Humulone

Med Mol Morphol. 2013 Dec;46(4):203-9.

Humulone suppresses replication of respiratory syncytial virus and release of IL-8 and RANTES in normal human nasal epithelial cells.[Pubmed: 23381605 ]

Respiratory syncytial virus (RSV) is the major infectious agent causing serious respiratory tract inflammation in infants and young children. However, an effective vaccine and anti-viral therapy for RSV infection have not yet been developed. Hop-derived bitter acids have potent pharmacological effects on inflammation.
METHODS AND RESULTS:
Therefore, we investigated the effects of Humulone, which is the main constituent of hop bitter acids, on the replication of RSV and release of the proinflammatory cytokine IL-8 and chemokine RANTES in RSV-infected human nasal epithelial cells (HNECs). We found that Humulone prevented the expression of RSV/G-protein, formation of virus filaments and release of IL-8 and RANTES in a dose-dependent manner in RSV-infected HNECs.
CONCLUSIONS:
These findings suggest that Humulone has protective effects against the replication of RSV, the virus assembly and the inflammatory responses in HNECs and that it is a useful biological product for the prevention and therapy for RSV infection.

Carcinogenesis. 2007 Jul;28(7):1491-8.

Humulone inhibits phorbol ester-induced COX-2 expression in mouse skin by blocking activation of NF-kappaB and AP-1: IkappaB kinase and c-Jun-N-terminal kinase as respective potential upstream targets.[Pubmed: 17372274 ]

Humulone, a bitter acid derived from hop (Humulus lupulus L.), possesses antioxidative, anti-inflammatory and other biologically active activities.
METHODS AND RESULTS:
We investigated effects of Humulone on COX-2 expression in mouse skin stimulated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of Humulone (10 mumol) significantly inhibited TPA-induced epidermal COX-2 expression. Humulone also diminished TPA-induced DNA binding of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Pre-treatment with Humulone attenuated TPA-induced phosphorylation of p65 and nuclear translocation of NF-kappaB subunit proteins. Humulone blunted TPA-induced activation of inhibitory kappaB (IkappaB) kinase (IKK) in mouse skin, which accounts for its suppression of phosphorylation and subsequent degradation of IkappaBalpha. An in vitro kinase assay revealed that Humulone could directly inhibit the catalytic activity of IKKbeta. Humulone suppressed the activation of mitogen-activated protein kinases (MAPKs) in TPA-treated mouse skin.
CONCLUSIONS:
Taken together, Humulone suppressed TPA-induced activation of NF-kappaB and AP-1 and subsequent expression of COX-2 by blocking upstream kinases IKK and JNK, respectively, which may account for its antitumor-promoting effects on mouse skin carcinogenesis.

Biochem Biophys Res Commun. 2001 Nov 23;289(1):220-4.

Inhibition of angiogenesis by humulone, a bitter acid from beer hop.[Pubmed: 11708802]

METHODS AND RESULTS:
On the basis of our previous finding that Humulone, a bitter acid from beer hop extract, was a potent inhibitor of bone resorption and inhibited the catalytic activity of cyclooxygenase-2 (COX-2) and more potently the transcription of the COX-2 gene, we examined the effect of Humulone on angiogenesis, using chick embryo chorioallantoic membranes (CAMs) and vascular endothelial and tumor cells. Humulone significantly prevented in vivo angiogenesis in CAM in a dose-dependent manner with an ED(50) of 1.5 microg/CAM. Humulone also inhibited in vitro tube formation of vascular endothelial cells. Moreover, it suppressed the proliferation of endothelial cells and the production of vascular endothelial growth factor (VEGF), an angiogenic growth factor, in endothelial and tumor cells.
CONCLUSIONS:
Thus, Humulone is a potent angiogenic inhibitor, and may be a novel powerful tool for the therapy of various angiogenic diseases involving solid tumor growth and metastasis.

Front Neurosci . 2020 Oct 14;14:594708.

Humulone Modulation of GABA A Receptors and Its Role in Hops Sleep-Promoting Activity[Pubmed: 33177986]

Abstract Humulus lupulus L. (hops) is a major constituent of beer. It exhibits neuroactive properties that make it useful as a sleeping aid. These effects are hypothesized to be mediated by an increase in GABAA receptor function. In the quest to uncover the constituents responsible for the sedative and hypnotic properties of hops, recent evidence revealed that Humulone, a prenylated phloroglucinol derivative comprising 35-70% of hops alpha acids, may act as a positive modulator of GABAA receptors at low micromolar concentrations. This raises the question whether Humulone plays a key role in hops pharmacological activity and potentially interacts with other modulators such as ethanol, bringing further enhancement in GABAA receptor-mediated effects of beer. Here we assessed electrophysiologically the positive modulatory activity of Humulone on recombinant GABAA receptors expressed in HEK293 cells. We then examined Humulone interactions with other active hops compounds and ethanol on GABA-induced displacement of [3H]EBOB binding to native GABAA receptors in rat brain membranes. Using BALB/c mice, we assessed Humulone's hypnotic behavior with pentobarbital- and ethanol-induced sleep as well as sedation in spontaneous locomotion with open field test. We demonstrated for the first time that Humulone potentiates GABA-induced currents in α1β3γ2 receptors. In radioligand binding to native GABAA receptors, the inclusion of ethanol enhanced Humulone modulation of GABA-induced displacement of [3H]EBOB binding in rat forebrain and cerebellum as it produced a leftward shift in [3H]EBOB displacement curves. Moreover, the additive modulatory effects between Humulone, isoxanthohumol and 6-prenylnaringenin were evident and corresponded to the sum of [3H]EBOB displacement by each compound individually. In behavioral tests, Humulone shortened sleep onset and increased the duration of sleep induced by pentobarbital and decreased the spontaneous locomotion in open field at 20 mg/kg (i.p.). Despite the absence of Humulone effects on ethanol-induced sleep onset, sleep duration was increased dose-dependently down to 10 mg/kg (i.p.). Our findings confirmed Humulone's positive allosteric modulation of GABAA receptor function and displayed its sedative and hypnotic behavior. Humulone modulation can be potentially enhanced by ethanol and hops modulators suggesting a probable enhancement in the intoxicating effects of ethanol in hops-enriched beer. Keywords: GABAA receptors; allosteric modulation; electrophysiology; ethanol; Humulone; radioligand binding; sleep.

Leuk Res. 1998 Jul;22(7):605-10.

Induction of differentiation of myelogenous leukemia cells by humulone, a bitter in the hop.[Pubmed: 9680110]

The active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (VD3), inhibits proliferation and induces differentiation of myelomonocytic leukemia cells, but its clinical use is limited by the adverse effect of hypercalcemia. VD3 mobilizes calcium stores from bone by inducing the dissolution of bone mineral and matrix. We have recently found that Humulone, a bitter in the hop extract for beer brewing, effectively inhibits bone resorption.
METHODS AND RESULTS:
In this study we examined the effect of Humulone on the differentiation of human myelogenous leukemia cells. Humulone alone inhibited the growth of monoblastic leukemia U937 cells while only slightly increasing differentiation markers such as nitroblue tetrazolium (NBT)-reducing and lysozyme activities. Humulone effectively enhanced the differentiation-inducing action of VD3. Other myelomonocytic leukemia cells were induced to differentiate by VD3 and this was also enhanced by Humulone.
CONCLUSIONS:
Since Humulone is a less-toxic inhibitor of bone resorption, the combination of Humulone and VD3 may be useful in differentiation therapy of myelomonocytic leukemia.