PMID: 

Iran J Basic Med Sci. 2016 Aug ;19(8):910-915. PMID: 27746874

Abstract Title: 

Hepatoprotective effects of licochalcone B on carbon tetrachloride-induced liver toxicity in mice.

Abstract: 

OBJECTIVES: The objective of this study was to investigate the hepatoprotective effect of licochalcone B (LCB) in a mice model of carbon tetrachloride (CCl)-induced liver toxicity.MATERIALS AND METHODS: Hepatotoxicity was induced in mice by a single subcutaneous injection (SC) of CCl4. The LCB was administered orally once a day for seven days (PO) as pretreatment at three doses of 1, 5, and 25 mg/kg/day. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed by ELISA. The protein expression degrees of p38 mitogen activated protein kinases (p38) and nuclear factor-k-gene binding (NF-κB) were assayed by western blotting.RESULTS: CCl4-induced hepatotoxicity was manifested by an increase in the levels of ALT, AST, MDA, IL-6, CRP, and TNF-ɑ, and a decrease in the SOD level and GSH/GSSG ratio in the serum. The histopathological examination of the liver sections revealed necrosis and inflammatory reactions. Pretreatment with LCB decreased the levels of ALT, AST, MDA, GSSG, IL-6, CRP, TNF-ɑ, and the protein expression of p38 and NF-κB, increased the level of SOD and GSH, and normalized the hepatic histo-architecture.CONCLUSION: LCB protected the liver from CCl4-induced injury. Protection may be due to inhibition of p38 and NFκB signaling, which subsequently reduced inflammation in the liver.

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PMID: 

Iran J Basic Med Sci. 2017 Feb ;20(2):131-137. PMID: 28293388

Abstract Title: 

Protective role of licochalcone B against ethanol-induced hepatotoxicity through regulation of Erk signaling.

Abstract: 

OBJECTIVES: Oxidative stress has been established as a key cause of alcohol-induced hepatotoxicity. Licochalcone B, an extract of licorice root, has shown antioxidative properties. This study was to investigate the effects and mechanisms of licochalcone B in ethanol-induced hepatic injury in anstudy.MATERIALS AND METHODS: Anmodel of Ethanol-induced cytotoxicity in BRL cells was used in this study. Cell injury was assessed using WST-1 assay and lactate dehydrogenase, alanine transaminase, and aspartate aminotransferase release assay. Cell apoptosis were quantified by flow cytometric analysis. The intracellular oxidative level was evaluated by reactive oxidative species, malondialdehyde and glutathione detection. Furthermore, the expression level of Erk, p-Erk, Nrf-2 were assessed using Western blot.RESULTS: Treatment with ethanol induced marked cell injury and cell apoptosis in BRL cells. Licochalcone B significantly attenuated ethanol-induced cell injury, and inhibited cell apoptosis. Furthermore, licochalcone B significantly inhibited ethanol-induced intracellular oxidative level, upregulated the expression of p-Erk, and promoted nuclear localization of Nrf2. Additionally, this hepatoprotective role was significantly abolished by inhibition of Erk signaling. However, no apparent effects of Erk inhibition were observed on ethanol-induced hepatotoxicity.CONCLUSION: This study demonstrates that licochalcone B protects hepatocyte from alcohol-induced cell injury, and this hepatoprotective role might be attributable to apoptosis reduction, inhibition of oxidative stress, and upregulation of Erk-Nrf2. Therefore, licochalcone B might possess potential as a novel therapeutic drug candidate for alcohol-related liver disorders.

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PMID: 

Oncol Lett. 2017 May ;13(5):3662-3668. Epub 2017 Mar 16. PMID: 28521469

Abstract Title: 

Licochalcone-E induces caspase-dependent death of human pharyngeal squamous carcinoma cells through the extrinsic and intrinsic apoptotic signaling pathways.

