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Breast cancer ranks as the most widespread malignant condition in women, emerging as a primary contributor to mortality. The primary challenges in cancer treatments involve undesirable side effects. Therefore, exploring natural compounds as additional therapy could provide valuable insights. Isoliquiritigenin (ILN), an isoflavonoid featuring a chalcone moiety primarily sourced from Glycyrrhiza species, has garnered increasing interest in breast cancer research. This review aims to provide a comprehensive understanding of ILN's mechanisms of action in breast cancer, drawing from a range of in vitro and in vivo studies. ILN primarily acts by inhibiting angiogenesis, aromatase, inflammation, and cell proliferation, and preventing invasion and metastasis. Mechanistically, it downregulates miR-374a, phosphoinositide-3-kinase–protein kinase B/Akt, maternal embryonic leucine zipper kinase, vascular endothelial growth factor, and estrogen receptor protein levels, and causes enhancement of Wnt inhibitory factor-1, and Unc-51-like kinase 1 expression to treat breast cancer. ILN emerges as a promising natural option, offering therapeutic advantages with minimal side effects. However, it is important to note that current research on ILN is primarily limited to preclinical models, underscoring the need for further investigation to validate its potential efficacy. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world. New non-invasive diagnostic tools are needed to promptly treat this disease and avoid its complications. This study aimed to find key metabolites and related variables that could be used to predict and diagnose NAFLD. Ninety-eight subjects with NAFLD and 45 controls from the Fatty Liver in Obesity (FLiO) Study (NCT03183193) were analyzed. NAFLD was diagnosed and graded by ultrasound and classified into two groups: 0 (controls) and ≥ 1 (NAFLD). Hepatic status was additionally assessed through magnetic resonance imaging (MRI), elastography, and determination of transaminases. Anthropometry, body composition (DXA), biochemical parameters, and lifestyle factors were evaluated as well. Non-targeted metabolomics of serum was performed with high-performance liquid chromatography coupled to time-of-flight mass spectrometry (HPLC-TOF-MS). Isoliquiritigenin (ISO) had the strongest association with NAFLD out of the determinant metabolites. Individuals with higher concentrations of ISO had healthier metabolic and hepatic status and were less likely to have NAFLD (OR 0.13). Receiver operating characteristic (ROC) curves demonstrated the predictive power of ISO in panel combination with other NAFLD and IR-related variables, such as visceral adipose tissue (VAT) (AUROC 0.972), adiponectin (AUROC 0.917), plasmatic glucose (AUROC 0.817), and CK18-M30 (AUROC 0.810). Individuals with lower levels of ISO have from 71 to 82% more risk of presenting NAFLD compared to individuals with higher levels. Metabolites such as ISO, in combination with visceral adipose tissue, IR, and related markers, constitute a potential non-invasive tool to predict and diagnose NAFLD. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a serious and complex metabolic disorder characterized by hyperglycemia. In recent years natural products has gained much more interest by researchers as alternative sources for diabetes treatment. Though many potential agents are identified so far but their clinical utility is limited because of their adverse effects. Therefore, there is a keen interest in discovering natural compounds to treat diabetes efficiently with less side effects. Dalbergia latifolia is well explored because of its diverse pharmacological activities including diabetes. Therefore, the present research work aimed to identify and isolate the potential antidiabetic agents from the heart wood of Dalbergia latifolia. We successfully extracted DGN and ISG from the heartwood and evaluated their antidiabetic potential both in-vivo and in-vitro. Alpha amylase activity inhibition of ISG and DGN was found to be 99.05 ± 8.54% (IC50 = 0.6025 µg/mL) and 84.68 ± 5.2% (IC50 = 0.0216 µg/mL) respectively. Glucose uptake assay revealed DGN (158%) promoted maximum uptake than ISG (77%) over control. In vivo anti diabetic activity was evaluated by inducing diabetes in SD rats with the help of HFD and STZ (35 mg/kg body weight). After the continuous administration of DGN (5 mg/kg, 10 mg/kg) and ISG (5 mg/kg, 10 mg/kg) for 14 days, we observed the reduction in the blood glucose levels, body weight, total cholesterol, low density lipoprotein, very low-density lipoprotein, blood urea, serum creatinine, serum glutamate oxaloacetic transaminase, serum glutamate pyruvate transaminase and alkaline phosphatase levels than vehicle group indicates the potency of ISG and DGN against diabetes. [ABSTRACT FROM AUTHOR]

Main conclusion: Two glycosyltransferase genes belonging to UGT88 family were identified to have 6ʹ-deoxychalcone 4ʹ-glucosyltransferase activity in dahlia. 6ʹ-Deoxychalcones (isoliquiritigenin and butein) are important pigments for yellow and orange to red flower color. 6ʹ-Deoxychalcones are glucosylated at the 4ʹ-position in vivo, but the genes encoding 6ʹ-deoxychalcone 4ʹ-glucosyltransferase have not yet been identified. In our previous study, it was indicated that snapdragon (Antirrhinum majus) chalcone 4ʹ-O-glucosyltransferase (Am4ʹCGT) has isoliquiritigenin 4ʹ-glucosylation activity. Therefore, to identify genes encoding 6ʹ-deoxychalcone 4ʹ-glucosyltransferase in dahlia (Dahlia variabilis), genes expressed in ray florets that shared high homology with Am4ʹCGT were explored. As a result, c34671_g1_i1 and c35662_g1_i1 were selected as candidate genes for 6ʹ-deoxychalcone 4ʹ-glucosyltransferases in dahlia. We conducted transient co-overexpression of three genes (c34671_g1_i1 or c35662_g1_i1, dahlia aldo-keto reductase1 (DvAKR1) or soybean (Glycine max) chalcone reductase5 (GmCHR5), and chili pepper (Capsicum annuum) MYB transcription factor (CaMYBA)) in Nicotiana benthamiana by agroinfiltration. Transient overexpression of c34671_g1_i1, DvAKR1, and CaMYBA resulted in increase in the accumulation of isoliquiritigenin 4ʹ-glucosides, isoliquiritigenin 4ʹ-O-glucoside, and isoliquiritigenin 4ʹ-O-[6-O-(malonyl)-glucoside]. However, transient overexpression of c35662_g1_i1, DvAKR1, and CaMYBA did not increase accumulation of isoliquiritigenin 4ʹ-glucosides. Using GmCHR5 instead of DvAKR1 showed similar results suggesting that c34671_g1_i1 has isoliquiritigenin 4ʹ-glucosyltransferase activity. In addition, we conducted co-overexpression of four genes (c34671_g1_i1, c35662_g1_i1 or Am4ʹCGT, DvAKR1 or GmCHR5, CaMYBA, and chalcone 3-hydroxylase from dahlia). Accumulation of butein 4ʹ-O-glucoside and butein 4ʹ-O-[6-O-(malonyl)-glucoside] was detected for c35662_g1_i1, suggesting that c35662_g1_i1 has butein 4ʹ-glucosyltransferase activity. Recombinant enzyme analysis also supported butein 4ʹ-glucosyltransferases activity of c35662_g1_i1. Therefore, our results suggested that both c34671_g1_i1 and c35662_g1_i1 are 6ʹ-deoxychalcone 4ʹ-glucosyltransferases but with different substrate preference. [ABSTRACT FROM AUTHOR]

