Hispidulin

Hispidulin’s distinctive claim. Isolated from sage as a human-brain benzodiazepine-receptor binder ^{3Reference 3Kavvadias D et al. · 2003Constituents of sage (Salvia officinalis) with in-vitro affinity to human brain benzodiazepine receptorView study →}, it is a positive allosteric modulator that gives oral/i.p. anticonvulsive protection in seizure models and — importantly — was directly shown to cross the blood-brain barrier ^{2Reference 2Kavvadias D et al. · 2004The flavone hispidulin, a benzodiazepine-receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effectsView study →}; a separate line shows activity at α6-subunit-containing cerebellar GABA-A receptors, attenuating methamphetamine-induced hyperlocomotion ^{4Reference 4Liao YH et al. · 2016Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at α6-subunit-containing GABA-A receptors in the cerebellumView study →}.

Gap: all rodent/in-vitro, with no human anxiolytic or anticonvulsant data for the isolate and unresolved α6-vs-classic-benzodiazepine-site selectivity ^{2,4Reference 2Kavvadias D et al. · 2004The flavone hispidulin, a benzodiazepine-receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effectsView study →Reference 4Liao YH et al. · 2016Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at α6-subunit-containing GABA-A receptors in the cerebellumView study →}.

Hispidulin sensitizes ovarian cancer cells to TRAIL via AMPK activation (blocking Mcl-1 translation) ^{5Reference 5Yang JM et al. · 2010Hispidulin sensitises human ovarian cancer cells to TRAIL-induced apoptosis by AMPK activation blocking Mcl-1 translationView study →}, inhibits gallbladder cancer via HIF-1α ^{6Reference 6Gao H et al. · 2015Hispidulin inhibits proliferation and enhances chemosensitivity of gallbladder cancer cells by targeting HIF-1αView study →} and suppresses pancreatic-tumor angiogenesis via VEGFR2/PI3K/Akt/mTOR ^{7Reference 7He L et al. · 2011Hispidulin suppresses the angiogenesis and growth of human pancreatic cancer by targeting VEGFR2-mediated PI3K/Akt/mTOR signallingView study →}, with a 2020 review cataloguing the wider apoptosis/STAT3/NF-κB literature ^{8Reference 8Liu K et al. · 2020ReviewHispidulin: a promising flavonoid with diverse anti-cancer properties (review)View study →}.

Gap: the classic “flavone hits everything” pattern — scattered mechanisms, single labs per tumor, no isolate trials, and effective concentrations far above achievable plasma levels ^{8Reference 8Liu K et al. · 2020ReviewHispidulin: a promising flavonoid with diverse anti-cancer properties (review)View study →}.

Hispidulin suppresses Akt/NF-κB/STAT3 in LPS-activated BV2 microglia ^{9Reference 9Yu CI et al. · 2020Hispidulin inhibits neuroinflammation in LPS-activated BV2 microglia by attenuating Akt, NF-κB and STAT3View study →} and alleviates imiquimod psoriasis-like skin inflammation by reducing Th1/Th17 populations ^{10Reference 10Kim N et al. · 2020Hispidulin alleviates imiquimod-induced psoriasis-like skin inflammation by inhibiting splenic Th1/Th17 populations and keratinocyte activationView study →}.

Gap: preclinical only, and shared with most dietary flavones — not distinctive ^{9,10Reference 9Yu CI et al. · 2020Hispidulin inhibits neuroinflammation in LPS-activated BV2 microglia by attenuating Akt, NF-κB and STAT3View study →Reference 10Kim N et al. · 2020Hispidulin alleviates imiquimod-induced psoriasis-like skin inflammation by inhibiting splenic Th1/Th17 populations and keratinocyte activationView study →}.

Hispidulin attenuates bone resorption and osteoclast differentiation via suppression of RANKL-induced NF-κB and NFATc1 ^{11Reference 11Nepal M et al. · 2013Hispidulin attenuates bone resorption and osteoclastogenesis via the RANKL-induced NF-κB and NFATc1 pathwaysView study →}.

Gap: essentially a single isolate study, with no in-vivo bone-density confirmation for hispidulin alone ^{11Reference 11Nepal M et al. · 2013Hispidulin attenuates bone resorption and osteoclastogenesis via the RANKL-induced NF-κB and NFATc1 pathwaysView study →}.