PMID: 

Neuropharmacology. 2018 03 15 ;131:440-452. Epub 2017 Oct 28. PMID: 29111385

Abstract Title: 

JNK1 inhibition by Licochalcone A leads to neuronal protection against excitotoxic insults derived of kainic acid.

Abstract: 

The mitogen-activated protein kinase family (MAPK) is an important group of enzymes involved in cellular responses to diverse external stimuli. One of the members of this family is the c-Jun-N-terminal kinase (JNK). The activation of the JNK pathway has been largely associated with the pathogenesis that occurs in epilepsy and neurodegeneration. Kainic acid (KA) administration in rodents is an experimental approach that induces status epilepticus (SE) and replicates many of the phenomenological features of human temporal lobe epilepsy (TLE). Recent studies in our group have evidenced that the absence of the JNK1 gene has neuroprotective effects against the damage induced by KA, as it occurs with the absence of JNK3. The aim of the present study was to analyse whether the pharmacological inhibition of JNK1 by Licochalcone A (Lic-A) had similar effects and if it may be considered as a new molecule for the treatment of SE. In order to achieve this objective, animals were pre-treated with Lic-A and posteriorly administered with KA as a model for TLE. In addition, a comparative study with KA was performed between wild type pre-treated with Lic-A and single knock-out transgenic mice for the Jnk1gene. Our results showed that JNK1 inhibition by Lic-A, previous to KA administration, caused a reduction in the convulsive pattern. Furthermore, it reduced phosphorylation levels of the JNK, as well as its activity. In addition, Lic-A prevented hippocampal neuronal degeneration, increased pro-survival anti-apoptotic mechanisms, reduced pro-apoptotic biomarkers, decreased cellular stress and neuroinflammatory processes. Thus, our results suggest that inhibition of the JNK1 by Lic-A has neuroprotective effects and that; it could be a new potential approach for the treatment of SE and neurodegeneration.

read more

PMID: 

Free Radic Biol Med. 2018 02 1 ;115:471-483. Epub 2017 Dec 9. PMID: 29233793

Abstract Title: 

Licochalcone A activates Keap1-Nrf2 signaling to suppress arthritis via phosphorylation of p62 at serine 349.

Abstract: 

Licochalcone A (LCA) is derived from glycyrrhizae radix with antimicrobial, antitumor and anti-inflammatory activities. However, the anti-arthritic function of LCA and underlying mechanism has not been yet explored. The current study investigated the anti-arthritic effect of LCA and elucidated the underlying mechanism. The results showed that LCA significantly suppressed arthritis via the activation of SQSTM1 (p62)/nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling in the collagen-induced arthritis (CIA) model of DBA mice. In coincided with the results, this anti-arthritic effect of LCA was remarkably diminished in the collagen antibody-induced arthritis (CAIA) model of Nrf2-/- mice. These findings indicate that p62/Nrf2 signaling is a crucial pathway for the induction and treatment of arthritis. To further validate the effect of LCA on the arthritis, rheumatoid arthritis synovial fibroblasts (RASFs) isolated from the synovium of RA patients were employed in the study. In coincided with in vivo results, LCA inhibited the cell proliferation and arrested the cell cycle, induced apoptosis, suppressed pro-inflammatory cytokine secretion and increased expression of antioxidant enzymes via the activation of Keap1-Nrf2 signaling by enhancing p62 phosphorylation and expression, Nrf2 accumulation and Nrf2 nucleus translocation. Findings in the current study provide evidence that p62-Keap1-Nrf2 axis is a pivotal signaling pathway in development of arthritis and therapeutic efficacy of drugs, and LCA activates of Keap1-Nrf2 signaling to suppress arthritis by phosphorylation of p62 at Ser349. Collectively, LCA is valuable to be further investigated as a lead compound for application in anti-arthritis, and interference with the interaction between Nrf2 and Keap1 by phosphorylation of p62 may be a promising strategy for the discovery of anti-arthritic agents.

read more

PMID: 

Oncol Rep. 2018 Mar ;39(3):1181-1190. Epub 2017 Dec 14. PMID: 29286170

Abstract Title: 

Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway.

