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Flavonoids are naturally occurring compounds that show health benefits on the liver. However, there is little investigation about identification and evaluation of new flavonoid-containing drugs for cholestatic liver disease, one of the most common liver illnesses. We aimed to a systematic search regarding efficacy of flavonoids for treatment of cholestatic liver disease, and then evaluate naringenin (NG) as representative flavonoid in an obstructive cholestasis model. We searched for information of experimental and clinical studies in four major databases without time and language limits. Intervention was defined as any flavonoid derivate compared with other flavonoid, placebo, or without comparator. In addition, we evaluated NG on a bile duct-ligated model in order to contribute evidence of its actions. Eleven experimental reports that support the efficacy of flavonoids in cholestatic liver disease were identified. However, there was no homogeneity in efficacy endpoints evaluated and methodology. On the other hand, NG showed beneficial effects by improving specific metabolic (cholesterol and lipoproteins) and liver damage (bilirubin and alkaline phosphatase) biomarkers. The review lacks homogeneous evidence about efficacy of flavonoids in experimental settings, and is susceptible to risk for bias. NG only showed improvements in specific disease biomarkers. More investigation is still needed to determine its potential for drug development.

Previously, we described tracheal rat rings relaxation by several flavonoids, being 6-hydroxyflavone (6-HOF) the most active derivative of the series. Thus, its mechanism of action was determined in an ex vivo tracheal rat ring bioassay. The anti-asthmatic effect was assayed in in vivo OVAlbumin (OVA)-sensitized guinea pigs. Finally, the toxicological profile of 6-HOF was studied based on Organization of Economic Cooperation and Development guidelines with modifications. 6-HOF-induced relaxation appears to be related with receptor-operated calcium channel and voltage-operated calcium channel blockade as the main mechanism of action, and also through the production of relaxant second messengers NO and cGMP. Molecular docking supports that 6-HOF acts as calcium channel blocker and by activation of nitric oxide synthase. In addition, the in vivo anti-asthmatic experiments demonstrate the dose-dependent significant anti-allergic effect of 6-HOF induced by OVA, with best activity at 50 /kg. Finally, toxicological studies determined a LD50 > 2,000 mg/kg and, after 28 day of treatment with 6-HOF (50 mg/kg) by intragastric route, mice did not exhibit evidence of any significant toxicity. In conclusion, experiments showed that 6-HOF exerts significant relaxant activity through calcium channel blockade, and possibly, by NO/cGMP-system stimulation on rat trachea, which interferes with the contraction mechanism of smooth muscle cells in the airways. In addition, the flavonoid shows potential anti-asthmatic properties in an anti-allergic pathway. Furthermore, because the pharmacological and safety evidence, we propose this flavonoid as lead for the development of a novel therapeutic agent for the treatment of asthma and related respiratory diseases., (© 2018 Wiley Periodicals, Inc.)

Agastache mexicana has gained importance during the last decade as a natural source of bioactive compounds, mainly due to the antidiabetic, antihyperlipidemic, and vasorelaxant effects derived from its flavonoids, particularly tilianin. The goal of this work was to evaluate the production of tilianin during the in-vitro process of morphogenesis leading to plant regeneration and to investigate the vasorelaxant activity of its methanolic extracts. The cultures were established from nodal segments and leaf explants, inoculated on Murashige and Skoog (MS) media supplemented with various concentrations of benzyl aminopurine (BAP) alone or in combination with 2,4-Dichlorophenoxyacetic acid (2,4-D). Callus inductions were obtained in all treatments from both types of explants, but the presence of auxin was essential. Maximal shoot multiplication and elongation was achieved with 0.1 mg/l 2,4-D and 1.0 mg/l BAP from nodal- segment explants. Shoots were rooted in 75% MS medium and the plantlets were transferred to a greenhouse with 33% average survival. Analysis of tilianin production in methanolic extracts from calli (0.15-2.01 ± 0.06 mg/g dry weight), shoots (4.45 ± 0.01 mg/g DW), and whole plants (9.77 ± 0.02 mg/g DW) derived from in-vitro cultured nodal segments reveals that tilianin accumulation is associated with high cell differentiation and morphogenetic response to the plant-growth regulators. All of the extracts showed strong vasorelaxant activity, as compared to those of wild plant extracts. These results indicate that plant-tissue cultures of A. mexicana possess vast potential as a source of tilianin and other bioactive compounds.