Abstract: 

The aim of the present study was to investigate licochalcone-E (Lico-E)-induced apoptosis and the associated apoptotic signaling pathway in FaDu cells, a human pharyngeal squamous carcinoma cell line. Treatment with Lico-E exhibited significant cytotoxicity on FaDu cells in a concentration-dependent manner. The ICvalue of Lico-E in FaDu cells was ~50µM. Treatment with Lico-E increased the number of dead FaDu cells. Furthermore, chromatin condensation, which is associated with apoptotic cell death, was observed in FaDu cells treated with Lico-E for 24 h. By contrast, Lico-E did not produce cytotoxicity or increase the number of dead cells whenapplied to human normal oral keratinocytes (hNOKs). Furthermore, chromatin condensation was not observed in hNOKs treated with Lico-E. Treatment with Lico-E increased the expression of Fas ligand and the cleaved form of caspase-8 in FaDu cells. Furthermore, treatment with Lico-E increased the expression of pro-apoptotic factors, including apoptosis regulator BAX, Bcl-2-associated agonist of cell death, apoptotic protease-activating factor 1, caspase-9 and tumor suppressor p53, while decreasing the expression of anti-apoptotic factors, including apoptosis regulator Bcl-2 and Bcl-2-like protein1 in FaDu cells. The expression of cleaved caspases-3 and poly (ADP-ribose) polymerase was significantly upregulated following treatment with Lico-E in FaDu cells, while Lico-E-induced apoptotic FaDu cell death was partially suppressed by treatment with Z-VAD-FMK, a pan caspase inhibitor. Therefore,Lico-E-induced oral cancer (OC) cell-specific apoptosis is mediated by the death receptor-dependent extrinsic and mitochondrial-dependent intrinsic apoptotic signaling pathways. In conclusion, these data suggested that Lico-E exhibits potential chemopreventive effects and warrants further developedas a chemotherapeutic agent against OC.

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PMID: 

Mol Med Rep. 2017 Oct ;16(4):5269-5276. Epub 2017 Aug 17. PMID: 28849019

Abstract Title: 

Licochalcone E protects against carbon tetrachloride‑induced liver toxicity by activating peroxisome proliferator-activated receptor gamma.

Abstract: 

The present study aimed to investigate the hepatoprotective role of Licochalcone E (LCE) and its mechanism of action in a mouse model of carbon tetrachloride (CCl4)‑induced liver toxicity. Hepatotoxicity was induced in Kunming mice via an intraperitoneal injection (IP) of CCl4, 10 ml/kg body weight, diluted with corn oil at a 1:500 ratio. LCE was administered once a day for 7 days (IP) as pretreatment at a dose of 5 mg/kg/day. The levels of C‑reactive protein (CRP) and tumor necrosis factor (TNF)‑α were analyzed to determine the inflammation status. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed using ELISA assays. Liver ultrastructure was observed via optical microscopy. The mRNA and protein expression levels of peroxisome proliferator‑activated receptor (PPAR)γ, and nuclear factor (NF)‑κB were assayed using quantitative polymerase chain reaction and western blot analysis, respectively. Pretreatment with LCE decreased levels of ALT, AST, CRP and TNF‑α, and NF‑κB expression in the experimental hepatotoxicity mice model induced by CCl4. In addition, LCE increased the expression of PPARγ and normalized the hepatic histoarchitecture. However, the effects of LCE were reversed by cotreatment with the PPARγ inhibitor GW9662. The present study suggests that LCE may be used for the treatment of hepatotoxicity, and primarily exhibits its protective role through a PPARγ/NF‑κB‑mediated pathway.

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PMID: 

Phytother Res. 2017 Dec ;31(12):1858-1867. Epub 2017 Oct 13. PMID: 29027311

Abstract Title: 

Natural Compound Licochalcone B Induced Extrinsic and Intrinsic Apoptosis in Human Skin Melanoma (A375) and Squamous Cell Carcinoma (A431) Cells.

