria, such as Lactobacillus, Bacteroides, and Akkermansia, whereas pathogenic bacteria, such as Oscillospira and Ruminococcus were inhibited. Our findings indicate that GPS can effectively prevent LPS-induced acute colitis and exert beneficial effects on the intestinal health.
Glycyrrhiza uralensis (or licorice) is a widely used Oriental herbal medicine from which the phenylflavonoids dehydroglyasperin C (DGC), dehydroglyasperin D (DGD), and isoangustone A (IsoA) are derived. The purpose of the present study was to evaluate the antioxidant properties of DGC, DGD, and IsoA. The three compounds showed strong ferric reducing activities and effectively scavenged DPPH, ABTS(+), and singlet oxygen radicals. Among the three compounds tested, DGC showed the highest free radical scavenging capacity in human hepatoma HepG2 cells as assessed by oxidant-sensitive fluorescent dyes dichlorofluorescein diacetate and dihydroethidium bromide. In addition, all three compounds effectively suppressed lipid peroxidation in rat tissues as well as H(2)O(2)-induced ROS production in hepatoma cells. This study demonstrates that among the three phenylflavonoids isolated from licorice, DGC possesses the most potent antioxidant activity, suggesting it has protective effects against chronic diseases caused by reactive oxygen species as well as potential as an antioxidant food additive.
Breast cancer and melanoma cells commonly metastasize to the brain using homing mechanisms that are poorly understood. Cancer patients with brain metastases display poor prognosis and survival due to the lack of effective therapeutics and treatment strategies. Recent work using intravital microscopy and preclinical animal models indicates that metastatic cells colonize the brain specifically in close contact with the existing brain vasculature. However, it is not known how contact with the vascular niche promotes microtumor formation. Here, we investigate the role of connexins in mediating early events in brain colonization using transparent zebrafish and chicken embryo models of brain metastasis. We provide evidence that breast cancer and melanoma cells utilize connexin gap junction proteins (Cx43, Cx26) to initiate brain metastatic lesion formation in association with the vasculature. RNAi depletion of connexins or pharmacological blocking of connexin-mediated cell-cell communication with carbenoxolone inhibited brain colonization by blocking tumor cell extravasation and blood vessel co-option. Activation of the metastatic gene twist in breast cancer cells increased Cx43 protein expression and gap junction communication leading to increased extravasation, blood vessel co-option, and brain colonization. Conversely, inhibiting twist activity reduced Cx43-mediated gap junction coupling and brain colonization. Database analyses of patient histories revealed increased expression of connexins 26 and 43 in primary melanoma and breast cancer tumors, respectively, which correlated with increased cancer recurrence and metastasis. Together our data indicate that connexins 43 and 26 mediate cancer cell metastasis to the brain and suggests that connexins might be exploited therapeutically to benefit cancer patients with metastatic disease.
Rapid onset of bone loss is a frequent complication of systemic glucocorticoid therapy which may lead to fragility fractures. Glucocorticoid action in bone depends upon the activity of 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1). Regulations of 11β-HSD1 activity may protect the bone against bone loss due to excess glucocorticoids. Glycyrrhizic acid (GCA) is a potent inhibitor of 11β-HSD. Treatment with GCA led to significant reduction in bone resorption markers. In this study we determined the effect of GCA on 11β-HSD1 activity in bones of glucocorticoid-induced osteoporotic rats. Thirty-six male Sprague-Dawley rats (aged 3 months and weighing 250-300 g) were divided randomly into groups of ten. (1) G1, sham operated group; (2) G2, adrenalectomized rats administered with intramuscular dexamethasone 120 μg/kg/day and oral vehicle normal saline vehicle; and (3) G3, adrenalectomized rats administered with intramuscular dexamethasone 120 μg/kg/day and oral GCA 120 mg/kg/day The results showed that GCA reduced plasma corticosterone concentration. GCA also reduced serum concentration of the bone resorption marker, pyridinoline and induced 11β-HSD1 dehydrogenase activity in the bone. GCA improved bone structure, which contributed to stronger bone. Therefore, GCA has the potential to be used as an agent to protect the bone against glucocorticoid induced osteoporosis.
The anti-inflammatory actions of therapeutic glucocorticoids are well established and these drugs are widely used to treat a variety of inflammatory conditions. It is also clear that endogenously synthesised glucocorticoids have an important role in regulating inflammatory responses. Traditionally, our understanding of the effects of endogenous glucocorticoids has been based on the levels of glucocorticoids within the circulation. These levels are controlled by the hypothalamic-pituitary-adrenal axis. However, more recently it has been established that the local level of glucocorticoids is of potential importance. Situations where the local level of glucocorticoids may differ from the level in the circulation are illustrated in this review. In addition, the mechanisms regulating local glucocorticoid levels and actions are identified. Increasingly, it will be important to understand how the levels of glucocorticoids within the circulation and within the tissues are regulated in a coordinated manner.
Chronic hepatitis C patients often fail to respond to interferon-based therapies. This phase III study aimed at confirming the efficacy and safety of glycyrrhizin in interferon + ribavirin-based therapy non-responders. A randomised, double-blind, placebo-controlled, comparison of glycyrrhizin, administered intravenously 5×/or 3×/week, and 5×/week placebo for 12 weeks to 379 patients, was followed by a randomised, open comparison of glycyrrhizin i.v. 5×/versus 3×/week for 40 weeks. Primary endpoints were: (1) the proportion of patients with ≥50% ALT (alanine aminotransferase) reduction after 12 weeks double-blind phase, and (2) the proportion of patients with improvement of necro-inflammation after 52 weeks as compared with baseline. The proportion of patients with ALT reduction ≥50% after 12 weeks was significantly higher with 5×/week glycyrrhizin (28.7%, P < 0.0001) and 3×/week glycyrrhizin (29.0%, P < 0.0001) compared with placebo (7.0%). The proportion of patients with improvement in necro-inflammation after 52 weeks was 44.9% with 5×/week and 46.0% with 3×/week, respectively. Glycyrrhizin exhibited a significantly higher ALT reduction compared to placebo after 12 weeks of therapy and an improvement of necro-inflammation and fibrosis after 52-weeks treatment. Generally, glycyrrhizin treatment was well tolerated.
Angiogenesis is one of the crucial steps in the transition of a tumor from a small, harmless cluster of mutated cells to a large, malignant growth, capable of spreading to other organs throughout the body. Vascular endothelial growth factor (VEGF) that stimulates vasculogenesis and angiogenesis is thought to be as an anti-angiogenic target for cancer therapy. Liquiritigenin (LQ), a flavanone existing in Radix glycyrrhiza, shows extensive biological activities, such as anti-inflammatory and anti-cancer properties. In our studies, liquiritigenin effectively inhibited the growth of tumors xenografted in nude mice from human cervical cancer cell line HeLa cells, and microvascular density (MVD) of the tumor exposed to liquiritigenin was reduced in a dose dependent manner, especially in the high dose group. Moreover, the expression and secretion of VEGF were down-regulated by the drug in vivo and in vitro. Therefore, liquiritigenin can be further studied on cancer and other diseases associated with VEGF up-regulation.
In this study, we demonstrate that activation of AMP-activated protein kinase (AMPK) with glabridin alleviates adiposity and hyperlipidemia in obesity. In several obese rodent models, glabridin decreased body weight and adiposity with a concomitant reduction in fat cell size. Further, glabridin ameliorated fatty liver and plasma levels of triglyceride and cholesterol. In accordance with these findings, glabridin suppressed the expression of lipogenic genes such as sterol regulatory element binding transcription factor (SREBP)-1c, fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase (SCD)-1 in white adipose tissues and liver, whereas it elevated the expression of fatty acid oxidation genes such as carnitine palmitoyl transferase (CPT)1, acyl-CoA oxidase (ACO), and peroxisome proliferator-activated receptor (PPAR)α in muscle. Moreover, glabridin enhanced phosphorylation of AMPK in muscle and liver and promoted fatty acid oxidation by modulating mitochondrial activity. Together, these data suggest that glabridin is a novel AMPK activator that would exert therapeutic effects in obesity-related metabolic disorders.