Extensive knowledge of diabetes and its complications is helpful to find new drugs for proper treatment to stop degenerative changes derived from this disease. In this context, chrysin (5,7-dihydroxyflavone) is a natural product that occurs in a variety of flowers and fruits with anti-inflammatory and antidiabetic effects, among others. Thus, a diabetic model in athymic nude mice was developed and used to establish the ability of chrysin to decrease the secretion of pro-inflammatory cytokines. Also, it was determined the acute (50 mg/kg) and sub-acute (50 mg/kg/day/10 days) antidiabetic and antihyperlipidemic activities after the period of time treatment. Results indicate that chrysin has significant acute antihyperglycemic and antidiabetic effects in nude diabetic mice ( p < 0.05). Moreover, triglyceride blood levels were reduced and IL-1β and TNF-α were diminished after 10 days' treatment compared with control group ( p < 0.05). In conclusion, it was found that chrysin could produce similar effects as metformin, a drug used for the treatment of diabetes, since both test samples decreased glucose and triglycerides levels, they impaired the generation of pro-inflammatory cytokines involved in the development of diabetes and its consequences, such as atherosclerosis and other cardiovascular diseases., Competing Interests: The authors declare no conflict of interest.

Flavonoids from medicinal plants have been used in traditional medicine to treat a variety of prevalent diseases. Flavones activate the signaling pathways promoting fuel metabolism and insulin sensitizing in hepatocytes and adipocytes, which suggests that flavones may have the potential to exert in vivo antidiabetic and antihyperlipidemic effects. Thus, the aim of the current study was to determine the antidiabetic, antihyperlipidemic and anti-inflammatory effects of tilianin in diabetic rats. Also, to understand the mechanism involved using in vitro 3T3-L1 cells and tissues from experimental animals treated with test samples through molecular profile studies. Non insulin-dependent diabetic mellitus (NIDDM) rats were treated over a short period (for 10 days) with 60mg/Kg/day of tilianin. After treatment, a biochemical blood profile was determined. Also, adipose and thoracic aortic tissues were used to determine pro-inflammatory profile, adiponectin and adhesion molecules by real-time PCR. In 3T3-L1 cells pretreated with tilianin (10μM), PPARα, PPARγ, GLUT4, FATP-1 and ACSL-1 mRNA expression were measured. In order to explain the potential PPARα interaction with tilianin, a docking study with PPARα was carried out. Thus, intragastric administration of tilianin and metformin induced a decrease in plasma glucose (GLU) in diabetic rats on day 6, and remained significantly lower until the end of the treatment; also blood triacylglycerides (TAG) and cholesterol (CHOL) (p<0.05) were diminished. Moreover, IL-1β and IL-18 expression was significantly decreased in adipose tissue (p<0.05); meanwhile adiponectin was significantly overexpressed (p<0.05). Besides, ICAM-1 expression was significantly reduced in aortic tissue (p<0.05). In 3T3-L1 cells it was found that tilianin increased PPARα and ACSL1 mRNA levels (p<0.05). Finally, tilianin docking studies with PPARα showed polar interactions with Glu269, Tyr314, His 440 and Tyr464 residues. In conclusion, short-term tilianin treatment might exert its antidiabetic and antihyperlipidemic effect by modulating a pro-inflammatory profile, and increasing adiponectin expression. In addition, our results suggest the possible interaction of tilianin with PPARα., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Ethnopharmacological Relevance: Agastache mexicana is used in Mexican traditional medicine for the treatment of hypertension, anxiety and related diseases., Aim of the Study: Current work was developed to establish pharmacological/toxicological parameters of tilianin, a flavone extracted from Agastache mexicana in order to propose it for clinical trials., Materials and Methods: Acute and sub-acute toxicology studies in Imprinting Control Region (ICR) mice and median effective dose (ED50) determination in conscious spontaneously hypertensive rats (SHR) were done., Results: A median lethal dose (LD50) of 6624 mg/kg (6201, 7076) in mice and significant antihypertensive effect (ED50=53.51 mg/kg) in SHR were determined. Moreover, sub-acute oral administration of tilianin did not alter body weight, clinical chemistry parameters (alanine amino-transferase, aspartate amino-transferase, total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, glucose and insulin), and also did not induce any toxic or adverse effects on kidney, heart, liver, and lung functions., Conclusions: We have shown that tilianin, isolated from Agastache mexicana, was not toxic for rodents. Also, its antihypertensive