Abstract: 

Licochalcone B (Lico B), which is normally isolated from the roots of Glycyrrhiza inflata (Chinese Licorice), generally classified into organic compounds including retrochalcones. Potential pharmacological properties of Lico B include anti-inflammatory, anti-bacterial, anti-oxidant, and anti-cancer activities. However, its biological effects on melanoma and squamous cell carcinoma (SCC) are unknown. Based on these known facts, this study investigated the role of Lico B in apoptosis, through the extrinsic and intrinsic pathways and additional regulation of specificity protein 1 in human skin cancer cell lines. Annexin V/7-aminoactinomycin D staining, western blot analysis, mitochondrial membrane potential assay, and an anchorage-independent cell transformation assay demonstrated that Lico B treatment of human melanoma and SCC cells significantly inhibited cell proliferation and induced apoptotic cell death. More specifically, Lico B induced apoptosis through the regulation of specificity protein 1 and apoptosis-related proteins including CCAAT/enhancer-binding protein homologous protein, death receptors, and poly (ADP-ribose) polymerase. These results indicate that Lico B has apoptotic effect on A375 and A431 skin cancer cells, suggesting the potential value of Lico B for the treatment of human melanoma and SCC. Copyright© 2017 John Wiley&Sons, Ltd.

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PMID: 

Oncol Rep. 2018 May ;39(5):2160-2170. Epub 2018 Mar 20. PMID: 29565458

Abstract Title: 

Licochalcone D induces apoptosis and inhibits migration and invasion in human melanoma A375 cells.

Abstract: 

The aim of the present study was to determine the effects of Licochalcone D (LD) on the apoptosis and migration and invasion in human melanoma A375 cells. Cell proliferation was determined by sulforhodamine B assay. Apoptosis was assessed by Hoechst 33258 and Annexin V‑FITC/PI staining and JC‑1 assay. Total intracellular reactive oxygen species (ROS) was examinedby DCFH‑DA. Wound healing and Transwell assays were used to detect migration and invasion of the cells. The activities of matrix metalloproteinase (MMP‑2 and MMP‑9) were assessed via gelatin zymography. Tumor growth in vivo was evaluated in C57BL/6 mice. RT‑PCR, qPCR, ELISA and western blot analysis were utilized to measure the mRNA and protein levels. Our results showed that LD inhibited the proliferation of A375 and SK‑MEL‑5 cells in a concentration‑dependent manner. After treatment with LD, A375 cells displayed obvious apoptotic characteristics, and the number of apoptotic cells was significantly increased. Pro‑apoptotic protein Bax, caspase‑9 and caspase‑3 were upregulated, while anti‑apoptotic protein Bcl‑2 was downregulated in the LD‑treated cells. Meanwhile, LD induced the loss of mitochondrial membrane potential (ΔΨm) and increased the level of ROS.ROS production was inhibited by the co‑treatment of LD and free radical scavenger N‑acetyl‑cysteine (NAC). Furthermore, LD also blocked A375 cell migration and invasion in vitro which was associated with the downregulation of MMP‑9 and MMP‑2. Finally, intragastric administration of LD suppressed tumor growth in the mouse xenograft model of murine melanoma B16F0 cells. These results suggest that LD may be a potential drug for human melanoma treatment by inhibiting proliferation, inducing apoptosis via the mitochondrial pathway and blocking cell migration and invasion.

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PMID: 

J Cell Physiol. 2019 02 ;234(2):1780-1793. Epub 2018 Aug 2. PMID: 30070696

Abstract Title: 

Licochalcone D directly targets JAK2 to induced apoptosis in human oral squamous cell carcinoma.

Abstract: 

Licochalcone (LC) families have been reported to have a wide range of biological function such as antioxidant, antibacterial, antiviral, and anticancer effects. Although various beneficial effects of LCD were revealed, its anticancer effect in human oral squamous cancer has not been identified. To examine the signaling pathway of LCD's anticancer effect, we determined whether LCD has physical interaction with Janus kinase (JAK2)/signal transducer and activator of transcription-3 (STAT3) signaling, which is critical in promoting cancer cell survival and proliferation. Our results demonstrated that LCD inhibited the kinase activity of JAK2, soft agar colony formation, and the proliferation of HN22 and HSC4 cells. LCD also induced mitochondrial apoptotic events such as altered mitochondrial membrane potential and reactive oxygen species production. LCD increased the expression of apoptosis-associated proteins in oral squamous cell carcinoma (OSCC) cells. Finally, the xenograft study showed that LCD significantly inhibited HN22 tumor growth. Immunohistochemical data supported that LCD suppressed p-JAK2 and p-STAT3 expression and induced cleaved-caspase-3 expression. These results indicate that the anticancer effect of LCD is due to the direct targeting of JAK2 kinase. Therefore, LCD can be used for therapeutic application against OSCC.