Licorice (the root of Glycyrrhizae plant) has been used as an oriental herbal medicine for thousands of years. The licorice flavonoid components are reported to possess immunomodulatory activities. In this present study, we investigated the immunomodulatory effects of liquiritigenin (LG) and liquiritin (LQ), licorice flavonoid components, against disseminated candidiasis due to Candida albicans, a dimorphic fungus, that causes severe disease via hematogenous dissemination and local diseases such as vaginitis and thrush. Results showed that direct interaction of LG or LQ with C. albicans yeast cells resulted in no growth-inhibition, in vitro. When tested in a murine model of disseminated candidiasis, mice given LQ intraperitoneally before intravenous challenge with live C. albicans yeast cells had similar mean survival times (MST) as untreated mice groups. On the contrary, mice given LG in the same manner as LQ above had longer MST than the untreated mice groups (P < 0.05). In one experiment, 3 out of 5 LG-treated mice survived during the entire period of the 55-day observation. Furthermore, the 3 survivors were cured—shown by a lack of CFU (colony forming unit) in the kidneys. This protection was nulled when mice were pretreated with anti-CD4+ antibody before LG-treatment and challenge with the yeast. However, the protection was transferable by the CD4+ T cells isolated from LG-treated mice not infected with the yeast. In addition, mice given CD4+ T cells that were pre-treated with LG, in vitro were also protected against disseminated candidiasis. ELISA analysis revealed that in LG-treated mice IFNγ and IL-2 were dominantly produced compared to IL-4 and IL-10. When LG-given mice were treated with anti-mouse IFNγ, the protection was again nulled. Combined together, these results indicate that LG protects mice against disseminated candidiasis by the CD4+ Th1 immune response.
One of the plant extracts, glycyrrhizin (GL) was investigated for its antiviral action on varicella-zoster virus (VZV) in vitro. When human embryonic fibroblast (HEF) cells were treated with GL after inoculation of virus (post-treatment), the average 50%-inhibitory dose (ID50) for five VZV strains was 0.71 mM, and the selectivity index (ratio of ID50 for host-cell DNA synthesis to ID50 for VZV replication) was 30. GL was also effective against VZV replication when HEF cells were treated 24 h before the inoculation (pretreatment). Furthermore, at a concentration of 2.4 mM GL inactivated more than 99% of virus particles within 30 min at 37°C. In combination with other anti-herpes drugs (acyclovir, adenine arabinoside, bromovinyldeoxyuridine, and phosphonoformate) or human native beta-interferon, GL had an additive or slightly synergistic effect on VZV replication. The mechanism of anti-VZV action is still unclear. We postulate that GL inhibits the penetration, uncoating or release of virus particles.
Glycyrrhizin (GL), a molecule of glycyrrhetinic acid (GA), is an aqueous extract from licorice root. These compounds are well known for their anti-inflammatory, hepatocarcinogenesis, antiviral, and interferon-inducing activities. This study is the first attempt to investigate the binding of GL and GA with DNA. The effect of ligand complexation on DNA aggregation and condensation was investigated in aqueous solution at physiological conditions, using constant DNA concentration (6.25 mM) and various ligands/polynucleotide (phosphate) ratios of 1/240, 1/120, 1/80, 1/40, 1/20, 1/10, 1/5, 1/2, and 1/1. Fourier transform infrared and ultraviolet (UV)-visible spectroscopic methods were used to determine the ligand binding modes, the binding constants, and the stability of ligand-DNA complexes in aqueous solution. Spectroscopic evidence showed that GL and GA bind DNA via major and minor grooves as well as the backbone phosphate group with overall binding constants of K(GL-DNA)=5.7×10(3) M(-1), K(GA-DNA)=5.1×10(3) M(-1). The affinity of ligand-DNA binding is in the order of GL>GA. DNA remained in the B-family structure, whereas biopolymer aggregation occurred at high triterpenoid concentrations.
The aim of the present study was to look into the possible protective effects of glycyrrhizic acid (GA) against isoproterenol-induced acute myocardial infarction in Sprague-Dawley rats. The effect of three doses of glycyrrhizic acid in response to isoproterenol (ISO)-induced changes in 8-isoprostane, lipid hydroperoxides, super oxide dismutase and total glutathione were evaluated. Male Sprague-Dawley rats were divided into control, ISO-control, glycyrrhizic acid alone (in three doses-5, 10 and 20 mg/kg BW) and ISO with glycyrrhizic acid (in three doses) groups. ISO was administered at 85 mg/kg BW at two consecutive days and glycyrrhizic acid was administered intraperitoneally for 14 days. There was a significant increase in 8-isoprostane (IP) and lipid hydroperoxide (LPO) level in ISO-control group. A significant decrease in total superoxide dismutase (SOD) and total glutathione (GSH) was seen with ISO-induced acute myocardial infarction. Treatment with GA significantly increased SOD and GSH levels and decreased myocardial LPO and IP levels. Histopathologically, severe myocardial necrosis and nuclear pyknosis and hypertrophy were seen in ISO-control group, which was significantly reduced with GA treatment. Gycyrrhizic acid treatment proved to be effective against isoproterenol-induced acute myocardial infarction in rats and GA acts as a powerful antioxidant and reduces the myocardial lipid hydroperoxide and 8-isoprostane level.
Triterpenoic acids show many pharmacological effects, among them an antiinflammatory or an antitumor activity. One of these, glycyrrhetinic acid (1) is of interest because of its antitumor profile. Glycyrrhetinic acid is not only cytotoxic but also triggers apoptosis in various human tumor cell lines. To improve the cytotoxicity of parent 1 we set out to synthesize new derivatives of it--differing in structure and lipophilicity. These compounds were tested in a sulforhodamine B assay for cytotoxicity, and screened for their ability to induce apoptosis using an acridine orange/ethidium bromide assay and trypan blue staining. The most active compound, 34, a benzyl glycyrrhetinate holding an extra 3-N-(3-aminopropyl)glycyl substituent showed IC(50) between 1.96 and 5.14 μm for five human cancer cell lines and triggers apoptosis in 80% of the cells.
The formation of aqueous intercellular channels mediating gap junctional intercellular coupling (GJIC) is a canonical function of connexins (Cx). In contrast, mechanisms of GJIC-independent involvement of connexins in cancer formation and metastasis remain a matter of debate. Because of the role of Cx43 in the determination of carcinoma cell invasive potential, we addressed the problem of the possible Cx43 involvement in early prostate cancer invasion. For this purpose, we analysed Cx43-positive DU-145 cell subsets established from the progenies of the cells most readily transmigrating microporous membranes. These progenies displayed motile activity similar to the control DU-145 cells but were characterized by elevated Cx43 expression levels and GJIC intensity. Thus, apparent links exist between Cx43 expression and transmigration potential of DU-145 cells. Moreover, Cx43 expression profiles in the analysed DU-145 subsets were not affected by intercellular contacts and chemical inhibition of GJIC during the transmigration. Our observations indicate that neither cell motility nor GJIC determines the transmigration efficiency of DU-145 cells. However, we postulate that selective transmigration of prostate cancer cells expressing elevated levels of Cx43 expression may be crucial for the "leading front" formation during cancer invasion.
Cocaine, as an indirect dopamine agonist, induces selective behavioral and physiological events such as hyperlocomotion and dopamine release. These changes are considered as consequences of cocaine-induced molecular adaptation such as CREB and c-Fos. Recently, methanolic extracts from licorice was reported to decrease cocaine-induced dopamine release and c-Fos expression in the nucleus accumbens. In the present study, we investigated the effects of liquiritigenin (LQ), a main compound of licorice, on acute cocaine-induced behavioral and molecular changes in rats. LQ attenuated acute cocaine-induced hyperlocomotion in dose-dependent manner. In addition, LQ inhibited CREB phosphorylation and c-Fos expression in the striatum and the nucleus accumbens induced by acute cocaine. Results provide strong evidence that LQ effectively attenuates the acute behavioral effects of cocaine exposure and prevents the induction of selective neuroadaptive changes in dopaminergic signaling pathways. Further investigation of LQ from licorice extract might provide a novel therapeutic strategy for the treatment of cocaine addiction.
