Xanthohumol

The herbs of Humulus lupulus

Valosin-containing protein (VCP) inhibitor. Binds to the N domain of VCP, suppressing function and impairing autophagosome maturation. Inhibits growth of a wide variety of human cancer cell lines by inhibiting proliferation and inducing apoptosis.

Xanthohumol induces growth inhibition and apoptosis in ca ski human cervical cancer cells.[Pubmed:25949267]

Evid Based Complement Alternat Med. 2015;2015:921306.

We investigate induction of apoptosis by Xanthohumol on Ca Ski cervical cancer cell line. Xanthohumol is a prenylated chalcone naturally found in hop plants, previously reported to be an effective anticancer agent in various cancer cell lines. The present study showed that Xanthohumol was effective to inhibit proliferation of Ca Ski cells based on IC50 values using sulforhodamine B (SRB) assay. Furthermore, cellular and nuclear morphological changes were observed in the cells using phase contrast microscopy and Hoechst/PI fluorescent staining. In addition, 48-hour long treatment with Xanthohumol triggered externalization of phosphatidylserine, changes in mitochondrial membrane potential, and DNA fragmentation in the cells. Additionally, Xanthohumol mediated S phase arrest in cell cycle analysis and increased activities of caspase-3, caspase-8, and caspase-9. On the other hand, Western blot analysis showed that the expression levels of cleaved PARP, p53, and AIF increased, while Bcl-2 and XIAP decreased in a dose-dependent manner. Taken together, these findings indicate that Xanthohumol-induced cell death might involve intrinsic and extrinsic apoptotic pathways, as well as downregulation of XIAP, upregulation of p53 proteins, and S phase cell cycle arrest in Ca Ski cervical cancer cells. This work suggests that Xanthohumol is a potent chemotherapeutic candidate for cervical cancer.

Inhibition of hepatitis C virus replication in vitro by xanthohumol, a natural product present in hops.[Pubmed:24356905]

Planta Med. 2014 Feb;80(2-3):171-6.

Hepatitis C virus is a major cause of chronic liver disease worldwide. Xanthohumol, a prenylated flavonoid from hops, has various biological activities including an antiviral effect. It was previously characterized as a compound that inhibits bovine viral diarrhea virus, a surrogate model of hepatitis C virus. In the present work, Xanthohumol was examined for its ability to inhibit hepatitis C virus replication in a cell culture system carrying replicating hepatitis C virus RNA replicon. 0.2 % DMSO and 500 units/mL interferon-alpha treatments were set as a negative and positive control, respectively. The inhibitory effect by Xanthohumol was determined by the luciferase activity of the infected Huh7.5 cell lysates and the hepatitis C virus RNA levels in the culture. Xanthohumol at 3.53 microM significantly decreased the luciferase activity compared to the negative control (p < 0.01). Xanthohumol at 7.05 microM further decreased the luciferase activity compared to Xanthohumol at 3.53 microM (p = 0.015). Xanthohumol at 7.05 microM or 14.11 microM achieved an inhibitory effect similar to that of interferon-alpha 2b (p > 0.05). Xanthohumol at 3.53 microM significantly reduced the hepatitis C virus RNA level compared to the negative control (p = 0.001). Although the results of Xanthohumol at 7.05 microM had a higher variation, Xanthohumol at the 7.05 microM and 14.11 microM decreased the hepatitis C virus RNA level to that achieved by interferon-alpha (p > 0.05). In conclusion, Xanthohumol displays anti-hepatitis C virus activity in a cell culture system and may be potentially used as an alternative or complementary treatment against the hepatitis C virus.

The hop constituent xanthohumol exhibits hepatoprotective effects and inhibits the activation of hepatic stellate cells at different levels.[Pubmed:25999863]

Front Physiol. 2015 May 6;6:140.

Xanthohumol is the principal prenylated flavonoid of the female inflorescences of the hop plant. In recent years, various beneficial Xanthohumol effects including anti-inflammatory, antioxidant, hypoglycemic activities, and anticancer effects have been revealed. This review summarizes present studies indicating that Xanthohumol also inhibits several critical pathophysiological steps during the development and course of chronic liver disease, including the activation and pro-fibrogenic genotype of hepatic stellate cells. Also the various mechanism of action and molecular targets of the beneficial Xanthohumol effects will be described. Furthermore, the potential use of Xanthohumol or a Xanthohumol-enriched hop extract as therapeutic agent to combat the progression of chronic liver disease will be discussed. It is notable that in addition to its hepatoprotective effects, Xanthohumol also holds promise as a therapeutic agent for treating obesity, dysregulation of glucose metabolism and other components of the metabolic syndrome including hepatic steatosis. Thus, therapeutic Xanthohumol application appears as a promising strategy, particularly in obese patients, to inhibit the development as well as the progression of non-alcoholic fatty liver disease.

Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3beta-Nrf2 signal axis.[Pubmed:28285192]

Redox Biol. 2017 Aug;12:311-324.

