Miguel Payá

A review of natural products and plants as potential antidiabetic drugs

The present paper reviews the active, natural principles and crude extracts of plants which have been experimentally studied for hypoglycemic activity in the last ten years. Phytoconstituents with known structures have been classified in appropriate chemical groups and the active crude extracts have been listed alphabetically according to genus. Data are reported on their pharmacological activity, mechanism of action, toxicity and other properties.

Structure-activity relationships of polymethoxyflavones and other flavonoids as inhibitors of non-enzymic lipid peroxidation.

Polymethoxylated flavones and C-glycosyl derivatives isolated from medicinal plants besides other flavonoid compounds were studied for their influence on lipid peroxidation induced by FeSO4+ cysteine in rat liver microsomes. A number of hydroxyflavones (e.g. luteolin); C-glycosyl-flavones (e.g. orientin); methoxyflavones (e.g. gardenin D) and flavonols (e.g. datiscetin), as well as the flavanol leucocyanidol and the biflavone amentoflavone behaved as inhibitors of non-enzymic lipid peroxidation. Structure-activity relationships were established and it was observed that the structural features for active polyhydroxylated compounds were different from those of polymethoxylated flavones, antiperoxidative flavonoids possessing a high lipophilicity.

Inhibitory effects of phenolic compounds on CCl4-induced microsomal lipid peroxidation.

The antiperoxidative effects of 35 phenolic compounds, most of them belonging to the flavonoid class, were investigated using CCl4-induced peroxidation of rat liver microsomes. This system was rather insensitive to gallic acid, methyl gallate and ellagic acid. Nevertheless it was inhibited by flavonoids and structure/activity relationships were established. The most potent compounds were gardenin D, luteolin, apigenin (flavones), datiscetin, morin, galangin (flavonols), eriodictyol (flavanone), amentoflavone (biflavone) and the reference compound, (+)-catechin. The natural polymethoxyflavone gardenin D has shown a potency comparable to that of (+)-catechin and higher than that of silybin. Thus, it may be considered as a new type of natural antioxidant with potential therapeutical applications.

The synthesis and effect of fluorinated chalcone derivatives on nitric oxide production

Dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, were synthesized and evaluated for their influence on nitric oxide production. Some of them, chalcones 1, 5, 7, 10, 11 and 17, inhibited NO production with an IC(50) in the submicromolar range; 17 is especially noteworthy because of its potency (IC(50) 30nM). These effects were not the consequence of a direct inhibitory action on enzyme activity but the inhibition of enzyme expression.

Morelloflavone, a novel biflavonoid inhibitor of human secretory phospholipase A2 with anti-inflammatory activity.

The flavanonylflavone morelloflavone inhibited secretory phospholipase A2 (PLA2) in vitro, with a high potency on the human recombinant synovial and bee venom enzymes (IC50 = 0.9 and 0.6 microM, respectively). The inhibition was apparently irreversible. In contrast, the compound was inactive on cytosolic PLA2 activity from human monocytes. Morelloflavone scavenged reactive oxygen species generated by human neutrophils (IC50 = 2.7 and 1.8 microM for luminol and lucigenin, respectively) but did not modify cellular responses such as degranulation or eicosanoid release. This biflavonoid exerted anti-inflammatory effects in animal models, with a potent inhibition of 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear inflammation in mice after topical administration. In this test, morelloflavone was found to decrease oedema and myeloperoxidase levels in ear homogenates ID50 = 58.5 and 74.3 micrograms/ear, respectively). In contrast, this biflavonoid failed to modify arachidonic acid-induced ear inflammation or eicosanoid levels in ear homogenates. A significant anti-inflammatory effect was also observed in the mouse paw carrageenan edema after oral administration, with the highest inhibition at 3 hr after induction of inflammation. Morelloflavone is an inhibitor of secretory PLA2 with selectivity for groups II and III enzymes and may be a pharmacological tool. In addition, it shows anti-inflammatory activity apparently not related to the synthesis of eicosanoids, but likely dependent on other mechanisms such as scavenging of reactive oxygen species.

Avarol and avarone, two new anti-inflammatory agents of marine origin.

The anti-inflammatory activity of avarol and avarone, sesquiterpenoid derivatives from the Mediterranean sponge Dysidea avara, was investigated. Both compounds potently inhibited paw oedema induced by carrageenan (approximated ED50 = 9.2 and 4.6 mg/kg, p.o., respectively) as well as ear oedema induced by 12-O-tetradecanoylphorbol acetate (TPA; ED50 = 97 and 397 micrograms/ear, respectively) in mice, with effects comparable to those of indomethacin. In A23187-stimulated rat peritoneal leukocytes, avarol showed an IC50 = 0.6 and 1.4 microM for inhibition of leukotriene B4 and thromboxane B2 release, respectively, with avarone showing a slightly lower potency. Both marine metabolites failed to show xanthine oxidase inhibitory activity or superoxide scavenging effects but were potent inhibitors of superoxide generation in rat peritoneal leukocytes activated by different stimuli, with an IC50 below the microM range. Only avarol was able to inhibit human recombinant synovial phospholipase A2 activity with an IC50 = 158 microM, and thus this compound showed a potency higher than that of mepacrine. Avarol and avarone effectively control acute inflammation in experimental models after either oral or topical administration and their anti-inflammatory activity may result from inhibition of eicosanoid release and depression of superoxide generation in leukocytes.

Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines.

The scavenging and iron-reducing properties of a series of benzylisoquinolines of natural and synthetic origin have been studied. Bulbocapnine, boldine, glaucine, and stepholidine acted as scavengers of hydroxyl radical in the deoxyribose degradation by Fe(3+)-EDTA + H2O2. On the contrary, laudanosoline, apomorphine, protopapaverine, anonaine, and tetrahydroberberine increased deoxyribose degradation by a mechanism related to generation of superoxide anion. Only apomorphine had a stimulating effect in the system using citrate instead of ethylenediaminetetraacetic acid (EDTA) as well as in the absence of chelator. Apomorphine also stimulated DNA damage by Cu2+. The iron-ion reducing ability of apomorphine and laudanosoline was confirmed using cytochrome c. Both compounds scavenged peroxyl radicals in an aqueous medium, while in Fe(3+)-induced microsomal lipid peroxidation apomorphine acted as an inhibitor and laudanosoline stimulated the process. It is suggested that in microsomes the chain-breaking antioxidant properties of apomorphine overcome its possible influence on redox cycling of iron, or prooxidant properties.

Accelerated communication: Effects of flavonoids on Naja Naja and human recombinant synovial phospholipases A2 and inflammatory responses in mice

Six flavonoid derivatives were tested for their influence on Naja naja and human recombinant synovial phospholipase A2. They showed a selectivity for the last enzyme with IC50 = 14.3, 17.6, 12.2 and 28.2 microM for quercetagetin, kaempferol-3-O-galactoside, scutellarein and scutellarein-7-O-glucuronide, respectively, while reduced effects were observed for hispidulin and hibifolin. After topical application all the flavonoids inhibited 12-O-tetradecanoylphorbol-13-acetate-induced ear oedema in mice with a potency comparable to that of indomethacin and they were also able to inhibit carrageenan-induced mouse paw oedema at a dose of 150 mg/kg p.o. The blockade of the free hydroxyl at C-7 or C-6 reduced the anti-inflammatory activity and also the inhibitory effect on human recombinant synovial phospholipase A2. These results are in accordance with the notion that group II phospholipases A2 may play a role in experimental inflammation, although several mechanisms seems to be involved in the anti-inflammatory effect of this group of flavonoids.

Modulation of acute and chronic inflammatory processes by cacospongionolide B, a novel inhibitor of human synovial phospholipase A2

Cacospongionolide B is a novel marine metabolite isolated from the sponge Fasciospongia cavernosa. In in vitro studies, this compound inhibited phospholipase A2 (PLA2), showing selectivity for secretory PLA2 (sPLA2) versus cytosolic PLA2 (cPLA2), and its potency on the human synovial enzyme (group II) was similar to that of manoalide. This activity was confirmed in vivo in the 8 h zymosan‐injected rat air pouch, on the secretory enzyme accumulating in the pouch exudate. Cacospongionolide B, that is bioavailable when is given orally, reduced the elevated levels of sPLA2 present in paw homogenates of rats with adjuvant arthritis. This marine metabolite showed topical anti‐inflammatory activity on the mouse ear oedema induced by 12‐O‐tetradecanoylphorbol acetate (TPA) and decreased carrageenin paw oedema in mice after oral administration of 5, 10 or 20 mg kg−1. In the mouse air pouch injected with zymosan, cacospongionolide B administered into the pouch, induced a dose‐dependent reduction in the levels of eicosanoids and tumour necrosis factor α (TNFα) in the exudates 4 h after the stimulus. It also had a weak effect on cell migration. The inflammatory response of adjuvant arthritis was reduced by cacospongionolide B, which did not significantly affect eicosanoid levels in serum, paw or stomach homogenates and did not induce toxic effects. Cacospongionolide B is a new inhibitor of sPLA2 in vitro and in vivo, with anti‐inflammatory properties in acute and chronic inflammation. This marine metabolite was active after oral administration and able to modify TNFα levels, and may offer an interesting approach in the search for new anti‐inflammatory agents.

NF-κB and STAT3 Inhibition as a Therapeutic Strategy in Psoriasis: In Vitro and In Vivo Effects of BTH

Benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) is a simple and interesting synthetic derivative of petrosaspongiolide M, a natural compound isolated from a sea sponge with demonstrated potent anti-inflammatory activity through inhibition of the NF-κB signaling pathway. In the present study, we report the in vitro and in vivo pharmacological effect of BTH on some parameters related to the innate and adaptive response in the pathogenesis of psoriasis. BTH inhibited the release of some of the key psoriatic cytokines such as tumor necrosis factor α, IL-8, IL-6, and CCL27 through the downregulation of NF-κB in normal human keratinocytes. Moreover, it impaired signal transducers and activators of transcription 3 (STAT3) phosphorylation and translocation to the nucleus, which resulted in decreased keratinocyte proliferation. These results were confirmed in vivo in two murine models of psoriasis: the epidermal hyperplasia induced by 12-O-tetradecanoylphorbol-13-acetate and the imiquimod-induced skin inflammation model. In both cases, topical administration of BTH prevented skin infiltration and hyperplasia through suppression of NF-κB and STAT3 phosphorylation. Our results confirm the pivotal role of both transcriptional factors in skin inflammation, as occurs in psoriasis, and highlight the potential of small molecules as therapeutic agents for the treatment of this skin disease, with BTH being a potential candidate for future drug research.