Gap junctional communication is likely one means by which neurons can endure glutamate cytotoxicity associated with CNS insults (i.e. ischemia). To examine this neuroprotective role of gap junctions, we employed gap junctional blockers to neuronal and astrocytic co-cultures during exposure to a high concentration of extracellular glutamate. Co-cultures were treated with the blocking agents carbenoxolone (CBX; 25 microM), 18alpha-glycyrrhetinic acid (AGA; 10 microM), vehicle or the inactive blocking analogue glycyrrhizic acid (GZA; 25 microM). Twenty-four hours following the insult, cell mortality was analyzed and quantified by the release of lactate dehydrogenase (LDH) into the media, the cells' inability to exclude propidium iodide, and terminal dUTP nick end labeling (TUNEL). Measurement of LDH release revealed that the glutamate insult was detrimental to the co-cultures when gap junctions were blocked with CBX and AGA. Based on propidium iodide and TUNEL labeling, the glutamate insult caused significant cell death compared to sham vehicle and mortality was amplified in the presence of CBX and AGA. Since blockers were not themselves toxic and did not affect astrocytic uptake of glutamate, it is likely that blocked gap junctions lead to the increased glutamate cytotoxicity. These findings support the hypothesis that gap junctions play a neuroprotective role against glutamate cytotoxicity.
Isoliquiritigenin (4,2 ',4 ' -trihydroxychalcone, ISL) is a natural pigment with a simple chalcone structure. In this study, we report the ISL-induced inhibition on the growth of human hepatoma cells (Hep G2) for the first time. The cell growth inhibition achieved by ISL treatment resulted in programmed cell death in a caspase activation-dependent manner, with an IC50 of 10.51 mu g/mL. Outcomes of ISL treatment included the up-regulation of I kappa B alpha expression in the cytoplasm, and the decrease of NF-kappa B level as well as its activity in the nucleus. In addition, ISL also suppressed the expression of Bcl-X-L and c-IAP1/2 protein, the downstream target molecule of NF-kappa B. These results demonstrated that ISL treatment inhibited the NF-kappa B cell survival-signaling pathway and induced apoptotic cell death in Hep G2 cells.
Phytoestrogens are a diverse class of non-steroidal compounds that have an affinity for estrogen receptors α and β, for the peroxisome proliferator-activated receptor (PPAR) family and for the aryl hydrocarbon receptor. Examples of phytoestrogens include prenylated flavonoids, isoflavones, coumestans and lignans. Many phytoestrogens counteract the cellular derailments that are responsible for the development of metabolic syndrome. Here we propose a mechanism of action which is based on five pillars/principles. First, phytoestrogens are involved in the downregulation of pro-inflammatory cytokines, such as COX-2 and iNOS, by activating PPAR and by inhibiting IκB activation. Second, they increase reverse cholesterol transport, which is mediated by PPARγ. Third, phytoestrogens increase insulin sensitivity, which is mediated via PPARα. Fourth, they exert antioxidant effects by activating antioxidant genes through KEAP. Fifth, phytoestrogens increase energy expenditure by affecting AMP-activated kinase signalling cascades, which are responsible for the inhibition of adipogenesis. In addition to these effects, which have been demonstrated in vivo and in clinical trials, other effects, such as eNOS activation, may also be important. Some plant extracts from soy, red clover or licorice can be described as panPPAR activators. Fetal programming for metabolic syndrome has been hypothesized; thus, the consumption of dietary phytoestrogens during pregnancy may be relevant. Extracts from soy, red clover or licorice oil have potential as plant-derived medicines that could be used to treat polycystic ovary syndrome, a disease linked to hyperandrogenism and obesity, although clinical trials have not yet been conducted. Phytoestrogens may help prevent metabolic syndrome, although intervention studies will be always be ambiguous, because physical activity and reduced calorie consumption also have a significant impact. Nevertheless, extracts rich in phytoestrogens may be an alternative treatment or may complement conventional treatment for diseases linked with metabolic syndrome.
Maternal intake of licorice from dietary sources has been associated with adverse maternal and fetal outcomes. We prospectively studied the outcome of 185 singleton pregnancies who took over-the-counter or naturopathic formulations containing licorice during their pregnancy, and 370 age-matched singleton pregnant controls that were not exposed to any potential teratogen. The indication in 56.8 % of the women taking licorice was for cough and cold control, with the maximum dose of 2104 mg/day and exposure occurring between the 4th day and 25th week of gestation. The rate of stillbirths was marginally higher among women who took licorice than those who did not (OR = 7.9; 95 % CI 0.9-71.5; p = 0.048), and significantly higher when compared to the general population in the Republic of Korea (OR = 13.3; 95 % CI 4.9-35.8; p < 0.001). Other fetal outcomes assessed in the study were similar between the two study groups, e.g., the OR of major malformations was 3.9 (95 % CI 0.4-43.5; p = 0.27). In conclusion, the present study suggests that licorice is not a major teratogen. However, whether licorice may increase the risk of stillbirths requires careful consideration in further studies with a larger sample size.
Advanced glycation end products (AGEs)-induced vasculopathy, including oxidative stress, inflammation and apoptosis responses, contributes to the high morbidity and mortality of coronary artery diseases in diabetic patients. The present study was conducted to evaluate the protective activity of liquiritin (Liq) on AGEs-induced endothelial dysfunction and explore its underlying mechanisms. After pretreatment with Liq, a significant reduction in AGEs-induced apoptosis, as well as reactive oxygen species generation and malondialdehyde level in human umbilical vein endothelial cells (HUVECs) were observed via acridine orange/ethidium bromide fluorescence staining test. Notably, Liq also significantly increased AGEs-reduced superoxide dismutase activity. Furthermore, the pretreatment with receptor for advanced glycation end products (RAGE)-antibody or Liq remarkably down-regulated TGF-beta1 and RAGE protein expressions and significantly blocked NF-κB activation which were proved by immunocytochemistry or immunofluorescence assays. These results indicated that Liq held potential for the protection on AGEs-induced endothelial dysfunction via RAGE/NF-κB pathway in HUVECs and might be a promising agent for the treatment of vasculopathy in diabetic patients.
Glucocorticoids are widely used in the clinical setting as remedies for inflammatory diseases, such as asthma and chronic obstructive pulmonary disease. However, the constant increase in the number of patients suffering from glucocorticoid resistance could present a serious problem for clinicians. In these cases, it may be reasonable to use additional treatments to restore the therapeutic effect of glucocorticoids. Glycyrrhizic acid (GA) and 18β-glycyrrhetinic acid (18βGA) are bioactive compounds in licorice that have been used for thousands of years in traditional Chinese medicine to treat coughs. We showed that GA and 18βGA exhibit potential anti-inflammatory and antioxidant properties. GA and 18βGA induced dual specificity protein phosphatase 1 (DUSP1) expression, and this effect was unchanged by the addition of RU486, a glucocorticoid receptor antagonist. The stimulation of DUSP1 expression by GA and 18βGA occurred via both glucocorticoid receptor (GR) and PI3K signaling, and the simultaneous activation of transcription elements, such as AP1 (activator protein 1), CRE (cAMP response element), GRE (glucocorticoid receptor element) and NFAT (nuclear factor of activated T-cells), was confirmed. Furthermore, we designed an in vitro glucocorticoid resistance model to verify the effects of GA and 18βGA on glucocorticoid resistance that was induced by ROS. The data showed that these two phytochemicals restored glucocorticoid sensitivity by depleting ROS through HO-1 expression. p38 and NO, which are factors that are induced by reactive oxygen species and caused depletion of GR signaling, were inhibited by GA and 18βGA treatment. This phenomenon was considered to be related to the coordinated modulation of GR and PI3K signaling by GA and 18βGA, in conjugation with AP1, CRE, GRE and NFAT activation. This study provides a possible strategy for enhancing the efficacy of glucocorticoids and may improve the prognosis of patients with serious inflammatory diseases.