To investigate the effect of isoliquiritigenin (ISL) on high glucose (HG)-induced glomerular mesangial cells (GMCs) proliferation, extracellular matrix (ECM) deposition and inflammation, and the underlying mechanisms. Mouse GMCs (SV40-MES-13) were cultured in HG medium, with or without ISL. The proliferation of GMCs was determined by MTT assay. The production of proinflammatory cytokines was detected by qRT-PCR and ELISA. The expression of connective tissue growth factor (CTGF), TGF-β1, collagen IV, and fibronectin was measured by qRT-PCR and western blot. The phosphorylation of JAK2 and STAT3 was examined by western blot. Next, JAK2 inhibitor AG490 was applied to HG-exposed GMCs. The levels of JAK2/STAT3 phosphorylation and pro-fibrotic markers were analyzed by western blot, and the secretion of TNF-α and IL-1β was evaluated by ELISA. GMCs were treated with HG, HG plus ISL or HG plus ISL, and recombinant IL-6 (rIL-6) which is a JAK2 activator. The levels of JAK2/STAT3 activation, ECM formation, and proinflammatory cytokines secretion were determined by western blot and ELISA, respectively. In mouse GMCs, ISL successfully repressed HG-induced hyperproliferation; production of TNF-α and IL-1β; expression of CTGF, TGF-β1, collagen IV, and fibronectin; and activation of JAK2/STAT3. Similar to ISL, AG490 was able to reverse the inflammation and ECM generation caused by HG. Moreover, rIL-6 impeded the amelioration of ISL on HG-induced adverse effects. Our study demonstrated that ISL displayed preventive effects on HG-exposed GMCs through inhibiting JAK2/STAT3 pathway and provided an insight into the application of ISL for diabetic nephropathy (DN) treatment. [ABSTRACT FROM AUTHOR]

To investigate the protective efficacy of ultrasound targeted microbubble destruction (UTMD) combined with Isoliquiritigenin on myocardial injury in rats. The GK rat model of cardiomyopathy was successfully established by the induction of adriamycin. Then these rats with cardiomyopathy were randomly assigned into the model group, isoliquiritigenin microbubbles and ultrasound alone or combination group, using healthy ones as normal control. After 8-week consecutive treatment, the relevance indexes of diabetes, echocardiography as well as the hyperlipidemia, oxidative stress of model animals were examined. In addition, the fibrosis, morphological changes and inflammation response of myocardial tissues were also assessed. After further 4-week intervention, the blood biochemical indexes and the cardiac functions of model rats received the combined treatment were improved (all P < 0.05) compare to those received either monotherapy or saline. After chronic treatment, the heart/body weight ratio and serum cardiac index levels in model rats received combined treatment were significantly changed (all P < 0.05) compared with others. Furthermore, combination therapy could ameliorate excessive oxidation stress and inflammation response as well as up-regulate the expression levels of AMPK/SIRT1/eNOS signaling pathway. Targeted delivery of isoliquiritigenin by ultrasonic microbubbles can ameliorate the myocardial injury via activating AMPK/SIRT1/eNOS signaling pathways. [ABSTRACT FROM AUTHOR]

In recent years, research on the antioxidant activity of natural antioxidants has become more and more popular. Polyphenols are a large number of natural antioxidants in plants. This paper selected three common polyphenols to study their antioxidant activity based on quantum chemistry theory. This experiment hopes to provide a theoretical basis for the further development of polyphenol health food with strong antioxidant activity. Three polyphenols resveratrol, liquiritigenin, and isoliquiritigenin were optimized at the level of B3lyp/6-311G (d, p), and the single point energy was calculated with B3lyp/6–311 + + G (2d, 2p). The phenol hydroxyl bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE) were calculated in different phase states study the antioxidant mechanism. Draw the frontier molecular orbital and conduct dynamic simulation analysis scavenging · OH and · OOH to explore the most possible active sites in different phenolic hydroxyl sites. The bond length, dihedral angle, BDE, IP, PDE, PA and ETE were compared to speculate the antioxidant activity: Resveratrol > isoliquiritigenin > liquiritigenin. By analyzing the frontier molecular orbital and dynamic simulation results, it is speculated that the phenolic hydroxyl groups at C4', C4', and C4 are the most likely active sites of resveratrol, liquiritigenin, and isoliquiritigenin, respectively. In different phase states, the three compounds showed the same antioxidant activity, and the phenolic hydroxyl activities of the three compounds were different at different sites. [ABSTRACT FROM AUTHOR]

Liquiritigenin (LTG) and its bioprecursor isoliquiritigenin(ISL), the main bioactives from roots of Glycyrrhiza genus are progressively documented as a potential pharmacological agent for the management of chronic diseases. The aim of this study was to evaluate the pharmacological potential of liquiritigenin, isoliquiritigenin rich extract of Glycyrrhiza glabra roots (IVT-21) against the production of pro-inflammatory cytokines from activated macrophages as well as further validated the efficacy in collagen-induced arthritis model in rats. We also performed the safety profile of IVT-21 using standard in-vitro and in-vivo assays. Results of this study revealed that the treatment of IVT-21 and its major bioactives (LTG, ISL) was able to reduce the production of pro-inflammatory cytokines (TNF-α, IL-6) in LPS-activated primary peritoneal macrophages in a dose-dependent manner compared with vehicle-alone treated cells without any cytotoxic effect on macrophages. In-vivo efficacy profile against collagen-induced arthritis in Rats revealed that oral administration of IVT-21 significantly reduced the arthritis index, arthritis score, inflammatory mediators level in serum. IVT-21 oral treatment is also able to reduce the NFкB-p65 expression as evidence of immunohistochemistry in knee joint tissue and mRNA level of pro-inflammatory cytokines in paw tissue in a dose-dependent manner when compared with vehicle treated rats. Acute oral toxicity profile of IVT-21 demonstrated that it is safe up to 2000 mg/kg body weight in experimental mice. This result suggests the suitability of IVT-21 for further study in the management of arthritis and related complications. [ABSTRACT FROM AUTHOR]