Abstract: 

Licochalcone A (LicA) is a chalcone extracted from liquorice which has been used as a traditional Chinese medicine for many generations. Increased glucose consumption and glycolytic activity are important hallmarks of cancer cells, and hexokinase 2 (HK2) upregulation is a major contributor to the elevation of glycolysis. Recently, the antitumor activities of LicA have been reported in various cancers; however, its effect on tumor glycolysis in gastric cancer and the underlying mechanisms are completely unknown. In vitro, cell proliferation and clonogenic survival were substantially inhibited after LicA treatment. LicA reduced HK2 expression, and both glucose consumption and lactate production in gastric cancer cells were significantly suppressed. Mechanistic investigations revealed that multiple signaling pathways including Akt, ERK and NF‑κB were suppressed by LicA. Further studies demonstrated that the inhibition of glycolysis by LicA was mainly attributed to the blockade of the Akt signaling pathway, and the suppression of glycolysis was substantially attenuated when Akt was exogenously overexpressed. In addition to the role in the inhibition of glycolysis, reduction in HK2 was confirmed to be involved in the induction of cell apoptosis. The apoptosis induced by LicA was substantially impaired after HK2 overexpression in gastric cancer cells. The in vivo experiment showed that MKN45 xenograft growth was markedly delayed after LicA treatment and HK2 expression in LicA‑treated tissues was markedly decreased. All of these data demonstrated that blockade of the Akt/HK2 pathway was the underlying mechanism required for LicA to exert its biological activities in glycolysis inhibition and apoptosis induction.

read more

PMID: 

Oncol Lett. 2018 Feb ;15(2):1869-1873. Epub 2017 Nov 21. PMID: 29399197

Abstract Title: 

Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation and promotes autophagy in breast cancer cells.

Abstract: 

Previous studies have demonstrated that Licochalcone A possesses anti-inflammatory, anticancer, anti-bacterial, anti-malarial and anti-parasitic activities. In the present study the potential anticancer effects of Licochalcone A on MCF-7 cells were investigated. Licochalcone A significantly decreased cell viability and promoted autophagy and apoptosis, as demonstrated by an MTT assay, acridine orange staining and Annexin V-fluorescein isothiocyanate staining, respectively. Western blot analyses demonstrated that Licochalcone A treatment activated the LC3-II signaling pathway while suppressing the phosphoinositide 3-kinase (PI3K)/RAC-α serine-threonine-protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. In addition, Licochalcone A significantly increased caspase-3 activity and significantly decreased B-cell lymphoma-2 expression. The results from the present study indicate that Licochalcone A inhibits PI3K/Akt/mTOR activation, and promotes autophagy and apoptosis in MCF-7 cells.

read more

PMID: 

Biomed Pharmacother. 2018 Jun ;102:922-929. Epub 2018 Apr 5. PMID: 29710547

Abstract Title: 

NF-κB and Nrf2 pathways contribute to the protective effect of Licochalcone A on dextran sulphate sodium-induced ulcerative colitis in mice.

Abstract: 

Licochalcone A (Lico A) is a characteristic chalcone isolated from licorice root which is widely recognized in traditional Chinese medicine for the ability of anti-inflammatory, antioxidant, anti-parasitic and anti-cancer. The present study was aimed to investigate the effect of Lico A on dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in a mouse model which was induced by administration of 3% DSS in drinking water. Mice were then treated with Lico A (20, 40 and 80 mg/kg, p.o.) or 0.9% saline (20 ml/kg, p.o.) for 17 days. The results showed that treatment with Lico A significantly reduced the colon length, histological damage scores, and colonic myeloperoxidase (MPO) activity in a dose-dependent manner as compared to the UC control group. Besides, Lico Asignificantly decreased the oxidative stress and pro-inflammatory cytokines, downregulated nuclear transcription factor kappa B (NF-κB) pathway and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Collectively, Lico A is effective in alleviating DSS-induced colitis in mice and the mechanism is associated with its inhibition of NF-κB-regulated pro-inflammatory signaling and activation of Nrf2-regulated cytoprotective protein expression.

read more

PMID: 

Iran J Microbiol. 2018 Feb ;10(1):51-58. PMID: 29922419

Abstract Title: 

Antimicrobial effect of Licochalcone A and Epigallocatechin-3-gallate againstTyphimurium isolated from poultry flocks.

