Hinokiflavone and Related C-O-C-Type Biflavonoids as Anti-cancer Compounds:Properties and Mechanism of Action

Biflavonoids are divided in two classes:C-C type compounds represented by the dimeric compound amentoflavone and C-O-C-type compounds typified by hinokiflavone(HNK)with an ether linkage between the two connected apigenin units.This later sub-group of bisflavonyl ethers includes HNK,ochnaflavone,delicaflavone and a few other dimeric compounds,found in a variety of plants,notably Selaginella species.A comprehensive review of the anticancer properties and mechanism of action of HNK is provided,to highlight the anti-proliferative and anti-metastatic activities of HNK and derivatives,and HNK-containing plant extracts.The anticancer effects rely on the capacity of HNK to interfere with the ERK1-2/p38/NFκB signaling pathway and the regulation of the expression of the matrix metalloproteinases MMP-2 and MMP-9(with a potential direct binding to MMP-9).In addition,HNK was found to function as a potent modulator of pre-mRNA splicing,inhibit-ing the SUMO-specific protease SENP1.As such,HNK represents a rare SENP1 inhibitor of natural origin and a scaffold to design synthetic compounds.Oral formulations of HNK have been elaborated to enhance its solubility,to facilitate the compound delivery and to enhance its anticancer efficacy.The review shed light on the anticancer potential of C-O-C-type biflavonoids and specifically on the pharmacological profile of HNK.This compound deserves further attention as a regu-lator of pre-mRNA splicing,useful to treat cancers(in particular hepatocellular carcinoma)and other human pathologies.

Potential hepatic and renal toxicity induced by the biflavonoids from Ginkgo biloba

Evidence continues to grow on potential health risks associated with Ginkgo biloba and its constituents.While biflavonoid is a subclass of the flavonoid family in Ginkgo biloba with a plenty of pharmacological properties,the potential toxicological effects of biflavonoids remains largely unknown.Thus,the aim of this study was to investigate the in vitro and in vivo toxicological effects of the biflavonoids from Ginkgo biloba(i.e.,amentoflavone,sciadopitysin,ginkgetin,isoginkgetin,and bilobetin).In the in vitro cytotoxicity test,the five biflavonoids all reduced cell viability in a dose-dependent manner in human renal tubular epithelial cells(HK-2)and human normal hepatocytes(L-02),indicating they might have potential liver and kidney toxicity.In the in vivo experiments,after intragastrical administration of these biflavonoids at 20 mg·kg^–1·d^–1 for 7 days,serum biochemical analysis and histopathological examinations were performed.The activity of alkaline phosphatase was significantly increased after all the bifl avonoid administrations and widespread hydropic degeneration of hepatocytes was observed in ginkgetin or b ilobetin-treated mice.Moreover,the five biflavonoids all induced acute kidney injury in treated mice and the main pathological lesions were confirmed to the tubule,glomeruli,and interstitium injuries.As the in vitro and in vivo results suggested that these biflavonoids may be more toxic to the kidney than the liver,we further detected the mechanism of biflavonoids-induced nephrotoxicity.The increased TUNEL-positive cells were detected in kidney tissues of biflavonoids-treated mice,accompanied by elevated expression of proapoptotic protein BAX and unchanged levels of antiapoptotic protein BCL-2,indicating apoptosis was involved in biflavonoids-induced nephrotoxicity.Taken together,our results suggested that the five biflavonoids from Ginkgo biloba may have potential hepatic and renal toxicity and more attentions should be paid to ensure Ginkgo biloba preparations safety.

A New Biflavonoid from Stellera chamaejasme L.

A new biflavonoid, stelleranol, was isolated from the roots of Stellera chamaejasme L.. Its structure was determined by the analysis of MS and NMR data, especially 2D NMR spectra.

A new biflavonoid from Selaginella labordei Hieron.ex Christ

A new biflavonoid, 2,3-dihydro-5,5″,7,7,4′-pentahydroxy-6,6＂-dimethyl-[3′-O-4″]-biflavone 1 and two known biflavonoids 2,3＂-dihydroochnaflavone 2 and 2″,3″-dihydro-3′,3-biapigenin 3 were isolated from the herb of Selaginella labordei Hieron. ex Christ. Their structures were elucidated by spectroscopic methods. ？2009 Ke Li Chert. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Antimalarial potential of kolaviron,a biflavonoid from Garcinia kola seeds,against Plasmodium berghei infection in Swiss albino mice

Objective:To investigate the antimalarial potential of kolaviron(KV),a biflavonoid fraction from Garcinia kola seeds,against Plasmodium berghei(P.berghei)infection in Swiss albino mice.Methods:The study consists of seven groups of ten mice each.Groups I,II and III were normal mice that received com oil.KV1 and chloroquine(CQ),respectively.Groups IV,V,ⅥandⅦwere infected mice that received corn oil.CQ,KYI and KV2.respectively.CQ.KY1 and KV2were given at 10-,100-and 200-mg/kg daily,respectively for three consecutive days.Results:Administration of KV1 and KV2 significantly(P<0.05)suppressed P.berghei-infection in the mice by 85%and 90%.respectively,while CQ produced 87%suppression relative to untreated infected group after the fifth day of treatment.Also,KV2 significantly(P<0.05)increased the mean survival time of the infected mice by 175%.The biflavonoid prevented a drastic reduction in HCV from day4 of treatment,indicating its efficacy in ameliorating anaemia.Significant(P<0.05)oxidative stress assessed by the elevation of serum and hepatic malondialdehydewere observed in unlrealed P.berghei-infected mice.Specifically,senum and hepatic malondialdehyde levels increased by93%and 78%,resjiectively in the unlrealed infecled mice.Furlhennore,antioxidant indices,viz;superoxide dismutase.catalase,glutathione-s-transferasc.glualhione peroxidase and reduced gluathione decreased significantly(P<0.05)in the tissues of untreated P.berghei-infected mice.KV significantly(P<0.05)ameliorated the P.berghei-induced decrease in antioxidant status of the infected mice.Conclusions:This study shows that kolaviron,especially at 200 mg/kg,has high antimalarial activities in P.berghei-infected mice,in addition to its known antioxidant properties.

A review of traditional use, phytoconstituents and biological activities of Himalayan yew, Taxus wallichiana

Plants synthesize certain phytoconstituents for their protection, which, because they are not of primary need, are known as secondary metabolites. These secondary metabolites of plants, have often been found to have medicinal uses for human beings. One such gymnosperm having secondary metabolites of medicinal potential for humans is Taxus wallichiana （Himalayan yew）. Besides being the source of taxol, this plant has been investigated for its essential oil, diterpenoids, lignans, steroids, sterols and biflavonoids. Traditionally, it is used to treat disorders of the digestive, respiratory, nervous and skeletal systems. Although pharmacologically underexplored, it has been used for antiepileptic, anti-inflammatory anticancer, antipyretic, analgesic, immunomodulatory and antimicrobial activities. The present review compiles traditional uses, phytochemical constituents （specifically the secondary metabolites） pharmacological activities and the toxicity of T. wallichiana.

A BIFLAVONOID AMENTOFLAVONE FROM GARCINIA XANTHOCHYMUS FRUIT EXHIBITEDANTI-ANGIOGENIC ACTIVITIES IN ZEBRAFISH EMBRYOS

Edible fruits of Garcinia xanthochymus were traditionally used to treat diarrhoea and dysentery.Our previous work showed that some components of G.xanthochymus fruits induced apoptosis in colon cancer cells.In this study,the aril(edible pulp of the fruit)and seed of G.xanthochymus fruits were further investigated for their