Main conclusion: A novel gene belonging to the aldo–keto reductase 13 family is involved in isoliquiritigenin biosynthesis in dahlia. The yellow pigments of dahlia flowers are derived from 6′-deoxychalcones, which are synthesized via a two-step process, involving the conversion of 3-malonyl-CoA and 4-coumaloyl-CoA into isoliquiritigenin in the first step, and the subsequent generation of butein from isoliquiritigenin. The first step reaction is catalyzed by chalcone synthase (CHS) and aldo–keto reductase (AKR). AKR has been implicated in the isoflavone biosynthesis in legumes, however, isolation of butein biosynthesis related AKR members are yet to be reported. A comparative RNA-seq analysis between two dahlia cultivars, 'Shukuhai' and its butein-deficient lateral mutant 'Rinka', was used in this study to identify a novel AKR gene involved in 6'-deoxychalcone biosynthesis. DvAKR1 encoded a AKR 13 sub-family protein with significant differential expression levels, and was phylogenetically distinct from the chalcone reductases, which belongs to the AKR 4A sub-family in legumes. DNA sequence variation and expression profiles of DvAKR1 gene were correlated with 6′-deoxychalcone accumulation in the tested dahlia cultivars. A single over-expression analysis of DvAKR1 was not sufficient to initiate the accumulation of isoliquiritigenin in tobacco, in contrast, its co-overexpression with a chalcone 4′-O-glucosyltransferase (Am4′CGT) from Antirrhinum majus and a MYB transcription factor, CaMYBA from Capsicum annuum successfully induced isoliquiritigenin accumulation. In addition, DvAKR1 homologous gene expression was detected in Coreopsideae species accumulating 6′-deoxychalcone, but not in Asteraceae species lacking 6′-deoxychalcone production. These results not only demonstrate the involvement of DvAKR1 in the biosynthesis of 6'-deoxychalcone in dahlia, but also show that 6′-deoxychalcone occurrence in Coreopsideae species developed evolutionarily independent from legume species. [ABSTRACT FROM AUTHOR]

Isoliquiritigenin (ISL) is a type of flavonoid, derived from the root of the legume plant Glycyrrhiza, that has multiple pharmacological properties. However, its role in cardiac remodeling induced by pressure overload has yet to be fully elucidated. Aortic banding (AB) surgery was used to establish a cardiac hypertrophy model in male C57BL/6 mice. Mice were randomly divided into four groups (n = 20 per group) as follows: Sham + vehicle, sham + ISL, AB + vehicle and AB + ISL. ISL was administered to the mice intragastrically for 1 week after the operation. To evaluate the role of ISL in mice challenged with AB, echocardiography, histological analysis and molecular biochemistry examinations were performed. ISL treatment decreased cardiac hypertrophy and improved cardiac dysfunction induced by pressure overload. In addition, ISL decreased the cross-sectional area of cardiomyocytes. Furthermore, ISL reversed the AB-mediated increase in phosphorylated (p-)mTOR and p-ERK protein levels and further increased the protein expression of p-AMP-activated protein kinase (AMPK)α in response to AB, whereas knockout of AMPKα abolished the protective effects of ISL. The present study suggested that ISL could suppress pressure overload-induced cardiac hypertrophy through the activation of AMPKα. Therefore, ISL may serve as a therapeutic target for cardiac remodeling. [ABSTRACT FROM AUTHOR]

Glycyrrhiza extract has been used for the treatment of oral and gastric ulcers, but the analgesic mechanism remains unknown. In the present study, we investigated the effects of isoliquiritigenin, an active ingredient of Glycyrrhiza, on Nav channels in vitro and nociceptive behaviors in vivo. In an autopatch-clamp study, isoliquiritigenin inhibited the currents of Nav1.1, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 in a channel expression system. In small- and medium-sized cultured trigeminal ganglion neurons, the compound suppressed Nav currents in many neurons (78%) and Kv currents in all neurons, dose-dependently. In current-clamp mode, isoliquiritigenin blocked action potential generation in many neurons (64%), but it conversely accelerated action potential generation in the remaining neurons. The opposing effects on action potentials were reproduced in a computational simulation of a modified Hodgkin-Huxley-based model, based on the electrophysiological data. In behavioral experiments, local treatment with isoliquiritigenin suppressed nociceptive behaviors in response to oral ulcer development or nociceptive TRP channel agonists in the oral mucosa and hind paw. These results suggest that isoliquiritigenin exerts an analgesic effect predominantly via inhibitory action on Nav channels on sensory nociceptive fibers. This pharmacological mechanism indicates that isoliquiritigenin is useful for pain relief and provides scientific evidence for Glycyrrhiza at the ingredient level. [ABSTRACT FROM AUTHOR]

Excessive microglial cell activation in the brain can lead to the production of various neurotoxic factors (e.g., pro-inflammatory cytokines, nitric oxide) which can, in turn, initiate neurodegenerative processes. Recent research has been reported that mitochondrial dynamics regulate the inflammatory response of lipopolysaccharide (LPS). Isoliquiritigenin (ISL) is a compound found in Glycyrrhizae radix with anti-inflammatory and antioxidant properties. In this study, we investigated the function of ISL on the LPS-induced pro-inflammatory response in BV-2 microglial cells. We showed that ISL reduced the LPS-induced increase in pro-inflammatory mediators (e.g., nitric oxide and pro-inflammatory cytokines) via the inhibition of ERK/p38/NF-κB activation and the generation of reactive oxygen species (ROS). Furthermore, ISL inhibited the excessive mitochondrial fission induced by LPS, regulating mitochondrial ROS generation and pro-inflammatory response by suppressing the calcium/calcineurin pathway to dephosphorylate Drp1 at the serine 637 residue. Interestingly, the ISL pretreatment reduced the number of apoptotic cells and levels of cleaved caspase3/PARP, compared to LPS-treated cells. Our findings suggested that ISL ameliorated the pro-inflammatory response of microglia by inhibiting dephosphorylation of Drp1 (Ser637)-dependent mitochondrial fission. This study provides the first evidence for the effects of ISL against LPS-induced inflammatory response related and its link to mitochondrial fission and the calcium/calcineurin pathway. Consequently, we also identified the protective effects of ISL against LPS-induced microglial apoptosis, highlighting the pharmacological role of ISL in microglial inflammation-mediated neurodegeneration. [ABSTRACT FROM AUTHOR]