Ethnopharmacological relevance:
Shakuyakukanzoto (SKT) composed of Glycyrrhizae radix (G. radix) and Paeoniae radix (P. radix) has been traditionally used in Japan, Korea and China as an antispasmodic drug for the treatment of skeletal muscle cramps and intestinal cramps.
Aim of this study:
To evaluate the antispasmodic activity of SKT and its two components, as well as to identify the key constituents of the components which mediate this effect in skeletal muscles in vivo.
Materials and methods:
An experimental cramp model was constructed to evaluate the effects of peripherally-acting muscle relaxants on electrically-induced cramps under physiological conditions. This was accomplished by surgically isolating the motor supply to the gastrocnemius muscle in an anesthetized rat and delivering electrical stimuli to an isolated tibial nerve to induce tetanic contractions. We first tested dantrolene, a well-known peripherally-acting relaxant, to determine the sensitivity and reliability of our experimental model. We then evaluated the effects of SKT, P. radix, G. radix, and the eight active constituents of G. radix against tetanic contractions.
Results:
We found that dantrolene (10 and 30 mg/kg, i.d.) rapidly and significantly inhibited tetanic contractions (P<0.01) irrespective of dose. SKT (0.5, 1.0, and 2.0 g/kg, i.d.) and G. radix (0.5 and 1.0 g/kg, i.d.) also significantly inhibited tetanic contractions (P<0.01) but in a dose-dependent manner owing to the actions of six of the eight active constituents in G. radix (liquiritin apioside, liquiritigenin, isoliquiritin apioside, isoliquiritigenin, glycycoumarin, and glycyrrhetinic acid, 20 μmol/kg, i.v.). These constituents, which include flavonoids, a triterpenoid, and a courmarin derivative, demonstrated temporal variations in their inhibitory activity. In contrast, P. radix (0.5 and 1.0 g/kg, i.d.) did not show a statistically significant antispasmodic effect in our study; however, we previously found that it had a significant antinociceptive effect.
Conclusions:
Our findings show that SKT inhibits tetanic contractions in vivo and that G. radix is the main antispasmodic component due to the actions of its active constituents, thus supporting the traditional use of SKT. We further propose that SKT containing the antispasmodic G. radix and antinociceptive P. radix is a pharmaceutically elegant option for muscle cramps as treatment requires a two-pronged approach, i.e., inhibition of hyperexcitable skeletal tissues and modulation of the pain accompanying cramps.
Postinflammatory hyperpigmentation (PIH) is a reactive hypermelanosis and sequela of a variety of inflammatory skin conditions. PIH can have a negative impact on a patient's quality of life, particularly for darker-skinned patients. Studies show that dyschromias, including PIH, are one of the most common presenting complaints of darker-skinned racial ethnic groups when visiting a dermatologist. This is likely due to an increased production or deposition of melanin into the epidermis or dermis by labile melanocytes. A variety of endogenous or exogenous inflammatory conditions can culminate in PIH and typically most epidermal lesions will appear tan, brown, or dark brown while dermal hypermelanosis has a blue-gray discoloration.Depigmenting agents target different steps in the production of melanin, most commonly inhibiting tyrosinase. These agents include hydroquinone, azelaic acid, kojic acid, arbutin, and certain licorice (glycyrrhiza) extracts. Other agents include retinoids, mequinol, ascorbic acid (vitamin C), niacinamide, N-acetyl glucosamine, and soy, and these products depigment by different mechanisms. Certain procedures can also be effective in the treatment of PIH including chemical peeling and laser therapy. It is important to note that these same therapeutic modalities may also play a role in causing PIH. Lastly, those lesions that are not amenable to medical or surgical therapy may experience some improvement with cosmetic camouflage.
Licorice (LE) has been commonly used in traditional Chinese medicine (TCM) for over 4000years to reconcile various drugs and for hepatic disorders. Glycyrrhizin is the main bioactive component isolated from LE herbs. In the present study we examined the effects of glycyrrhizin on pregnane X receptor (PXR)-mediated CYP3A expression and its hepatoprotective activity. Treatment of HepG2 cells with glycyrrhizin resulted in marked increase in both CYP3A4 mRNA and protein levels. The transcriptional activation of the CYP3A4 gene through glycyrrhizin is PXR-dependent, as shown in transient transfection experiments. Glycyrrhizin activates the DNA-binding capacity of the PXR for the CYP3A4 element responding to xenobiotic signals, as measured by the electrophoretic-mobility shift assay (EMSA). These results indicate that the induction of the hepatic CYP3A4 by glycyrrhizin is mediated through the activation of PXR. The next aim of the current study was to determine whether the activation of PXR and induction of CYP3A by glycyrrhizin prevents hepatotoxicity during cholestasis as a mechanism of hepatoprotection. Mice were pretreated with glycyrrhizin prior to induction of intrahepatic cholestasis using lithocholic acid (LCA). Pre-treatment with glycyrrhizin, as well as the PXR activator pregnenolone 16α-carbontrile (PCN), prevents the increase in plasma ALT and AST activity, multifocal necrosis and prevents an increase in a level of serum LCA level in mice, as compared with the results in the mice treated with LCA alone. Activation of the PXR by glycyrrhizin results in induction of CYP3A11 (CYP3A4 for human) expression and inhibition of CYP7A1 through an increase in small heterodimer partner (SHP) expression. Glycyrrhizin regulates the expression of the gene mentioned above to prevent toxic accumulation of bile acids in the liver and it also protects mouse livers from the harmful effects of LCA. In conclusion, PXR-mediated effects on CYP3A and CYP7A may contribute to the hepatoprotective property of glycyrrhizin against LCA-induced liver injury.
Ethnopharmacological relevance:
In Chinese classic formulas, Ma Huang Tang (MHT), composed of Ephedra, Cassia twig, Bitter apricot kernel and Prepared licorice, has been widely used to treat cold, influenza, acute bronchitis, bronchial asthma and other pulmonary diseases. However, there is no quantitative interpretation about composition principle of MHT as well as other Chinese compound prescriptions. This study was aimed using structural equation modeling (SEM) to decipher 'monarch, minister, assistant and guide' which is the unique and integrated composition principle of Chinese compound recipes, by taking MHT for instance.
Materials and methods:
Sixteen prescriptions of different dose ratios were combined orthogonally from four herbal drugs of MHT, then their diaphoretic, antispasmodic and analgesic effects were assessed by the indicators of the rat sweating point number, the spasmolysis percentage of guinea pig trachea and the murine writhing number, respectively. Basing on SME, the systematology analysis method to complex causality, path diagrams for herbal drugs were drawn with the Amos software and the relationships of the four herbal ingredients and therapeutic effects were measured.
Results:
Sixteen recipes induced SD rats sweating, remitted spasm of guinea pig trachea smooth muscle, and relieved ICR mouse pain due to acetic acid in comparison with animal model group or normal control groups. Three different SME models were specified and the relevant relationship was analyzed. According to the results of measured standardized path coefficients, Ephedra exerts the greatest contribution to the integral potency, so it acts as the monarch drug in MHT; Cassia twig is slightly weakly effective than Ephedra, and has the most significant interaction with Ephedra, which shows that it is the minister drug; the direct effects of Bitter apricot kernel and Prepared licorice on the integral potency are non-significant, while these two drugs have very significant synergetic effect with Ephedra or Cassia twig, thus they can be interpreted as subordinate drugs to strengthen the therapeutical effects of the monarch and minister drugs; the higher interaction values of Bitter apricot kernel suggest that it is the assistant drug, and Prepared licorice is the guide drug with lower values.
Conclusion:
SME can be used to quantitatively analyze the composition principle of Chinese compound prescriptions like MHT, which demystifies the ancient and classical system theory of traditional Chinese medicine from a totally new viewpoint.