Abstract: 

Background and Objectives: Salmonellosis due to multi-drug resistantTyphimurium with biofilm formation ability is a serious public health threat worldwide. Studies have shown that medicinal plants inhibit the growth of bacterial species. The present study aimed at determining antibiotic resistance pattern and biofilm formation ability ofTyphimurium isolated from poultry flocks. Moreover, the antibacterial activity of Licochalcone A (LAA) and Epigallocatechin-3-gallate (EGCG) against the studied isolates were investigated in this study.Materials and Methods: Antibiotic susceptibility testing of. Typhimurium RITCC1730 and 23 clinical isolates ofTyphimurium against 8 antibiotics was performed using standard Kirby-Bauer disc diffusion method. The extent of biofilm formation was measured by Microtiter dish biofilm formation assay. Antimicrobials activities of LAA and EGCG were determined by MIC and MBC assays using microdilution method.Results: The highest antimicrobial resistance was detected against chloramphenicol (52.17%), followed by furazolidone (26.08%), and trimethoprim/sulfamethoxazole (21.73%). All isolates were sensitive to ciprofloxacin (100%), followed by gentamicin, imipenem (95.65%), and cefixime (91.30%). Most of the isolates (78.26%) were able to produce weak biofilm. LAA and EGCG inhibited the growth ofTyphimurium at the MIC levels of 62.5∼1000 and 1.56∼400 μg/mL, respectively. The MBC value of LAA was>1000μg/mL, while the corresponding value of EGCG varied from 100 to 800 μg/mL.Conclusion: Typhimurium isolates revealed a multiple antibiotic resistance with biofilm production ability. As a result, EGCG, and to a lesser extent, LAA displayed potential antibacterial activity against. Typhimurium and could be considered as useful compounds for the development of antibacterial agents against salmonellosis.

read more

PMID: 

Biochem Biophys Res Commun. 2018 09 10 ;503(3):2117-2123. Epub 2018 Aug 7. PMID: 30093114

Abstract Title: 

Anti-obesity potential of Glycyrrhiza uralensis and licochalcone A through induction of adipocyte browning.

Abstract: 

The main function of brown adipose tissue is to dissipate surplus caloric intake into heat energy by thermogenesis, increasing energy expenditure. Inducible brown adipocytes can develop within white adipose tissue (WAT) through a process referred to as browning. Browning of white fat represents a promising strategy for treatment of obesity and the related complications. We investigated whether Glycyrrhiza uralensis and its ingredients modulated adipogenesis through adipocyte browning using 3T3-L1 adipocytes and a high-fat diet (HFD)-induced obesity mice model. Amongst extracts and fractions of G. uralensis, methyl dichloride (MeCl) fraction was the most effective to induce expression of uncoupling protein 1 (UCP1), a fat browning marker, in 3T3-L1 adipocytes. Ingredients of G. uralensis such as licochalcone A (LicoA), isoliquiritigenin, and liquiritigenin induced UCP1 expression in 3T3-L1 adipocytes. After inducing obesity in mice by 6-week HFD, MeClfraction of G. uralensis or LicoA was intraperitoneally administered for additional 19 days. MeClfraction or LicoA significantly reduced body weight gain and inguinal fat pad weights. Furthermore, MeClfraction or LicoA improved metabolic disorders induced by HFD as the treatments decreased serum levels of glucose and cholesterol, and blocked insulin resistance. MeClfraction or LicoA enhanced expression of brown fat markers such as UCP1, PRDM16, and PGC-1α and increased brown fat phenotype population in inguinal WAT of HFD-fed mice. Our results demonstrate that G. uralensis and LicoA are effective to reduce obesity and to recover metabolic homeostasis by inducing the brown fat phenotype.

read more

PMID: 

J Cell Physiol. 2019 May ;234(5):7560-7568. Epub 2018 Nov 11. PMID: 30417353

Abstract Title: 

Licochalcone A attenuates abdominal aortic aneurysm induced by angiotensin II via regulating the miR-181b/SIRT1/HO-1 signaling.

Abstract: 