A large body of research has demonstrated a synergistic anticancer effect between docosahexaenoic acid (DHA) and standard chemotherapy regimens against colorectal cancer (CRC). In this study, we investigated the chemotherapeutic potential of cotreatment with DHA and isoliquiritigenin (ISL) against CRC HCT-116 cells. Apoptosis was confirmed by Annexin V/PI staining and expression of apoptosis-associated proteins. The synergistic effect of DHA and ISL combination on apoptosis was detected using combination index approaches. Flow cytometry was carried out using fluorescent probes to measure the production of reactive oxygen species (ROS). DHA and ISL in combination synergistically enhanced the decrease in cell viability versus the compounds used alone. Moreover, we demonstrated that the synergistic anti-CRC activity of cotreatment with these two compounds was achieved by inducing the apoptosis caspase-dependently mediated through augmented ROS generation followed by increased Fas ligand mRNA expression and cytochrome c release. Our data also demonstrated that cotreating with DHA and ISL strongly upregulated the phosphorylation of ERK and JNK, which are functionally associated with ROS induced by the two compounds in combination. Interestingly, further study revealed that inhibiting ERK phosphorylation strongly enhanced Fas ligand mRNA expression and the combination of the two compounds induced stronger cytotoxicity, whereas inhibiting JNK phosphorylation significantly reduced the apoptotic signals mediated by cotreatment with these two compounds. Excessive ROS-induced JNK activation and cytochrome c release from mitochondria played a key role in the synergistic anticancer activity of CRC cells by cotreating with DHA and ISL. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus that leads to significant vision loss. Isoliquiritigenin (ISL) is a bioactive flavonoid found in the root of licorice with reported anti-oxidant and anti-inflammatory activities. In the present study, we evaluated the effect of ISL administration on diabetes-induced retinal injury. Diabetes was induced in male Sprague-Dawley rats using single intraperitoneal streptozotocin (STZ, 50 mg/kg) injection. Diabetic rats showed up-regulated retinal miR-195, reduced retinal levels of SIRT-1, and increased levels of oxidative stress, nuclear factor-κB (NF-κB), inflammatory cytokines, and endothelin-1. Moreover, histopathological and electron microscopy studies revealed distorted retinal layers and reduced number of ganglion cells. Oral administration of ISL (20 mg/kg/day) to diabetic rats for 8 weeks improved diabetes-induced retinal injury via down-regulation of miR-195, restoration of retinal SIRT-1 level, attenuation of oxidative stress, inflammation, and endothelial damage as well as preservation of retinal normal histology and ultrastructure. In conclusion, our results showed that ISL could be a promising therapeutic intervention to prevent the development and progression of DR. It also suggested that the miR-195/SIRT-1/NF-κB pathway may contribute to ISL treatment–induced beneficial effects. [ABSTRACT FROM AUTHOR]

Epileptogenesis is a complex pathological process that occurs after an initial brain injury and involves a series of molecular events. Isoliquiritigenin (ISL), a flavonoid in licorice, is reported to have anti-inflammatory and antioxidant effects in various experimental models, but its specific roles and molecular mechanisms in the epileptogenic process following kainic acid (KA) treatment remain unclear. The purpose of this study was to explore the effects of ISL pretreatment in KA-induced epileptic rats and the underlying mechanisms. Our findings show that ISL pretreatment significantly attenuated the KA-induced expression of ionized calcium‐binding adapter molecule 1 (IBα1)-labeled microglia (F(3, 20) = 97.29, p < 0.01, ηp2 = 0.94) and glial fibrillary acidic protein (GFAP)-positive astrocytes (F(3, 20) = 72.48, p < 0.01, ηp2 = 0.92), and the release of inflammatory mediators, such as TNF-α (F(3, 20) = 133.14, p < 0.01, ηp2 = 0.95), IL-1β, and C–C motif chemokine ligand 3 (CCL3). ISL pretreatment given before KA also significantly prevented apoptotic neuronal injury by upregulating the activities of superoxide dismutase and glutathione peroxidase. It also significantly suppressed the protein levels of Toll-like receptor 4 (TLR4) (F(3, 20) = 63.23, p < 0.01, ηp2 = 0.91) and its downstream molecules, myeloid differentiation primary response 88 (MYD88), phosphorylated (p-)IκBα, and p-NF-κB. Blocking TLR4/MYD88 signaling also attenuated KA-induced neuroinflammation and neuronal damage in the hippocampus. Overall, our study demonstrates that ISL pretreatment plays neuroprotective and anti-inflammatory roles in KA-induced epileptogenesis, which may be mediated by the TLR4/MYD88 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The study was conducted to scrutinize the outcome of isoliquiritigenin (ISL) against cerebral injury in septic mice. Methods: The sepsis was introduced using cecal ligation and puncture (CLP) method in experimental mice. The effect of ISL was quantified using the content of brain water and blood brain barrier (BBB) permeability. The effect on the levels of myeloperoxidase (MPO), superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) in brain homogenates was also determined. The effect of ISL on the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in serum was also estimated. The levels of various inflammatory biomarkers (COX-2 and PGE2) were also studied. The expression of NF-κB signalling cascade and inducible nitric oxide synthase (iNOS) was estimated by Western blot. Results: Compared with CLP group, the brain water content was found to be reduced significantly together with the enhanced BBB integrity in ISL treated group. The level of MDA was reduced together with enhanced level of SOD and GSH in the ISL treated group. The levels of TNF-α, IL-1β, and IL-6 were also found to be modulated in ISL group. The level of COX-2 and PGE2 was reduced to near normal after ISL administration together with increase in the IκBα expression and reduction of p65 and p-p65 expression in a concentration-dependent manner. The expression of iNOS was also found to be reduced in ISL group. Conclusion: These results demonstrate that ISL causes protection of CLP-induced sepsis in experimental mice via multiple pathways. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a serious public health and medical problem worldwide. Oxidative stress plays a vital role in the pathogenesis of TBI. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important factor in the cellular defense against oxidative stress, is activated following TBI. In this study, the protective effects of Isoliquiritigenin (ILG), a promising antioxidant stress drug, was evaluated as a protective agent against TBI. In a mouse model of controlled cortical impact Injury, we found that the ILG administration reduced the Garcia neuroscore, injury histopathology, brain water content, cerebral vascular permeability, the expression of cleaved caspase3, aquaporin-4, glial fibrillary acidic protein and the increased the expression of neurofilament light chain protein, indicating the protective effects against TBI in vivo. ILG treatment after TBI also restored the oxidative stress and promoted the Nrf2 protein transfer from the cytoplasm to the nucleus. We then used Nrf2−/− mice to test the protective effect of Nrf2 during ILG treatment of TBI. Our findings indicated that Nrf2−/− mice had greater brain injury and oxidative stress than wild-type (WT) mice and ILG was less effective at inhibiting oxidative stress and repairing the brain injury than in the WT mice. In vitro studies in SY5Y cells under oxygen glucose deprivation/re-oxygenation stimulation yielded results that were consistent with those obtained in vivo showing that ILG promotes Nrf2 protein transfer from the cytoplasm to the nucleus. Taken together, our findings demonstrate that Nrf2 is an important protective factor against TBI-induced injuries, which indicates that the protective effects of ILG are mediated by inhibiting oxidative stress after TBI via a mechanism that involves the promotion of Nrf2 protein transfer from the cytoplasm to the nucleus. [ABSTRACT FROM AUTHOR]