Glycyrrhizic acid (GA) is the bioactive compound of licorice and has been used as a herbal medicine because of its anti-viral, anti-cancer, and anti-inflammatory properties. This study was designed to investigate the effects of GA on tumor growth, angiogenesis, and the mechanisms underlying the anti-angiogenic activities of GA. We observed that GA inhibited tumor growth and angiogenesis in mice. GA decreased angiogenic activities, such as the migration, invasion, and tube formation of endothelial cells. We also demonstrated that GA reduced the production of reactive oxygen species and activation of ERK in endothelial cells. Our findings suggest that GA is a promising anti-angiogenic therapeutic agent that targets the ERK pathway. Considering that angiogenesis is highly stimulated in the majority of cancers, GA could offer a potent therapeutic agent for cancer. Copyright © 2012 John Wiley & Sons, Ltd.
The Hsp90 inhibition has been shown to induce apoptosis in various cancer cells. The licorice compounds may enhance the anti-cancer drug effect. However, effect of the licorice compounds on the Hsp90 inhibition-induced apoptosis in ovarian cancer cells has not been studied. To assess the ability of 18β-glycyrrhetinic acid to promote apoptosis, we examined whether 18β-glycyrrhetinic acid potentiated the Hsp90 inhibitor-induced apoptosis in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. Radicicol and geldanamycin induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels, an increase in Bax levels, the mitochondrial transmembrane potential loss, cytochrome c release, activation of caspases (-8, -9, and -3), cleavage of PARP-1, and an increase in the tumor suppressor p53 levels. 18β-Glycyrrhetinic acid enhanced Hsp90 inhibitor-induced apoptosis-related protein activation, nuclear damage, and cell death. The results suggest that 18β-glycyrrhetinic acid may potentiate the Hsp90 inhibition-induced apoptosis in ovarian carcinoma cell lines via the activation of the caspase-8- and Bid-dependent pathways and the mitochondria-mediated cell death pathway, leading to activation of caspases. Combination of Hsp90 inhibitors and 18β-glycyrrhetinic acid may confer a benefit in the treatment of epithelial ovarian adenocarcinoma.
Carbenoxolone is the 3-hemisuccinate of glycyrrhetinic acid, the active principal of licorice (Glycyrrhiza glabra). It was reported that carbenoxolone improved glucose tolerance with increased insulin sensitivity in mice with high fat diet-induced obesity. In the present study, we elucidated the protective effect of carbenoxolone in fatty liver animal models of C57BL/6-Lep(ob/ob) mice through inhibition of hepatic lipogenesis and apoptosis. In addition, the potential mechanisms by which carbenoxolone could exert such protection were elucidated. Carbenoxolone was daily administrated by gavage for 28 days in C57BL/6 and C57BL/6-Lep(ob/ob) mice. Carbenoxolone prevented the plasma triglyceride and free fatty acid accumulation associated with the reduction of the expression of sterol regulatory element binding protein-1c, liver X receptor, fatty acid synthase and acethyl-CoA carboxylase in the livers of C57BL/6-Lep(ob/ob) mice. Carbenoxolone also prevented hepatic injury through anti-apoptotic action in the livers of C57BL/6-Lep(ob/ob) mice, accompanied by increased Bcl-2 expression and suppressed Bax and cytochrome c expression. As a mechanism, increased inflammatory cytokine expressions were inhibited by carbenoxolone in the fatty livers of C57BL/6-Lep(ob/ob) mice. Furthermore, carbenoxolone inhibited free fatty acid (oleate/palmitate) induced reactive oxygen species formation and reversed free fatty acid induced mitochondrial membrane depolarization in HepG2 cells. Carbenoxolone prevents the development of fatty liver by inhibiting sterol regulatory element binding protein-1c expression and activity with an anti-apoptotic mechanism via the inhibition of inflammatory cytokine and reactive oxygen species formation in the livers of C57BL/6-Lep(ob/ob) mice. It is suggested that carbenoxolone prevents the development and progression of fatty liver disease in patients with insulin resistance.
A large variety of natural products have been described as anti-HIV agents, and for a portion thereof the target of interaction has been identified. Cyanovirin-N, a 11-kDa protein from Cyanobacterium (blue-green alga) irreversibly inactivates HIV and also aborts cell-to-cell fusion and transmission of HIV, due to its high-affinity interaction with gp120. Various sulfated polysaccharides extracted from seaweeds (i.e., Nothogenia fastigiata, Aghardhiella tenera) inhibit the virus adsorption process. Ingenol derivatives may inhibit virus adsorption at least in part through down-regulation of CD4 molecules on the host cells. Inhibition of virus adsorption by flavanoids such as (−)epicatechin and its 3-O-gallate has been attributed to an irreversible interaction with gp120 (although these compounds are also known as reverse transcriptase inhibitors). For the triterpene glycyrrhizin (extracted from the licorice root Glycyrrhiza radix) the mode of anti-HIV action may at least in part be attributed to interference with virus-cell binding. The mannose-specific plant lectins from Galanthus, Hippeastrum, Narcissus, Epipac tis helleborine, and Listera ovata, and the N-acetylgl ucosamine-specific lectin from Urtica dioica would primarily be targeted at the virus-cell fusion process. Various other natural products seem to qualify as HIV-cell fusion inhibitors: the siamycins [siamycin I (BMY-29304), siamycin II (RP 71955, BMY 29303), and NP-06 (FR901724)] which are tricyclic 21-amino-acid peptides isolated from Streptomyces spp that differ from one another only at position 4 or 17 (valine or isoleucine in each case); the betulinic acid derivative RPR 103611, and the peptides tachyplesin and polyphemusin which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus, i.e., the 18-amino-acid peptide T22 from which T134 has been derived. Both T22 and T134 have been shown to block T-tropic X4 HIV-1 strains through a specific antagonism with the HIV corecept or CXCR4. A number of natural products have been reported to interact with the reverse transcriptase, i.e., baicalin, avarol, avarone, psychotrine, phloroglucinol derivatives, and, in particular, calanolides (from the tropical rainforest tree, Calophyllum lanigerum) and inophyllums (from the Malaysian tree, Calophyllum inophyllum). The natural marine substance illimaquinone would be targeted at the RNase H function of the reverse transcriptase. Curcumin (diferuloylmethane, from turmeric, the roots/rhizomes of Curcuma spp), dicaffeoylquinic and dicaffeoylt artaric acids, L-chicoric acid, and a number of fungal metabolites (equisetin, phomasetin, oteromycin, and integric acid) have all been proposed as HIV-1 integrase inhibitors. Yet, we have recently shown that L-c hicoric acid owes its anti-HIV activity to a specific interaction with the viral envelope gp120 rather than integrase. A number of compounds would be able to inhibit HIV-1 gene expression at the transcription level: the flavonoid chrysin (through inhibition of casein kinase II, the antibacter ial peptides melittin (from bee venom) and cecropin, and EM2487, a novel substance produced by Streptomyces. α-Trichosanthin (from the root tubers of Trichosanthes kirilowii), MAP30 (from Momordi ca charantia), GAP31 (from Gelonium multiflorum), DAP30 and DAP32 (from Dianthus caryophyllus) would act as RIPs (ribosome-i nactivating proteins), suppressing the translation process. As glycosylation inhibitors, castanospermine and 1-deoxynojirimycin would interfere with the infectivity and secondary spread of HIV-1. And so would bellenamine [(R)-3,6-diamino-N-(aminomethyl)hexanamide] (from Streptomyces nashvillensis), albeit by an unknown mechanism. Hypericin and pseudohype ricin, two aromatic polycyclic diones from Hypericum triquetrifolium (St. Johnswort), could block HIV-1 infection through a variety of mechanisms (direct virucidal effect, inhibition of secondary virus spread, inhibition of virus budding, and inactivation of the preintegration complex). A number of miscellaneous compounds, including propolis, pokeweed antiviral protein, and michellamines inhibit HIV replication by mechanisms that still have to be resolved. Cyclosporins do so by preventing the interaction of cyclophil in A with the capsid gag proteins, thus blocking both a late event (assembly) and early event (nuclear localization of the preintegration complex) in the HIV replicative cycle. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 5, 323–349, 2000
The efficacy of Shosaiko-to (SST) on 222 patients with chronic active hepatitis was studied in a double-blind multicenter
clinical study. One hundred and sixteen patients received SST in a daily oral dose of 5.4 g for 12 weeks, followed by the
same dose for a further 12 weeks. One hundred and six patients received a placebo containing 0.5 g of SST for 12 weeks, followed
by a cross-over to SST for a further 12 weeks. Among the liver tests, serum AST and ALT values decreased significantly with
the admisnistration of SST. The difference of the mean value between the SST group and the placebo group was significant after
12 weeks. In patients with chronic active type B hepatitis, a tendency towards a decrease of HBeAg and an increase of Anti-HBe
antibodies was also observed. No remarkable side effects were noticed.