Licochalcone A (LA), a chalcone derived from liquorice, exhibits multiple biological activities, including anti-oxidation and anti-inflammation. This study aimed to investigate the role and underlying mechanism of LA in the abdominal aortic aneurysm (AAA). AAA model was established by continuous infusion of 1000 ng/kg/min of angiotensin II (AngII) in ApoEmice for 4 weeks. At 7 days before AngII administration, 5 mg/kg/day or 10 mg/kg/day of LA was intraperitoneally administered to mice and continued for 4 weeks. The characteristics and quantification of AAAs were determined in situ. Real-time PCR or western blot was used to measure mRNA or protein levels of matrix metalloproteinase 2 and matrix metalloproteinase 9; pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6; apoptosis-related proteins Bax, Bcl-2, and active caspase-3; miR-181b; Sirtuin 1 (SIRT1); and heme oxygenase-1 (HO-1). Mouse-aorta-origin vascular smooth muscle (MOVAS) cells were used to confirm the involved pathways in vitro. We found LA administration dose-dependently reduced the incidence of AngII-induced AAA, aneurysm diameter enlargement, elastin degradation, matrix metalloproteinase production, pro-inflammatory cytokines and miR-181b expression, and vascular smooth muscle cell apoptosis. It elevated SIRT1 and HO-1 expression that was suppressed by AngII. AngII enhanced miR-181b but reduced SIRT1 and HO-1 expression in MOVAS cells. In AngII-stimulated MOVAS cells, downregulation of miR-181b significantly upregulated the expression of SIRT1 and HO-1, the effect of which was abrogated by SIRT1 siRNA. Collectively, LA could attenuate AngII-induced AAA by modulating the miR-181b/SIRT1/HO-1 signaling. LA might be a potential medical therapy for small AAA.

read more

PMID: 

Front Immunol. 2019 ;10:287. Epub 2019 Feb 25. PMID: 30858849

Abstract Title: 

Licochalcone A Protects the Blood-Milk Barrier Integrity and Relieves the Inflammatory Response in LPS-Induced Mastitis.

Abstract: 

Mastitis is an acute clinical inflammatory response. The occurrence and development of mastitis seriously disturb women's physical and mental health. Licochalcone A, a phenolic compound in, has anti-inflammatory properties. Here, we examined the effect of licochalcone A on blood-milk barrier and inflammatory response in LPS-induced mice mastitis., we firstly established mice models of mastitis by canal injection of LPS to mammary gland, and then detected the effect of licochalcone A on pathological indexes, inflammatory responses and blood-milk barrier in this model., Mouse mammary epithelial cells (mMECs) were treated with licochalcone A prior to the incubation of LPS, and then the inflammatory responses, tight junction which is the basic structure of blood-milk barrier were analyzed. Last, we elucidated the anti-inflammatory mechanism by examining the activation of mitogen-activated protein kinaseMAPK) and AKT/NF-κB signaling pathwaysand.Theresults showed that licochalcone A significantly decreased the histopathological impairment and the inflammatory responses, and improved integrity of blood-milk barrier. Theresults demonstrated that licochalcone A inhibited LPS-induced inflammatory responses and increase the protein levels of ZO-1, occludin, and claudin3 in mMECs. Theandmechanistic study found that the anti-inflammatory effect of licochalcone A in LPS-induced mice mastitis was mediated by MAPK and AKT/NF-κB signaling pathways.Our experiments collectively indicate that licochalcone A protected against LPS-induced mice mastitis via improving the blood-milk barrier integrity and inhibits the inflammatory response by MAPK and AKT/NF-κB signaling pathways.

read more

PMID: 

J Chromatogr B Analyt Technol Biomed Life Sci. 2019 May 1 ;1114-1115:134-145. Epub 2019 Jan 31. PMID: 30878379

Abstract Title: 

Enrichment of total flavones and licochalcone A from licorice residues and its hypoglycemic activity.

Abstract: 

Industrial processing of glycyrrhizic leads to a lot of residues which are usually threw away randomly or used as feed. Therefore, the purpose of this study was to study licorice residues as a source of bioactive compounds with potentially applications. In this study, the enrichment and purification of total flavones from the licorice residues was achieved by using macroporous resins. The performances and separation characteristics of four selected macroporous resins with different chemical and physical properties were investigated. HPD-100 resin was the most effective, the content of total flavones increased from 50.94% in the original extract to 82.98% in the 80% ethanol fraction (a 1.63-fold increase). Further purification treatment by polyamide resin, licochalcone A with a purity of 80.28% was obtained in a 45% ethanol fraction, and a higher purity (>85%) of licochalcone A can be obtained by single crystallization operation. And hypoglycemic effect of the total flavones from licorice residues on high fat diet and STZ induced diabetic c57 mice was preliminary investigated. The results showed: the fasting blood glucose of mice in the low and medium dose total flavones group decreased significantly. The proposed technique is uncomplicated, easily managed, cost-effective, and environmentally friendly and is proper for both large-scale licorice residues application and waste management.

read more