Isoliquiritigenin (ILG), a major ingredient of licorice, has been reported to have anti-oxidative and anti-inflammatory effects. The aim of this study was to investigate the protective effects of ILG on lung injury using an animal model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Male BALB/c mice were conditioned with ILG 1 h before intranasal instillation of LPS. The effects of ILG on lung injury were assessed by measuring lung histopathological examination, MPO assay, wet/dry (W/D) ratio, and inflammatory cytokine production. The results showed that ILG significantly inhibited LPS-induced lung histopathological changes and the MPO activity. Meanwhile, it attenuated the wet/dry (W/D) ratio in the lung tissues. The results also indicated that ILG inhibited LPS-induced ALI in the expression of inflammatory cytokines in the BALF. Furthermore, ILG can decrease the activity of NF-κB and can increase the expression of PPAR-γ. These findings suggested that ILG inhibited the inflammatory of LPS-induced lung injury by activating PPAR-γ and inhibiting NF-κB activation. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized with high heterogeneity. Recent studies have suggested that it is driven by both terminal keratinocyte differentiation defects and type 2 immune responses. The mainstay steroid topical therapy has severe side effect and new treatment is in demand. Isoliquiritigenin (ISLG) is a small phenolic bioactive molecule from licorice that has shown multiple pharmacological effects against cancer, inflammatory disorder, and cardiovascular diseases. ISLG was evaluated in AD-like lesion model induced by the repetitive application of 2,4-dinitrochlorobenzene (DNCB) in BALB/c mice. Overall symptom score, serological and molecular changes of the skin lesions were evaluated. ISLG could ameliorate the overall manifestation of AD-like symptoms including scratching behavior incidence and skin lesion severity. At blood level, ISLG significantly suppressed the DNCB-induced IgE and Th2 cytokines up-regulation. At skin lesion site, ISLG also inhibited DNCB-induced pro-inflammatory cytokines like TNF-α, IL-6 as well as IL-4 expressions. In a human monocyte model THP-1, ISLG suppressed the up-regulation of CD86 and CD54 and abolished the DNCB-induced p38-α and ERK activation, suggesting a molecular mechanism for ISLG therapy. This study indicated that ISLG could be a potential therapeutic agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

Isoliquiritigenin (ISL) has been reported to have a wide range of biological activities. This study evaluated the cytotoxic effect of ISL on norvegicus pheochromocytoma cell line (PC-12 cells) and its possible molecular mechanism. The cytotoxicity in vitro of ISL against PC-12 cells was investigated by MTT assay. The migration and invasion of PC-12 cells were performed by scratch test and transwell assay. Apoptosis was evaluated by microscopy and flow cytometry. The reactive oxygen species (ROS) and mitochondrial membrane potential were studied by fluorescent microscopy. DNA damage of PC-12 cells was analyzed by comet assay. The protein expression of caspase, Bcl-2 family member, autophagy-associated protein Beclin-1, and LC3 was detected by western blot. The autophagy of PC-12 cells was investigated by acridine orange (AO) and monodansylcadaverine (MDC) staining. The IC value of ISL against PC-12 cell is 17.8 ± 1.8 μM. ISL could suppress PC-12 cell migration and invasion. AO/ethidium bromide staining and flow cytometry suggested that ISL caused apoptosis of PC-12 cells. Significant DNA damages of PC-12 cells treated with ISL were observed in a comet assay. ISL inhibited the cell growth of PC-12 cells at S phase. Exposure of PC-12 cells to ISL increased the levels of cellular reactive oxygen species (ROS) and decreased the mitochondrial membrane potential. Additionally, ISL trigged the release of cytochrome c from the mitochondria to the cytoplasm. The expression levels of caspase-9, caspase-3, caspase-7, Bax, and Bim were upregulated, whereas the expression levels of Bcl-2 and Bcl-x were downregulated. AO and monodansylcadaverine (MDC) staining assay showed that ISL caused autophagy of PC-12 cells. The upregulation of protein Beclin-1 and LC3 was observed in PC-12 cells. Therefore, the results show that ISL induces apoptosis of PC-12 cells through ROS-mediated activation of the intrinsic mitochondria-cytochrome c-caspase protease mechanism and causes the autophagy of PC-12 cells. [ABSTRACT FROM AUTHOR]

Scavenging activities of isoliquiritigenin (ISO) and liquiritigenin (LIQ) toward hydroxyl (•OH) and hydroperoxyl (•OOH) radicals were studied using the density functional theory (DFT). Two representative reaction mechanisms, hydrogen atom transfer (HAT) and radical adduct formation (RAF), were investigated. In order to identify the scavenging activity of each active site of ISO and LIQ, the thermodynamic and kinetic parameters of all channels involved in two mechanisms were calculated in both gas and water phases. We found that RAF is the major mechanism of ISO scavenging •OH and •OOH. In the whole reaction of LIQ with •OH/•OOH, B′4-OH group in LIQ is always the most active site, meaning that HAT is the main mechanism of LIQ scavenging •OH/•OOH. For scavenging both radicals, ISO has a much higher activity than LIQ, which is probably due to the nearly planar conjugated conformation of ISO. The calculation results are valuable for designing high-activity scavengers against radicals. [ABSTRACT FROM AUTHOR]

An optimized, ceramide-based, nanostructured lipid carrier (NLC) formulation was developed for isoliquiritigenin (ILTG), and its potential as a transdermal delivery system was evaluated. ILTG-loaded NLCs were prepared by blending solid (ceramide, cholesterol) and liquid lipids (caprylic/capric triglyceride) in various proportions using a hot homogenization and ultrasonication method. The physicochemical characteristics were investigated by DLS, ZP, EE%, TEM, DSC and XRD analyses and in vitro skin permeation studies. The results showed that the particle size of the formulation was 150.19-251.69 nm with a ZP>−20mV. The EE% was 56.45-89.97%. The NLC structure was influenced by lipid ratio, and increasing the caprylic/capric triglyceride ratio caused a less ordered structure, as confirmed by DSC. The XRD analysis indicated that ILTG was not in the crystalline state in all formulations. The skin permeation study showed that the ILTG-NLCs promoted ILTG permeation. In conclusion, ceramide-based NLCs could be a promising vehicle for the ILTG transdermal delivery of ILTG. [ABSTRACT FROM AUTHOR]