A 51-year-old lady was referred to our clinic because of severe hypertension; blood pressure 214/119 mm Hg despite treatment with an angiotensin receptor antagonist and a calcium channel blocker. Her initial laboratory results showed hypokalaemic alkalosis with normal urea and creatinine levels. Her 24-h urinary sodium excretion was markedly elevated at 244 mmol (equivalent to a daily intake of approximately 16 g of salt). Hyperaldosteronism was suspected but her plasma aldosterone level was subsequently found to be normal. On further questioning, the patient admitted to eating considerable amounts of salted liquorice and a diagnosis of acquired apparent mineralocorticoid excess was made. Liquorice has a well-known mineralocorticoid activity as it inhibits the action of 11β-hydroxysteroid dehydrogenase 2 and can induce mineralocorticoid hypertension. After stopping eating the salted liquorice, the patient's blood pressure quickly normalised and all her antihypertensive medications were stopped.
Phytoestrogens are found in foods such as soy (isoflavones) and flaxseed (lignans), and certain botanical supplements. Their role in estrogen receptor positive (ER+) breast cancer recurrence and treatment is controversial, and it is unknown how this affects intake among patients. The Ontario Cancer Registry was used to identify 417 population-based breast cancer cases (mean time from diagnosis was 57 days). A questionnaire was mailed to determine intake of phytoestrogen foods and supplements in the last 2 mo, changes since diagnosis and differences by ER tumor status or hormonal treatment. Of 278 (67%) respondents, 56% consumed soy foods, 39% consumed isoflavone-rich foods (tofu, soybeans, soy milk, soy nuts), and 70% ate lignan-rich foods, including flaxseed (33%). Only soy milk, flaxseed, and flaxseed bread were commonly consumed more than once/wk. Few patients (4%) took isoflavone (soy, red clover, kudzu, licorice, isoflavones) or lignan/flaxseed supplements. Since diagnosis, 17% started or stopped soy foods (most stopped); this was more prevalent among those receiving hormonal treatment (20%; 95% confidence interval (CI): 14, 26) than not (6%; 95% CI: 1, 12). No other differences by ER status or hormonal treatment were observed. Research is needed to confirm this and to explore influencing factors.
Licorice, the root of the Glycyrrhiza species ( Glycyrrhiza uralensis Fisher), is known to have antioxidant, anti-inflammatory, antiviral, and antitumor properties. The objective of this study is to explore the neuroprotective effect of dehydroglyasperin C (DGC) against glutamate-induced oxidative stress in mouse hippocampal HT22 cells. DGC significantly reduced cytotoxicity and reactive oxygen species (ROS) generation induced by glutamate in HT22 cells, whereas DGC did not restore glutathione depletion caused by glutamate. In addition, it was further investigated whether DGC affected the expression of heme oxygenase (HO)-1, one of the major cellular antioxidant defense systems, and it was found that DGC dose-dependently increased HO-1 expression. DGC-mediated cytoprotection of HT22 neuronal cells from glutamate insult was abrogated by either HO-1 inhibitor (Tin protoporphyrin, SnPP) or AKT inhibitor (LY294002). In conclusion, the present results demonstrate for the first time that DGC protects neuronal cells against glutamate-induced oxidative injury through the induction of HO-1 expression, which is, in turn, activated maybe through Nrf2-Keap1 and PI3K/AKT signaling pathways.
Glycyrrhizin is a well known pharmacologically bioactive natural glycoside. Glycyrrhizin (GL) has been widely used as a therapeutic agent for chronic active liver diseases. Glycyrrhetinic acid is an aglycone and an active metabolite of glycyrrhizin. This study is the first attempt to locate the binding sites of glycyrrhizin and glycyrrhetinic acid to RNA. The effect of the ligand complexation on RNA aggregation was investigated in aqueous solution at physiological conditions, using constant RNA concentration (6.25 mM) and various ligand/polynucleotide (phosphate) ratios of 1/280, 1/240, 1/120, 1/80, 1/40, 1/20, 1/10, 1/5, 1/2 and 1/1. Fourier transform infrared (FTIR) and UV-Visible spectroscopic methods as well as molecular modeling were used to determine the ligand binding modes, the binding constants, and the stability of ligands-RNA complexes in aqueous solution. Spectroscopic evidence showed that glycyrrhizin and glycyrrhetinic acid bind RNA via G-C and A-U base pairs as well as the backbone phosphate group with overall binding constants of K(GL-RNA)=3.03×10(3)M(-1), K(GA-RNA)=2.71×10(3)M(-1). The affinity of ligands-RNA binding is in the order of glycyrrhizin>glycyrrhetinic acid. RNA remains in the A-family structure, while biopolymer aggregation occurred at high triterpenoid concentrations.
18β-Glycyrrhetinic acid (GA) is a major metabolite of glycyrrhizin (GL), which is one of the components of glycyrrhiza root, a constituent herb of the traditional Japanese medicine yokukansan. It is well known that most GL is metabolized to GA in the intestine by bacteria. A previous in vitro study using cultured rat cortical astrocytes suggested that GA activates glutamate transport, which is a putative mechanism of the psychotropic effect of yokukansan. To activate the glutamate transport in the brain, GA must be absorbed into the blood after oral administration of yokukansan and then cross the blood-brain barrier (BBB) to reach the brain. However, there is no data on the BBB permeability of GA derived from yokukansan. In the present study, the BBB permeability of GA was investigated in both in vivo and in vitro studies. In the in vivo study, GA was detected in the plasma, brain, and cerebrospinal fluid of rats orally administered yokukansan. In the in vitro study using a BBB model composed of co-culture of endothelial cells, pericytes, and astrocytes, the permeability rate and apparent permeability coefficient of GA were found to be 13.3 ± 0.5 % and 16.5 ± 0.7 × 10(-6) cm/s. These in vivo and in vitro results suggest that GL in orally administered yokukansan is absorbed into the blood as GA, and then reaches the brain through the BBB. This evidence further supports the possibility that GA is an active component in the psychotropic effect of yokukansan.
The pharmacological evidence for synergism between natural compounds is not fully elucidated. In this study, we investigated the synergistic function of one target compound in medicinal plant extract by using knock-out (KO) extract, which is one target compound-eliminated extract from whole crude extract. Licorice is the most important ingredient used in the traditional Chinese medicine (TCM) and the Japanese Kampo medicine, and one of the major active components of licorice is glycyrrhizin (GC). To identify the potential role of GC, we prepared GC-removed extract (GC-KO extract) from licorice extract (LE) using immunoaffinity column conjugated with anti-GC monoclonal antibody (MAb), which could eliminate 99.5% of GC from LE. LE inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-stimulated RAW264 murine macrophage cells. However, treatment of GC alone could not show the suppression of NO production and iNOS expression. Interestingly, the inhibitory effect of GC-KO extract was significantly attenuated compared with LE. Furthermore, the combined treatment with GC-KO extract and GC could improve the attenuated inhibition. Taken together, our results indicate that GC may exert synergistic suppression of iNOS expression when coexisting with the other constituents contained in LE, and KO extract is a useful approach for determination of real pharmacological functions of natural compound in the phytochemical mixture.