Abundant natural flavonoids can induce nuclear factor-erythroid 2 related factor 2 (Nrf2) and/or AMP-activated protein kinase (AMPK) activation, which play crucial roles in the amelioration of various inflammation- and oxidative stress-induced diseases, including acute lung injury (ALI). Xanthohumol (Xn), a principal prenylflavonoid, possesses anti-inflammation and anti-oxidant activities. However, whether Xn could protect from LPS-induced ALI through inducing AMPK/Nrf2 activation and its downstream signals, are still poorly elucidated. Accordingly, we focused on exploring the protective effect of Xn in the context of ALI and the involvement of underlying molecular mechanisms. Our findings indicated that Xn effectively alleviated lung injury by reduction of lung W/D ratio and protein levels, neutrophil infiltration, MDA and MPO formation, and SOD and GSH depletion. Meanwhile, Xn significantly lessened histopathological changes, reactive oxygen species (ROS) generation, several cytokines secretion, and iNOS and HMGB1 expression, and inhibited Txnip/NLRP3 inflammasome and NF-kappaB signaling pathway activation. Additionally, Xn evidently decreased t-BHP-stimulated cell apoptosis, ROS generation and GSH depletion but increased various anti-oxidative enzymes expression regulated by Keap1-Nrf2/ARE activation, which may be associated with AMPK and GSK3beta phosphorylation. However, Xn-mediated inflammatory cytokines and ROS production, histopathological changes, Txnip/NLRP3 inflammasome and NF-kappaB signaling pathway in WT mice were remarkably abrogated in Nrf2(-/-) mice. Our experimental results firstly provided a support that Xn effectively protected LPS-induced ALI against oxidative stress and inflammation damage which are largely dependent upon upregulation of the Nrf2 pathway via activation of AMPK/GSK3beta, thereby suppressing LPS-activated Txnip/NLRP3 inflammasome and NF-kappaB signaling pathway.

Xanthohumol improved cognitive flexibility in young mice.[Pubmed:25192637]

Behav Brain Res. 2014 Dec 15;275:1-10.

The protein palmitoylation cycle has been shown to be important for protein signaling and synaptic plasticity. Data from our lab showed a change in the palmitoylation status of certain proteins with age. A greater percentage of the NMDA receptor subunits GluN2A and GluN2B, along with Fyn and PSD95 proteins, were palmitoylated in the old mice. The higher level of protein palmitoylation was also associated with poorer learning scores. Xanthohumol is a prenylated flavonoid that has been shown to increase beta-oxidation in the livers of rodents, decreasing circulating free fatty acids in the serum. What is not known is whether the application of Xanthohumol could influence the palmitoylation status of proteins. In this study, young and old mice were fed a diet supplemented with Xanthohumol for 8 weeks. Spatial memory was assessed with the Morris water maze and protein palmitoylation quantified. The young Xanthohumol-treated mice showed a significant improvement in cognitive flexibility. However, this appeared to be associated with the young control mice, on a defined, phytoestrogen-deficient diet, performing as poorly as the old mice and Xanthohumol reversing this effect. The old mice receiving Xanthohumol did not significantly improve their learning scores. Xanthohumol treatment was unable to affect the palmitoylation of NMDA receptor subunits and associated proteins assessed in this study. This evidence suggests that Xanthohumol may play a role in improving cognitive flexability in young animals, but it appears to be ineffective in adjusting the palmitoylation status of neuronal proteins in aged individuals.

Effects of xanthohumol-rich extract from the hop on fatty acid metabolism in rats fed a high-fat diet.[Pubmed:24420065]

J Oleo Sci. 2014;63(2):159-68. Epub 2014 Jan 14.

Xanthohumol is the major prenylated flavonoid of female inflorescences of the hop plant (Humulus lupulus L.) and is a hydrophobic flavonoid. We examined the effects of dietary Xanthohumol-rich hop extract in obese rats that was induced by feeding a high-fat diet. Dietary Xanthohumol-rich hop extract significantly lowered the body weight gain of these rats compared to rats fed a high-fat diet without the extract. The increase of body weight, liver weight, and triacylglycerol levels in the plasma and liver of the rats fed a high-fat diet was ameliorated by dietary Xanthohumol-rich hop extract. Dietary Xanthohumol-rich hop extract tended to reduce hepatic fatty acid synthesis through the reduction of hepatic SREBP1c mRNA expression in the rats fed a high-fat diet. The excreted of triacylglycerol into feces also was promoted by dietary Xanthohumol-rich hop extract. Plasma adiponectin levels in the rats fed a high-fat diet also tended to be elevated by dietary Xanthohumol-rich hop extract. Thus, Xanthohumol-rich hop extract may inhibit the increase of body weight, liver weight, and triacylglycerol in the plasma and liver induced by feeding high-fat diet through the regulation of hepatic fatty acid metabolism and inhibition of intestinal fat absorption. Therefore, Xanthohumol-rich hop extract may exert preventive function on the increase of body weight and tissue triacylglycerol levels by overnutrition.

Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release.[Pubmed:28188927]

Free Radic Biol Med. 2017 Jul;108:247-257.

AIM: As the global population has reached 7 billion and the baby boom generation reaches old age, thrombosis has become the major contributor to the global disease burden. It has been reported that, in moderate doses, beer may protect against thrombosis. Xanthohumol (XN), an antioxidant, is found at high concentrations in hop cones (Humulus lupulus L.) and is a common ingredient of beer. Here, the aim of the present work was to investigate the effects of XN on antithrombotic and antiplatelet activities, and study its mechanism. APPROACH AND RESULTS: Using ferric chloride-induced carotid artery injury, inferior vena cava ligation model, and platelet function tests, we demonstrated that XN uniquely prevents both venous and arterial thrombosis by inhibiting platelet activation. Interestingly, in tail bleeding time studies, XN did not increase bleeding risk, which is recognized as a major limitation of current antithrombotic therapies. We also demonstrated that XN induces Sirt1 expression and thereby decreases reactive oxygen species (ROS) overload, prevents mitochondrial dysfunction, and reduces activated platelet-induced mitochondrial hyperpolarization, respiratory disorders, and associated membrane damage at low concentrations. In mitochondrial function assays designed to detect amounts of extracellular mitochondrial DNA (mtDNA), we found that XN prevents mtDNA release, which induces platelet activation in a DC-SIGN-dependent manner. CONCLUSIONS: XN exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing ROS accumulation and platelet mtDNA release without incurring a bleeding risk. This study has also provided novel insights into mechanisms of thrombotic diseases with possible therapeutic implications.

Xanthohumol, a novel anti-HIV-1 agent purified from Hops Humulus lupulus.[Pubmed:15550272]

Antiviral Res. 2004 Dec;64(3):189-94.

Xanthohumol, prenylchacone flavonoid, is a natural product with multi-biofunctions purified from Hops Humulus lupulus. Its anti-HIV-1 activity was tested in the present study. Results showed that Xanthohumol inhibited HIV-1 induced cytopathic effects, the production of viral p24 antigen and reverse transcriptase in C8166 lymphocytes at non-cytotoxic concentration. The EC50 values were 0.82, 1.28 and 0.50 microg/ml, respectively. The therapeutic index (TI) was about 10.8. Xanthohumol also inhibited HIV-1 replication in PBMC with EC50 value of 20.74 microg/ml. The activity of recombinant HIV-1 reverse transcriptase and the HIV-1 entry were not inhibited by Xanthohumol. The results from this study suggested that Xanthohumol is effective against HIV-1 and might serve as an interesting lead compound. It may represent a novel chemotherapeutic agent for HIV-1 infection. However, the mechanism of its anti-HIV-1 effect needs to be further clarified.

Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor.[Pubmed:28122154]

Cancer Sci. 2017 Apr;108(4):785-794.

Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin-containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest that there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells.

Insecticidal effects of extracts of Humulus lupulus (hops) L. cones and its principal component, xanthohumol.[Pubmed:28330519]

Bull Entomol Res. 2017 Aug;107(4):543-549.

Insecticidal effects of the dichloromethane, ethyl acetate, acetone, ethanol and methanol extracts of Humulus lupulus (hops) L. cones and its principal components, Xanthohumol was investigated on five stored pests, Sitophilus granarius (L.), Sitophilus oryzae (L.), Acanthoscelides obtectus (Say.), Tribolium castaneum (Herbst) and Lasioderma serricorne (F.). The mortality of adults of the insects treated with 2, 5, 5, 10 and 20 mg ml-1 concentrations of the extracts and xanthuhumol was counted after 24, 48, 72, 96 and 120 h. In order to determine the toxic effects of the substances tested against all tested insects, durations for 50% mortality of the adults, and LD50 values were also determined in the first 48 h by probit analysis. Our results also showed that Xanthohumol was more toxic against the pests in comparison with the extracts applications. LD50 values for Xanthohumol were found to be low dose as compared with the extracts. Xanthohumol was more toxic against S. granarius (L.) with 6.8 microg of LD50 value. Among the extracts, methanol extract was less effective than other extracts against all tested insects. The ethyl acetate extract of H. lupulus cones was the most effective extract against the tested pests. The quantitative amounts of Xanthohumol in the extracts were determined using a high-performance liquid chromatography. The quantitative data indicated that amount of Xanthohumol in the extracts increased with increase of polarity of the solvents used from methanol to dichloromethane. The methanol extract contained the high amount of Xanthohumol with 5.74 g/100 g extract (0.46 g/100 g plant sample).

Valosin-containing protein (VCP) inhibitor; impairs autophagosome maturation,Xanthohumol is one of the principal flavonoids isolated from hops, the inhibitor of diacylglycerol acetyltransferase (DGAT), COX-1 and COX-2, and shows anti-cancer and anti-angiogenic activities.

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