Purpose: Liver is the major site of biotransformation for exogenous toxins, in having a defense system against oxidative stress as well as cytochrome P450 system. Isoliquiritigenin (isoLQ) is an active component present in Glycyrrhizae radix and has been shown to have various biological activities. This study investigated the effect of isoLQ as a liver protectant against oxidative stress, both in vivo and in vitro, and also its molecular mechanisms. Methods: We used tert-butylhydroperoxide-induced hepatocyte damage model and cadmium (Cd)-stimulated liver toxicity animal model, which are assessed by immunoblot and flow cytometry as well as plasma and histopathological parameters. Results: In HepG2 cells, pretreatment of 10 and 30 µM isoLQ significantly inhibited the induction of apoptosis and mitochondrial damage, and production of reactive oxygen species. Moreover, isoLQ induced the activation of nuclear factor erythroid 2-related factor-2 (Nrf2), as indicated by an increase in its nuclear translocation and antioxidant response element-luciferase activity. IsoLQ also induced the expression of Nrf2 target phase II enzymes, such as heme oxygenase-1, glutamate-cysteine ligase catalytic subunit and NAD(P)H:quinone oxidoreductase 1. IsoLQ also induced phosphorylation of extracellular stimuli-regulated kinase (ERK), and its activation of Nrf2 was mediated with ERK-dependent phosphorylation of Nrf2, as determined by its chemical inhibitor. In rats, oral treatment of 5 and 20 mg/kg isoLQ prevented Cd-induced acute hepatic damage, as assessed by plasma parameters and semiquantative histology, such as the modified HAI grading scores and the degenerative regions in hepatic parenchyma. Conclusion: These findings are considered as scientific evidence that isoLQ in licorice has the function of being a hepatic protectant against oxidative damages through ERK-mediated Nrf2 activation. [ABSTRACT FROM AUTHOR]

Intestinal epithelial cells play an important role in the mucosal immune reaction in inflammatory bowel diseases via the expression of inflammatory mediators, such as cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1). Isoliquiritigenin (ISL; 4,2′,4′-trihydroxychalcone) has been shown to exhibit anti-inflammatory properties in murine macrophage cells. In the present study, we evaluated the anti-inflammatory properties of ISL in intestinal epithelial cells and determined its mechanism of action. ISL suppressed the expression of COX-2 and ICAM-1 in tumor necrosis factor-α (TNF-α) stimulated intestinal epithelium HT-29 cells. It also induced peroxisome proliferator-activated receptor-γ (PPARγ) protein expression. Moreover, using a PPARγ antagonist, GW9662, we found that the regulation of COX-2 and ICAM-1 expression by ISL in TNF-α-stimulated HT-29 cells is mediated via PPARγ expression. A signal transduction study revealed that ISL significantly attenuates TNF-α-mediated JNK phosphorylation. ISL-induced ERK1/2 phosphorylation was associated with PPARγ expression. Additionally, both the inhibitory effect on COX-2 and ICAM-1 expression and the induction of PPARγ expression by ISL in TNF-α-stimulated HT-29 cells was abolished by the addition of U0126, a specific ERK1/2 inhibitor. Collectively, ISL-induced PPARγ mediated, at least partially, the suppression of intestinal inflammation. These results suggest that ISL may be beneficial for the treatment of mucosal inflammation. [ABSTRACT FROM AUTHOR]

Isoliquiritigenin (ISL) is an important flavonoid component of licorice and has been reported to possess anti-inflammatory and antioxidant properties, but its exact mechanism of action remains poorly understood. Previously, we demonstrated that ISL could suppress IL-6 expression in multiple myeloma. Here, we further characterized the anti-inflammatory effects of ISL in several psoriasis models, including the keratin 14/vascular endothelial growth factor (VEGF) transgenic mouse, the imiquimod (IMQ)-induced psoriasis-like mouse, and the human keratinocytes HaCaT and NHEK in vitro. We found that ISL ameliorated the inflammatory process in psoriasis models but not in their respective controls. Moreover, the anti-inflammatory effects of ISL were attributed to the suppression of nuclear factor-κB (NF-κB) activity, which consequently resulted in the reduction of pro-inflammation cytokines IL-6 and IL-8 expression. In conclusion, ISL exhibited anti-inflammatory effects in psoriasis models, by downregulating IL-6 and IL-8 via suppression of NF-κB activity, suggesting that ISL might serve as a potential candidate for treatment of psoriasis and other autoimmune inflammatory diseases. Key message: [ABSTRACT FROM AUTHOR]

The methanol extract of the bark of Entada rheedii has been fractionated to afford petroleum ether, dichloromethane, ethyl acetate and aqueous soluble fraction through modified Kupchan partitioning protocol and those fractions has been subjected to repeated-chromatographic separation by Sephadex size exclusion chromatography and purification processes to isolate the secondary metabolites. A total of seven compounds have been isolated from the bark of E. rheedii, which were identified as epicatechin (1), liquiritigenin (2), glabridin (3), 4′- O-methylglabridin (4), isoliquiritigenin (5), hispaglabridin A (6) and shinflavanone (7). This is the first report of isolation of these compounds from E. rheedii. [ABSTRACT FROM AUTHOR]

Isoliquiritigenin (ISL, 1) and liquiritigenin (LTG, 2) were isolated from the rhizomes of Glycyrrhiza glabra. In an attempt to develop potent and selective antituberculosis agents, a series of ISL analogues were synthesized mainly via acid- and base-catalyzed Claisen-Schmidt condensation reaction for their antitubercular activity. Compared to ISL (MIC = 25 μg/mL), analogues 5, 8, and 1 0 showed similar antitubercular activity, but, interestingly, 6, 7, and 15 exhibited twofold higher activity (MIC = 12.5 μg/mL) over ISL, against Mycobacterium tuberculosis. Among the LTG derivatives, LTG 4′-acetate and LTG-oxime were found to be as active (MIC = 25 μg/mL) as LTG. It is the first report on antimycobacterial activity of these ISL- and LTG-based derivatives. Molecular docking and in silico ADME studies revealed that compounds 6, 7, and 15 are potent inhibitors of M. tuberculosis HRv alanine dehydrogenase and showed compliance with standard parameters of drug likeness. [ABSTRACT FROM AUTHOR]