Liquiritigenin (LQ) is a non-toxic dietary flavonoid with chemopreventive and anticancer properties. However, the mechanism of its antiangiogenesis remains unclear. Hypoxia-inducible factor-1α (HIF-1α) and its downstream target, vascular endothelial growth factor (VEGF), play a critical role in tumour angiogenesis and represent an attractive chemotherapeutic target. In this study, we investigated the effect of LQ on the molecular mechanism of angiogenesis. We found that LQ inhibited VEGF expression at both mRNA and protein levels. Liquiritigenin did not affect HIF-1α expression at the mRNA level, but it dramatically inhibited both serum- and mimicked hypoxic-induced HIF-1α protein accumulation in HeLa cells. Furthermore, we showed that LQ inhibited serum-induced expression of HIF-1α by reducing its stability and decreased the synthesis in a dose-dependent manner. Mechanistically, we demonstrated that LQ inhibited HIF-1α and VEGF expression involved in blocking the protein kinase B (PKB/Akt) signalling pathway, and the mechanisms correlated with dephosphorylation of the mammalian target of rapamycin (mTOR) and its effector ribosomal protein S6 kinase (p70S6K). In addition, LQ inhibited VEGF-induced formation of capillary-like structures in human umbilical vein endothelial cells (HUVEC). Taken together, our study provided valuable insights into the mechanism of antiangiogenic effect of LQ.
Liquiritigenin is one of the flavonoids present in Glycyrrhizae radix. In the present study, the effects of liquiritigenin on the function of osteoblastic MC3T3-E1 cells were studied. Liquiritigenin caused a significant elevation of cell growth, alkaline phosphatase activity, collagen synthesis, mineralization, and glutathione content in the cells (P<0.05). Moreover, liquiritigenin significantly decreased the production of reactive oxygen species (ROS) and osteoclast differentiation inducing factors such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and receptor activator of nuclear factor-κB ligand (RANKL) in the presence of antimycin A, which inhibits mitochondrial electron transport and has been used as a ROS generator. These results demonstrate that liquiritigenin may have positive effects on skeletal structure.
Several methods of treatment are available to patients with melasma. First-line therapy usually consists of topical compounds that affect the pigment production pathway, broad-spectrum photoprotection, and camouflage. Second-line therapy often consists of the addition of chemical peels, although these must be used cautiously in patients with darker skin. Laser and light therapies represent potentially promising options for patients who are refractory to other modalities, but also carry a significant risk of worsening the disease. A thorough understanding of the risks and benefits of various therapeutic options is crucial in selecting the best treatment.
Since cyclophosphamide is metabolically activated to teratogenic acrolein and cytotoxic phosphoramide mustard by cytochrome P-450 type 2B (CYP2B), we assessed the effects of licorice, a CYP2B inducer, on the fetal defects induced by cyclophosphamide.
Pregnant Sprague-Dawley rats were daily administered with licorice (100 mg/kg) by gavage for 7 days, from the 6th to 12th day of gestation, and intraperitoneally administered with cyclophosphamide (11 mg/kg) 1 hr after the final licorice treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarian section.
Cyclophosphamide was found to reduce fetal and placental weights without increasing resorption or death. In addition, it induced malformations in live fetuses; 93.8, 41.1, and 100% of the external (skull and limb defects), visceral (cleft palate and ureteric dilatation), and skeletal (acrania, vertebral/costal malformations, and delayed ossification) abnormalities, respectively. When pre-treated with licorice, cyclophosphamide-induced body weight loss and abnormalities of fetuses were remarkably aggravated. Moreover, repeated treatment with licorice greatly increased mRNA expression and activity of hepatic CYP2B.
The results indicate that repeated intake of licorice may aggravate cyclophosphamide-induced body weight loss and malformations of fetuses by upregulating CYP2B.
Glycyrrhizic acid (GA) is a main sweetening component of licorice roots and has been found to be associated with multiple therapeutic properties. In this study, we used GA as a protective agent against the clastogenic and nephrotoxic effects of cisplatin (CP).
Mice were given a prophylactic treatment of GA orally at doses of 75 and 150mg/kg body weight for seven consecutive days before the administration of a single intraperitoneal dose of CP at 7mg/kg body weight. The modulatory effects of GA on CP-induced nephrotoxicity and genotoxicity were investigated by assaying oxidative stress biomarkers, lipid peroxidation, serum kidney toxicity markers, DNA fragmentation, alkaline unwinding, and micronuclei and by histopathological examination of the kidneys.
A single intraperitoneal dose of cisplatin in mice enhanced renal lipid peroxidation, xanthine oxidase, and H(2)O(2) generation; depleted glutathione content, activities of the anti-oxidant enzymes glutathione peroxidase, glutathione reductase, catalase, glutathione-S-transferase and quinone reductase; induced DNA strand breaks and micronucleus formation (p<0.001); and majorly disrupted normal kidney architecture. Pretreatment with GA prevented oxidative stress by restoring the levels of antioxidant enzymes at both doses. A significant dose-dependent decrease in DNA fragmentation, micronucleus formation (p<0.05), and the kidney toxicity markers BUN (p<0.001), creatinine (p<0.01), and LDH (p<0.001) and restoration of normal kidney histology was observed.
Our study supports the claim that the phytochemical GA has the potential to attenuate the side effects of anticancer drug overdose.
Maintenance of normal potassium (K(+)) homeostasis has become an increasingly important limiting factor in the therapy of heart failure (HF). With the application of loop diuretics and digoxin, hypokalemia has become a frequent and feared side effect of treatment. Low serum K(+) in HF may be also a marker of increased neurohormonal activity and disease progression. To gain the maximum benefit from treatment, we need to individualize drug use and carefully monitor electrolytes. Symptomatic HF patients (New York Heart Association class III-IV) should be prescribed the lowest dose of diuretic necessary to maintain euvolemia. Mild hypokalemia may be corrected by the use of aldosterone receptor antagonists such as spironolactone or eplerenone. However, a more severe hypokalemia should preferably be corrected using K(+) supplement. Serum K levels should be frequently checked and maintained between 4.0 and 5.5 mEq/l (mmol/l).
High-mobility group box 1 (HMGB1) acts as an early mediator of inflammation and organ damage in hepatic ischemia-reperfusion (I/R) injury. Glycyrrhizin is a natural anti-inflammatory and antiviral triterpene in clinical use. The purpose of this study was to investigate the effect of glycyrrhizin on liver injury caused by I/R and production of HMGB1 by Kupffer cells in rats. In the first test period, rats were given saline or glycyrrhizin 20 min before segmental hepatic warm I/R. Serum alanine aminotransferase and HMGB1 levels and hepatic histopathological findings were evaluated after I/R. Furthermore, expression of HMGB1 in the liver was assessed by immunohistochemical staining after I/R. Kupffer cells were isolated by collagenase digestion and differential centrifugation, and production of HMGB1 was assessed. In another set of experiments, the effect of inhibition of Kupffer cells by injection of liposome-entrapped dichloromethylene diphosphonate (lipo-MDP) on liver injury and expression of HMGB1 were investigated after I/R. Liver injury was prevented in the glycyrrhizin group compared with the control group. Furthermore, serum HMGB1 levels were also significantly blunted in the glycyrrhizin group compared with the control group. Cells expressing HMGB1 were detected in the hepatic sinusoid by immunohistochemistry and recognized morphologically as Kupffer cells. Furthermore, the expression of HMGB1 was reduced in the glycyrrhizin group compared with the control group. Production of HMGB1 was reduced in Kupffer cells isolated from the glycyrrhizin group compared with the control group. It is noteworthy that treatment with lipo-MDP significantly blunted serum HMGB1 levels and prevented liver injury after I/R. These results suggest that glycyrrhizin has the therapeutic potential to prevent warm I/R-induced injury during hepato-biliary surgery.