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PMID: 

J Cell Biochem. 2018 12 ;119(12):10118-10130. Epub 2018 Aug 20. PMID: 30129052

Abstract Title: 

Licochalcone C induced apoptosis in human oral squamous cell carcinoma cells by regulation of the JAK2/STAT3 signaling pathway.

Abstract: 

Oral cancer is of an aggressive malignancy that arises on oral cavity and lip, 90% of cancers histologically originated in the squamous cells. Licochalcone (LC)C has been known as natural phenolic chalconoid substances, and its origin is the root of Glycyrrhiza glabra or Glycyrrhiza inflata. LCC inhibited oral squamous cell carcinoma (OSCC) cell viability, mitochondrial function, and anchorage-independent growth in a dose-dependent manner. To investigate the ability of LCC to target Janus kinase 2 (JAK2), we performed pull-down binding assay, kinase assay, and docking simulation. The molecular docking studies were performed between JAK2 and the potent inhibitor LCC. It was shown that LCC tightly interacted with ATP-binding site of JAK2. In addition, LCC inhibited the JAK2/signal transducer and activator of transcription 3 pathway, upregulated p21, and downregulated Bcl-2, Mcl-1, and Survivin, while it disrupted mitochondrial membrane potential and subsequently caused cytochrome c release with activation of multi-caspase, eventually leading to apoptosis in HN22 and HSC4 cells. LCC elevated the protein levels of Bax, cleaved Bid and PARP, and increased Apaf-1, and this effect was reversed by LCC treatment. Our results demonstrated that treatment of OSCC cells with LCC induced the death receptor (DR)4 and DR5 expression level with the generation of reactive oxygen species and the upregulation of CHOP protein expression. Taken together, these results could provide the basis for clinical application as a new therapeutic strategy in the treatment of oral cancer.

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PMID: 

Oncol Rep. 2019 Jan ;41(1):333-340. Epub 2018 Oct 11. PMID: 30320347

Abstract Title: 

Licochalcone H induces the apoptosis of human oral squamous cell carcinoma cells via regulation of matrin 3.

Abstract: 

Licochalcone H (LCH) is a chemical compound that is a positional isomer of licochalcone C (LCC), a chalconoid isolated from the root of Glycyrrhiza inflata, which has various pharmacological properties including anti‑inflammatory, antioxidant, antitumor, and anticancer effects. However, the efficacy of LCHon cancer cells has not been investigated. The present study examined the effects of LCH on cell proliferation, induction of apoptosis, and the regulation of matrin 3 (Matr3) protein in oral squamous cell carcinoma (OSCC) cells by Annexin V/propidium iodide (PI) staining and western blot analysis.LCH reduced cell viability and colony forming ability, and induced cell cycle arrest and apoptosis in HSC2 and HSC3 cells through the suppression of Matr3. It was also found that LCH directly bound to Matr3 in a Sepharose 4B pull‑down assay. Consequently, the results of the present study suggestthat LCH may be used as an anticancer drug in combination with conventional chemotherapy for the treatment of OSCC, and that Matr3 may be a potential effective therapeutic target.

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PMID: 

J Med Chem. 2004 Feb 26 ;47(5):1079-80. PMID: 14971887

Abstract Title: 

Sabadinine: a potential non-peptide anti-severe acute-respiratory-syndrome agent identified using structure-aided design.

Abstract: 

A novel human coronavirus has been reported to be the causative agent of severe acute respiratory syndrome (SARS). Since replication of HcoVs depends on extensive proteolytic processing, the main proteinase, 3CLpro, is an attractive drug target for anti-SARS agents. We have employed molecular docking of a chemical database into the active site of 3CLpro to search for non-peptidyl inhibitors. One compound was identified to be the natural product sabadinine, isolated from a historical herbal remedy.

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