In plants, phytoalexins induced by pathogen attack play an important role in disease resistance. In soybean [ Glycine max L. (Merr.)], attack by pathogenic bacteria induces the synthesis of isoflavonoids, especially daidzein. Chalcone reductase (CHR) is the key enzyme in the biosynthesis of daidzein. Along with chalcone synthase, it catalyzes the formation of isoliquiritigenin, which is a necessary substrate for daidzein biosynthesis. In this study, a CHR gene, Gmchr2 (GenBank code: KF758395), was isolated from the soybean cultivar Jinong 17. The cDNA consisted of a 1,417-bp fragment that included an open reading frame of 969 bp. The gene is located on chromosome 9 of the soybean genome. Phytophthora sojae was inoculated onto soybean roots, and changes in the transcript levels of the chr genes and the catalytic activity of CHR were investigated in different soybean tissues by real-time fluorescence quantitative PCR and high-performance liquid chromatography (HPLC), respectively. The results showed that the isoliquiritigenin content in roots significantly increased after pathogen inoculation. The Gmchr2 gene was transformed into tobacco, and the presence of isoliquiritigenin in the transformants was confirmed by HPLC. Expression of the Gmchr2 gene under the control of the 35S CaMV promoter was also confirmed. This characterization of a chr gene encoding a soybean CHR helps to shed light on the biological synthesis and regulation of soybean isoflavones and will be useful for manipulating the phenylpropanoid pathway leading to isoflavonoid phytoalexins. [ABSTRACT FROM AUTHOR]

Redox balance plays an important role in the maintenance of cell growth and survival. Disturbance of this equilibrium can alter normal cellular processes. Excessive reactive oxygen species (ROS) are often found in cancer cells. However, cancer cells have an efficient antioxidant system to counteract the increased generation of ROS. This high antioxidant capacity also favors resistance to drugs and radiation. Here, we show that isoliquiritigenin (ISL), a natural antioxidant, effectively decreased ROS in HepG2 cells in a time-dependant manner at 0.5, 1, and 2 h of treatment. The decreased ROS caused redox imbalance and reductive stress. To adapt to this state, nuclear factor erythroid-2-related factor 2, which regulates the antioxidant enzyme system, was significantly decreased. Antioxidant enzymes reached their lowest level at 6 h after ISL treatment. Endogenous ROS were still being generated so after 6 h of ISL treatment, ROS were clearly higher than before ISL treatment, causing redox imbalance in the HepG2 cells which changed from reductive to oxidative stress. At this stage, cells were irradiated with X-rays. The excess ROS induced serious oxidative stress, resulting in radiosensitization. Therefore, we concluded that ISL induced oxidative stress by disturbing the redox status and ultimately enhancing the radiosensitivity of HepG2 cells. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that isoliquiritigenin (ISL) has anti-carcinogenic activity in several kinds of solid tumors, however, little is known about the effects of ISL on hematologic malignancies. In this study, we investigated the effects of ISL on multiple myeloma (MM) cells both in vitro and in vivo. The results showed that ISL could inhibit the growth of MM cells and induce their apoptosis in time- and dose-dependent manners. ISL exhibited significant anti-tumor activity in MM xenograft models and synergistically enhanced the anti-myeloma activity of adriamycin. Further analysis demonstrated that ISL not only downregulated IL-6 expression but also significantly decreased levels of phosphorylated ERK and STAT3 and could inhibit phosphorylation levels of ERK and STAT3 induced by recombinant human IL-6, which are critical signaling proteins in IL-6 signaling regulation networks. Taken together, our findings suggested that ISL could inhibit the growth of MM via blocking IL-6 signaling and might serve as a promising therapeutic agent for treatment of MM. [ABSTRACT FROM AUTHOR]

The sleep-promoting effect of isoliquiritigenin (ILTG) was investigated by analyzing the sleep architecture in mice. A hypnotic diazepam (DZP, 2 mg/kg) significantly decreased sleep latency by 39.7% and increased the amount of non-rapid eye movement sleep (NREMS) by 103.8% for the first 3 h after administration. ILTG (50 mg/kg) also produced a significant decrease in sleep latency (30.7%) and an increase in the amount of NREMS (61.1%). DZP significantly decreased delta (0.5-4 Hz) activity as compared with the vehicle; however, ILTG did not alter the delta activity. These results mean that ILTG induces sleep similar to physiological sleep without a decline in sleep quality. [ABSTRACT FROM AUTHOR]

This study investigated an ethanol extract from Glycyrrhizae radix (GR), the root of Glycyrrhiza uralensis (Leguminosae), for possible neuroprotective effects on neurotoxicity induced by amyloid β protein (Aβ) (25-35) in cultured rat cortical neurons. Exposure of cultured cortical neurons to 10 μM Aβ (25-35) for 36 h induced neuronal apoptotic death. GR (10-50 μg/mL) prevented the Aβ (25-35)-induced neuronal apoptotic death, as assessed by a MTT assay and Hoechst 33342 staining. Furthermore, GR decreased the expression of Bax and active caspase-3, proapoptotic proteins, and increased Bcl-2, an antiapoptotic protein. GR also significantly inhibited Aβ (25-35)-induced elevation of the intracellular Ca concentration ([Ca]) and generation of reactive oxygen species (ROS) measured by fluorescent dyes. Isoliquiritigenin (1-20 μM), isolated from GR as an active component, inhibited Aβ (25-35)-induced neuronal apoptotic death, elevation of [Ca], ROS generation, and the change of apoptosis-associated proteins in cultured cortical neurons, suggesting that the neuroprotective effect of GR may be, at least partly, attributable to this compound. These results suggest that GR and isoliquiritigenin prevent Aβ (25-35)-induced neuronal apoptotic death by interfering with the increases of [Ca] and ROS, and GR may have a possible therapeutic role for preventing the progression of neurodegenerative disease such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Previous studies, including those from our laboratory, have demonstrated that isoliquiritigenin (ISL), a flavonoid isolated from licorice, is a promising cancer chemotherapeutic agent. However the mechanisms underlying its anticancer effects are still far from clear. We now show, for the first time, that ISL triggers the mammalian target of rapamycin (mTOR)-dependent autophagic and apoptotic cell death in adenoid cystic carcinoma (ACC). Exposure of both ACC-2 and ACC-M cells to ISL resulted in several specific features for autophagy, including the appearance of membranous vacuoles, formation of acidic vesicular organelles, punctate pattern of LC3 immunostaining, and an increase in autophagic flux. Moreover, ISL treatment also resulted in significantly increased apoptosis in ACC cells. The ISL-mediated autophagic and apoptotic cell death were obviously attenuated by transfection with dominant negative Atg5 (DN-Atg5) plasmids or treatment with 3-methyladenine(3-MA). In additon, the data also revealed that the autophagic and apoptotic cell death induced by ISL occurred through a mTOR-dependent pathway. More importantly, the xenograft model using ACC-M cells provided further evidence of the occurrence of ISL-induced autophagy and apoptosis in vivo, correlating with the suppresson of mTOR activation as well as up-regulation of Atg5 expression. Taken together, these findings in our study suggest that induction of mTOR-dependent autophagic and apoptotic cell death may be an important mechanism in cancer chemotherapy by ISL. [ABSTRACT FROM AUTHOR]

