Hispidulin

J. Funct. Foods, 2016, 27:392-405.

Ameliorative effects of hispidulin on high glucose-mediated endothelial dysfunction via inhibition of PKCβII-associated NLRP3 inflammasome activation and NF-κB signaling in endothelial cells[Reference: WebLink]

Endothelial dysfunction is closely relevant to atherosclerosis complications in diabetic patients. Hispidulin, a flavone derived from the herb Salvia plebeia R. Br., has numerous biological properties including anti-inflammatory and antioxidative effects, but the underlying mechanism of its anti-inflammatory action remains unclear. This study was designed to investigate the effects of Hispidulin on endothelial homeostasis and its mechanism.
METHODS AND RESULTS:
Hispidulin effectively inhibited high glucose-induced oxidative stress by attenuating PKCβII phosphorylation and downstream reactive oxygen species (ROS) production, furthermore reversing the loss of mitochondria membrane potential. Moreover, Hispidulin significantly suppressed the expression of NLRP3 inflammasome and IKKβ/NF-κB, and restored high glucose-impaired vasodilation in rat aorta.
CONCLUSIONS:
This study demonstrated that Hispidulin ameliorated high glucose-mediated endothelial dysfunction via inhibiting PKCβII-associated NLRP3 inflammasome activation and NF-κB signaling. Besides, these findings indicate the beneficial effects of Hispidulin on the improvement of endothelial dysfunction and explain its potential application in the prevention and treatment of diabetic vascular complications.

Eur J Pharmacol. 1988 Feb 16;147(1):1-6.

Hispidulin, a natural flavone, inhibits human platelet aggregation by increasing cAMP levels.[Pubmed: 2836213]

Hispidulin, a natural flavone, and theophylline inhibited platelet aggregation triggered by adenosine-5'-monophosphate, arachidonic acid, paf-acether and collagen.
METHODS AND RESULTS:
Hispidulin was 100-fold more potent than theophylline. A threshold concentration of PGE1 did not modify the anti-aggregatory effect of Hispidulin but potentiated the effect of theophylline. A threshold concentration of Hispidulin had no effect on the inhibitory action of theophylline. Hispidulin (100 microM) and theophylline (10 mM) increased the control cAMP level in platelets 4-fold. A threshold concentration of PGE1 had a small effect on Hispidulin-induced cAMP levels but increased the theophylline-induced cAMP levels 3-fold. Theophylline (10 mM)-induced cAMP levels were not modified by Hispidulin. We demonstrate a correlation between the inhibition of platelet aggregation and the increase in cAMP levels induced by Hispidulin.
CONCLUSIONS:
These data suggest that Hispidulin could inhibit platelet aggregation by elevating cAMP levels by a mechanism different from that of theophylline or PGE1.

Eur J Pharmacol. 2015 May 15;755:6-15.

Protective effect of hispidulin on kainic acid-induced seizures and neurotoxicity in rats.[Pubmed: 25746462]

Hispidulin is a flavonoid compound which is an active ingredient in a number of traditional Chinese medicinal herbs, and it has been reported to inhibit glutamate release. The purpose of this study was to investigate whether Hispidulin protects against seizures induced by kainic acid, a glutamate analog with excitotoxic properties.
METHODS AND RESULTS:
The results indicated that intraperitoneally administering Hispidulin (10 or 50mg/kg) to rats 30min before intraperitoneally injecting kainic acid (15mg/kg) increased seizure latency and decreased seizure score. In addition, Hispidulin substantially attenuated kainic acid-induced hippocampal neuronal cell death, and this protective effect was accompanied by the suppression of microglial activation and the production of proinflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α in the hippocampus. Moreover, Hispidulin reduced kainic acid-induced c-Fos expression and the activation of mitogen-activated protein kinases in the hippocampus.
CONCLUSIONS:
These data suggest that Hispidulin has considerable antiepileptic, neuroprotective, and antiinflammatory effects on kainic acid-induced seizures in rats.

Cell Biochem Biophys. 2014 Jun;69(2):311-7.

Hispidulin exerts anti-osteoporotic activity in ovariectomized mice via activating AMPK signaling pathway.[Pubmed: 24338527]

To investigate the effect of Hispidulin on ovariectomy (OVX)-induced bone loss in mice.
METHODS AND RESULTS:
Female mice subjected to OVX were treated with Hispidulin for 8 weeks. The total body bone mineral density was measured at the beginning and after the OVX at a time interval of 4 weeks. Micro-computed tomography of the tibia, bone histomorphometric analysis of the femur, and biomechanical analysis of tibia, vertebra, and femoral head were performed to fully evaluate the anti-osteoporotic effect of Hispidulin. Western blot analysis was performed to determine the level of activated AMPK. Hispidulin treatment effectively prevented OVX-induced body weight loss and attenuated OVX-induced bone loss. Hispidulin treatment also decreased trabecular spacing in OVX mice. The suppressing effect of Hispidulin on osteoclast surface and number was also found via histomorphometric analysis. Western blot analysis revealed that Hispidulin significantly elevated the activated AMPK levels.
CONCLUSIONS:
Our findings suggest that Hispidulin exerts anti-osteoporotic and bone resorption attenuating effects via activating the AMPK signaling pathway.