Triterpenes found in plants display a multitude of biological activities, including anti-tumor properties. The present study investigates the effect of 18β-glycyrrhetinic acid (GRA) a pentacyclic triterpenoid of the β-amyrin type, isolated from the root of Licorice (Glycyrrhizza glabra) on human breast cancer cells, MCF-7. GRA showed potent inhibitory effects on MCF-7 proliferation in a concentration- and time-dependent manner without affecting immortalized normal mammary epithelial cell line (MCF-10A). Growth inhibition of MCF-7 cells by GRA occurred through apoptosis, as evident from phosphatidyl serine externalization and DNA fragmentation. Apoptosis was primarily mediated through mitochondrial death cascade as evidenced by loss of mitochondrial membrane potential, release of cytochrome c and activation of caspase-9. GRA induced an increase in Bax:Bcl-2 ratio along with a significant increase in the protein level of the BH3 protein Bim. SiRNA-mediated knock down of Bim markedly attenuated GRA-mediated apoptosis. Profiling of transcriptional regulators of Bim revealed a role of Forkhead box O 3a transcription factor (FOXO3a) as judged by increased expression and nuclear translocation of FOXO3a. Silencing of FOXO3a resulted in marked attenuation in the expression of Bim as well as protection against GRA-mediated apoptosis. Furthermore, GRA-induced activation and nuclear localization of FOXO3a was associated with a reduced activity of Akt kinase. These results suggest that GRA induces apoptosis in human breast carcinoma MCF-7 cells via caspase activation and modulation of Akt/FOXO3a pathway.
Many flavonoids extracted from nature plants have been reported to exert antidepressant-like effect in animal studies. The present study was designed to observe the effects of liquiritin, a flavone compound derived from Glycyrrhiza uralensis, on the behaviors of chronic variable stress induced depression model rats and to explore the possible association between its antidepressant-like effect and antioxidative activity by measuring erythrocyte superoxide dismutase (SOD) activity and plasma malondialdehyde (MDA) level of the experimental animals. With the exposure to stressor once daily for consecutive 5 weeks, liquiritin and a positive control drug fluoxetine were administered via gastric intubation to rats once daily for consecutive 3 weeks from the 3rd week. The results showed that CVS reduced open-field activity and sucrose consumption significantly, but increased immobility time in forced swimming test. Treatment of liquiritin could effectively reverse alteration in immobility time and sucrose consumption but did not show significant effect on open-field activity. Moreover, liquiritin could increase SOD activity, inhibit lipid peroxidation, and lessen production of MDA, while fluoxetine did not. In conclusion, the present study demonstrated a potential antidepressant-like effect of liquiritin treatment on chronic variable stress induced depression model rats, which might be related to defense of liquiritin against oxidative stress.
(R)-4-(3,4-Dihydro-8,8-dimethyl)-2H,8H-benzo[1,2-b:3,4-b']dipyran-3yl)-1,3-benzenediol (glabridin), a flavonoid present in licorice extract, is known to have antimicrobial, anti-inflammatory, and cardiovascular protective activities. In the present study, we report the inhibitory effect of glabridin on nitric oxide (NO) production and inducible nitric oxide (iNOS) gene expression in murine macrophages. Glabridin attenuated lipopolysaccharide (LPS)-induced NO production in isolated mouse peritoneal macrophages and RAW 264.7 cells, a mouse macrophage-like cell line. Moreover, iNOS mRNA expression was also blocked by glabridin treatment in LPS-stimulated RAW 264.7 cells. Further study demonstrated that the LPS-induced nuclear factor (NF)-kappaB/Rel DNA binding activity and NF-kappaB/Rel-dependent reporter gene activity were significantly inhibited by glabridin in RAW 264.7 cells and that this effect was mediated through the inhibition of inhibitory factor-kappaB degradation and p65 nuclear translocation. Moreover, reactive oxygen species generation was also suppressed by glabridin treatment in RAW 264.7 cells. In contrast, the activity of mitogen-activated protein kinases was unaffected by glabridin treatment. In animal model, in vivo administration of glabridin increased the rate of survival of LPS-treated mice and inhibited LPS-induced increase in plasma concentrations of nitrite/nitrate and tumor necrosis factor-alpha. Collectively, these data suggest that glabridin inhibits NO production and iNOS gene expression by blocking NF-kappaB/Rel activation and that this effect was mediated, at least in part, by inhibiting reactive oxygen species generation. Furthermore, in vivo anti-inflammatory effect of glabridin suggests a possible therapeutic application of this agent in inflammatory diseases.
A review is made of the literature describing the structural changes to glycyrrhetic, oleanolic and ursolic acids and their influence on anti-ulcer activity. For the glycyrrhetic acid derivatives some analogues were prepared in which the ketonic group in position 11 was removed and the carboxylic function at position 30 was either intact, reduced to alcohol or transformed into ketone. This first series of compounds suggests the possibility of obtaining compounds devoid of the conjugated ketonic group, maintaining anti-ulcer activity but with reduced or lacking mineralocorticoid activity. Based on these findings, a series of carbenoxolone analogues in the beta-amyrin series of glycyrrhetic and oleanolic acid was prepared. In particular, the delta 9,11 unsaturated compounds 14b and 23b and the 11-methylene derivative 18 present advantages in terms of acute toxicity and mineralocorticoid activity as compared to the reference compound. The derivative 14b in the volunteer showed an increase of gastric PGE2 levels with minor pseudoaldosteronic effect. Among the ursolic acid derivatives, the dihemisuccinate sodium salt 35b demonstrated a good separation between anti-ulcer and mineralocorticoid activities. Nevertheless, kidney and liver toxicity was observed in the monkey thus jeopardizing its further development. Better results were obtained with the uvaol dihemiphthalate sodium salt and the diene analogue 39b. In particular, 38b and 39b showed a potent anti-ulcer activity, 3- to 25-fold higher than carbenoxolone. Furthermore, compound 38b does not show signs of liver toxicity in the monkey.
Twenty six 18β-glycyrrhetinic acid (GA) (1) derivatives 2-27 including twelve new GA derivatives 10, 11, 13-17, 21-25 were synthesized and evaluated for cytotoxicities against NTUB1 cells (human bladder cancer cell lines). seco-Compounds 9, 25, and 27 are the most potent compounds of this series, inhibiting cell growth of human NTUB1 cells with an IC(50) values of 2.34 ± 0.28, 4.76 ± 1.15, and 3.31 ± 0.61 μM, respectively. Exposure of NTUB1 to 25 for 24h significantly increased the production of reactive oxygen species (ROS). Flow cytometric analysis exhibited that treatment of NTUB1 with 25 did not induce cell cycle arrest but accompanied by an increase of apoptotic cell death in a dose-dependant manner after 24h. Mitochondrial membrane potential (MMP) decreased significantly in a dose-dependant manner when the NTUB1 cells were exposed to 25 for 24h. Marked collapse of the MMP suggested that dysfunction of the mitochondria may be involved in the oxidative burst and apoptosis induced by 25. Western blot analysis shows that NTUB1 cells treated with 25 increased the level of p-p53 in a dose-dependant manner. Further, NAC treatment prevented p53 phosphorylation stimulated by 25. These results suggested that 25 induced a mitochondrial-mediated apoptosis in NTUB1 cells through activation of p53, which are mainly mediated ROS generated by 25.
Gap junction provides intercellular communications that play a critical role in invasion of metastatic cancer cells. However, the effects of inhibiting this pathway in breast cancer cell migration have not been investigated. Here, we present data demonstrating that functional blockade of gap junctions during the formation of monolayer decreased the levels of aligned fibers of actin between neighboring breast cancer cells. Furthermore, gap junction inhibitors attenuated the invasion ability of highly metastatic MDA-MB-231 cells, but had no significant effects on less invasive MCF-7 cells, which caused by shRANKL. Our work is the first to demonstrate the inhibitory effect of gap junction channel inhibitors on the migration of highly invasive breast cancer cells.