Isoliquiritigenin, a chalcone found in licorice root and many other plants, has shown potential antioxidant, estrogenic and antitumor activities. The present study was to investigate urinary metabolism of isoliquiritigenin in Wistar rats by ultra-high pressure liquid chromatography coupled to electrospray ionization TOF-MS (UHPLC-TOF-MS)-based xenometabolomics. Urine samples were collected before and after oral administration of isoliquiritigenin, and analyzed by UHPLC-TOF-MS. After deconvolution, the resulting data matrices were subjected to multivariate data analysis. Projection to latent structures discriminant analysis was performed to screen the metabolites. Fifteen urinary metabolites of isoliquiritigenin were screened out and 13 of them were further identified by Agilent MassHunter Software. The results of this work show that UHPLC-TOF-MS-based xenometabolomics was able to comprehensively identify the metabolites of phytochemicals and may represent a valuable tool for monitoring the food consumption. [ABSTRACT FROM AUTHOR]

Isoliquiritigenin ( 1), one of the major constituents of licorice, is a natural pigment with a simple chalcone structure 4,2',4'-trihydroxychalcone. This study was performed to determine whether liquiritin, isoliquiritin, and liquiritigenin can be converted into isoliquiritigenin using alkaline conversion after acid hydrolysis. An orthogonal L (3) test design was used in the extraction mode and used for optimization of the extract conditions, and the yield from the conventional procedure and from the optimum procedure to extract 1 was compared. The results demonstrated that the yield of the novel procedure was increased about 27 times compared with the conventional procedure, which indicated that the novel procedure is powerful in separating and purifying isoliquiritigenin. [ABSTRACT FROM AUTHOR]

The article reports on the study on the combination of isoliquiritigenin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) overcomes apoptosis in colon cancer HT29 cells. It shows that a single treatment with isoliquiritigenin scarcely induced apoptosis in HT29 cells. Also, combined treatment with suboptimal concentrations of isoliquiritigenin and TRAIL markedly induced apoptosis.

Isoliquiritigenin(ISL), a calchone flavonoid, has cancer-preventing properties and is often used in Chinese medicine. In the present study, the authors use ISL to determine its effect on cell proliferation and cell cycle progression in primary cultured human uterine leiomyoma cells. Cell viability and cell proliferation assays were conducted. Flow cytometry, annexin V apoptosis assay, and DNA fragmentation assay were performed to determine the effect of ISL on cell cycle and apoptosis. The expression of cell cycle regulatory--related proteins urns evaluated by Western blot. The cell viability and proliferation of uterine leiomyoma cells were significantly reduced by ISL treatment in a dose-dependent manner. Flow cytometry results showed that ISL induced subG1 and G2/M arrest. DNA fragmentation assay and annexin V apoptosis assays revealed apoptosis induction. ISL-induced growth inhibition in uterine leiomyoma cells was associated with increased p21Cip1/Waf1 expression in a p53-dependent manner. Activation of caspase-3 and downregulation of Bcl-2, cdk 2/4, and E2F, with a concomitant increase in dephosphorylation of Rb and poly--ADP-ribose polymerase cleavage, were observed. This study demonstrates that ISL inhibits cell proliferation by initiating apoptosis in human uterine leiomyoma cells coupled with increased cell cycle arrest. These results indicate that ISL could prove to be a promising chemopreventive and therapeutic agent against human uterine leiomyoma. [ABSTRACT FROM AUTHOR]

Aim: To examine whether isoliquiritigenin (ISL) can attenuate myocardial ischemia-reperfusion (MI/R) injury in rats by inducing metallothionein (MT) through activation of janus kinase 2 (JAK 2)/signal transducers and activators of transcription 3 (STAT 3) pathway. Methods: The experimental model of MI/R in rats was generated by 30 min of ischemia and reperfusion for 2 h. The mRNA expression of MT, COX-2, and iNOS were measured by RT-PCR. The protein expressions of MT, JAK/STAT, extracellular signal-regulated kinase (ERK), and Akt were determined by Western blotting in the absence or presence of a JAK kinase inhibitor, tyrphostin AG490 (1.0 mg/kg, iv, 1 h before ischemia). Results: Pretreatment with ISL markedly decreased the severity of reperfusion-induced arrhythmias and myocardial infarct size. In the ISL 20 mg/kg group, the activities of lactate dehydrogenase (LDH) and creatinine phosphokinase (CPK) were reduced by 38.4% and 51.3% when compared with the vehicle group. Increased JAK 2/STAT 3 phosphoryla-tion was accompanied by increased synthesis of MT but not of COX-2 or iNOS in ISL-treated groups. AG490 can significantly weaken ISL-induced cardioprotection and prevent the increase of MT expression and JAK 2/STAT 3 phosphorylation. Conclusion: ISL protected MI/R injury through activation of JAK 2/STAT 3 signal transduction pathway, which might be involved in mediating the upregulation of MT expression. [ABSTRACT FROM AUTHOR]

The human fecal anaerobe Eubacterium ramulus is capable of degrading various flavonoids, including the flavone naringenin. The first step in the proposed degradation pathway is the isomerization of naringenin to the corresponding chalcone. Cell-free extracts of E. ramulus displayed chalcone isomerase activity. The enzyme from E. ramulus was purified to homogeneity. Its apparent molecular mass was estimated to be 136 and 129 kDa according to gel filtration and native polyacrylamide gel electrophoresis, respectively. Chalcone isomerase is composed of one type of subunit of 30 kDa. The purified enzyme catalyzed the isomerization of naringenin chalcone, isoliquiritigenin, and butein, three chalcones that differ in their hydroxylation pattern. N-bromosuccinimide, but also naringenin and phloretin, inhibited the purified enzyme considerably. This is the first report on a bacterial chalcone isomerase. The physiological function of the purified enzyme is unclear, but an involvement in the conversion of the flavanone naringenin to the chalcone is proposed. [ABSTRACT FROM AUTHOR]

The methanol extract of the stem of Sinofranchetia chinensis inhibited the activity of xanthine oxidase in vitro. Bioassay-guided purification led to the isolation of liquiritigenin and isoliquiritigenin as the main xanthine oxidase inhibitors. This inhibition of enzyme activity was found to be dose dependent, with an IC50 value of approximately 49.3 μM for liquiritigenin and 55.8 μM for isoliquiritigenin. Lineweaver-Burk transformation of the inhibition data indicated that the inhibition was of a mixed type for both liquiritigenin and isoliquiritigenin. For liquiritigenin, the Ki and KI were determined to be 14.0 μM and 151.6 μM, respectively. For isoliquiritigenin, the Ki and KI were determined to be 17.4 μM and 81.9 μM, respectively. These results suggest that these natural products could be used to treat conditions where the inhibition of xanthine oxidase is warranted. [ABSTRACT FROM AUTHOR]