Exp Cell Res. 2015 Mar 15;332(2):236-46.

Hispidulin inhibits proliferation and enhances chemosensitivity of gallbladder cancer cells by targeting HIF-1α.[Pubmed: 25499970 ]

Gallbladder cancer (GBC) is an aggressive malignancy of the bile duct, which is associated with a low (5-year) survival and poor prognosis. The transcription factor HIF-1α is implicated in the angiogenesis, cell survival, epithelial mesenchymal transition (EMT) and invasiveness of GBC.
METHODS AND RESULTS:
In this study, we have investigated the role of HIF-1α in the pathobilogy of GBC and effect of Hispidulin on the molecular events controlled by this transcription factor. We observed that Hispidulin caused induction of apoptosis, blockade of growth and cell cycle progression in GBC cells. Our results have demonstrated for the first time that Hispidulin-exerted anti-tumor effect involved the suppression of HIF-1α signaling. Hispidulin was found to repress the expression of HIF-1α protein dose-dependently without affecting the HIF-1α mRNA expression. In addition, the inhibition of HIF-1α protein synthesis was revealed to be mediated through the activation of AMPK signaling. Hispidulin also sensitized the tumor cells to Gemcitabine and 5-Fluoroucil by down-regulating HIF-1α/P-gp signaling.
CONCLUSIONS:
Given the low cost and exceedingly safe profile, Hispidulin appears to be a promising and novel chemosensitizer for GBC treatment.

Cancer Sci., 2011, 102(1):219-25.

Hispidulin, a small flavonoid molecule, suppresses the angiogenesis and growth of human pancreatic cancer by targeting vascular endothelial growth factor receptor 2-mediated PI3K/Akt/mTOR signaling pathway.[Pubmed: 21087351]

Hispidulin, an active component from Artemisia vestita, a traditional Tibetan medicinal plant, has been shown to possess anti-inflammatory and anti-oxidative activities. However, the functional role of Hispidulin on tumor growth and angiogenesis has not been elucidated.
METHODS AND RESULTS:
We found that Hispidulin significantly inhibited human pancreatic tumor growth in xenograft mice when s.c. treated at a dosage of 20 mg/kg daily, and this effect was accompanied with a potent inhibition on angiogenesis. When examining the cytotoxicity of Hispidulin on HUVECs and pancreatic cancer cells in vitro, we found that HUVECs were more susceptible to the treatment, suggesting angiogenesis might be the primary target of Hispidulin. Our results further showed that Hispidulin inhibited vascular endothelial growth factor (VEGF)-induced cell migration, invasion, and capillary-like structure formation of HUVECs in a dose-dependent manner. In ex vivo and in vivo angiogenesis assays, we showed that Hispidulin suppressed VEGF-induced microvessel sprouting of rat aortic rings and corneal neovascularization in C57/BL6 mice. To understand the underlying molecular basis, we next examined the effects of Hispidulin on different molecular components in treated HUVECs, and found that Hispidulin suppressed the VEGF-triggered activation of VEGF receptor 2, PI3K, Akt, mTOR, and ribosomal protein S6 kinase, but had little effect on focal adhesion kinase or extracellular signal-regulated kinase at an effective concentration.
CONCLUSIONS:
Taken together, our results indicate that Hispidulin targets the VEGF receptor 2-mediated PI3K/Akt/mTOR signaling pathway in endothelial cells, leading to the suppression of pancreatic tumor growth and angiogenesis.

J Ethnopharmacol. 2015 May 26;166:18-22.

Hispidulin, a constituent of Clerodendrum inerme that remitted motor tics, alleviated methamphetamine-induced hyperlocomotion without motor impairment in mice.[Pubmed: 25764963]

Previously, we found a patient with an intractable motor tic disorder that could be ameliorated by the ground leaf juice of Clerodendrum inerme (CI). Furthermore, the ethanol extract of CI leaves effectively ameliorated methamphetamine-induced hyperlocomotion (MIH) in mice, an animal model mimicking the hyper-dopaminergic status of tic disorders/Tourette syndrome, schizophrenia, or obsessive-compulsive disorder. Here, we for the first time identified a constituent able to reduce MIH from the CI ethanol extract that might represent a novel lead for the treatment of such disorders.
METHODS AND RESULTS:
The ethanol extract of CI was sub-divided into n-hexane, dichloromethane, n-butanol and water fractions. Using MIH alleviation as a bioassay, active compounds were identified in these fractions using silica gel chromatography, recrystallization and proton NMR spectroscopy. The dichloromethane and n-hexane fractions were active in the bioassay. Further subfractionation and re-crystallization resulted in an active compound that was identified to be Hispidulin by proton NMR spectroscopy. Hispidulin significantly alleviated MIH in mice at doses that did not affect their spontaneous locomotor activity or performance in the rotarod test, a measure for motor coordination.
CONCLUSIONS:
Hispidulin is a flavonoid that has been isolated from several plants and reported to have anti-oxidative, anti-inflammatory and anti-cancer activities. Here, we for the very first time found that Hispidulin can also alleviate MIH at doses that did not impair motor activity, suggesting a therapeutic potential of Hispidulin in hyper-dopaminergic disorders.