effect was dose-dependent and ED50 (53.51 mg/kg) calculated was lesser than LD50 determined (6624 mg/kg), which suggest a wide range of pharmacology-toxicology patterns. Results support the hypothesis that tilianin must be investigated and developed for clinical trials as antihypertensive drug., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: To optimize the obtention of tilianin, an antihypertensive flavonoid isolated from Agastache mexicana (Lamiaceae), a medicinal plant used in Mexico for the treatment of hypertension. Also, a validated HPLC method to quantify tilianin from different extracts, obtained by several extraction methods, was developed., Materials and Methods: The aerial parts of Agastache mexicana were dried at different temperatures (22, 40, 50, 90, 100 and 180°C) and the dry material was extracted with methanol by maceration to compare the content of the active constituent tilianin in the samples. Furthermore, EtOH:H(2)O (7:3), infusion and decoction extracts were prepared from air-dried samples at room temperature to compare the content and composition of the different extraction methods. Moreover, an ex vivo vasorelaxant test on endothelium-intact aortic rat rings was conducted, in order to correlate the presence of tilianin with the activity of each extract., Results: Higher concentration and amounts of tilianin were determined from chromatograms in the obtained methanolic extracts from plant material dried at 90, 50, 40 and 22°C, followed by 100°C; however, lower concentrations were observed in dried at 180°C and EtOH:H(2)O (7:3). It is worth to notice that methanolic extracts with higher amount of tilianin were the most potent vasorelaxant extracts, even though these extracts were less potent than carbachol, a positive control used. Finally, decoction, infusion and EtOH:H(2)O (7:3) extracts did not show any vasorelaxant effect., Conclusion: Results suggest that extracts with higher concentration of tilianin possess the best vasorelaxant activity, which allowed us to have a HPLC method for future quality control for this medicinal plant., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In our search for potential antihypertensive agents, a series of structurally-related flavonoids was screened. Ex vivo and in vitro biological evaluations indicated that compounds 1-7 displayed an important vasorelaxant effect on the endothelium-intact (E(+)) and -denuded (E(-)) aortic rings test. Their in vitro anti-calmodulin (CaM) properties were determined by means of the inhibitory effect on the activation of the calmodulin-sensitive cAMP phosphodiesterase (PDE1) assay. Molecular modeling experiments were also performed in order to explore the probable binding site of 1-7 with CaM, and the results indicated that they could bind to the protein in the same pocket as trifluoperazine (TFP), a well-known CaM inhibitor., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Current investigation was undertaken to elucidate the mode of action of tilianin, isolated from Agastache mexicana, as a vasorelaxant agent on in vitro functional rat thoracic aorta test and to investigate the in vivo antihypertensive effect on spontaneously hypertensive rats (SHR). Tilianin (0.002-933 microM) induced significant relaxation in a concentration- and endothelium-dependent and -independent manners in aortic rings pre-contracted with noradrenaline (NA, 0.1 microM), and serotonin (5-HT, 100 microM). Effect was more significant (p < 0.05) in endothelium-intact (+E) aorta rings than when endothelium was removed(E). Pre-treatment with N-nitro-L-arginine methyl ester (L-NAME; 10 microM) or 1-H-[1,2,4]-oxadiazolo-[4,3a]-quinoxalin-1-one (ODQ, 1 microM) produced a significant change of the relaxant response and activity was markedly inhibited, but not by indomethacin (10 microM) or atropine (1 microM). Furthermore, tilianin (130 microM) provoked a significant displacement to the left in the relaxation curve induced by sodium nitroprusside (SNP; 0.32 nM to 0.1 microM). Moreover, tilianin induced significant in vitro NO overproduction (1.49 +/- 0.86 microM of nitrites/g of tissue) in rat aorta compared with vehicle (p < 0.05). In addition, pre-treatment with tetraethylammonium (TEA, 5 mM) and 2-aminopyridine (2-AP, 0.1 microM) shifted to the right the relaxant curve induced by tilianin (p < 0.05). Finally, a single oral administration of tilianin (50 mg/kg) exhibited a significant decrease in systolic and diastolic blood pressures (p < 0.05) in SHR model. Results indicate that tilianin mediates relaxation mainly by an endothelium-dependent manner,probably due to NO release, and also through an endothelium-independent pathway by opening K+ channels, both causing the antihypertensive effect.

Objetivo: Determinar el efecto antidepresivo de tilianina obtenida de Agastache mexicana en modelos in vivo, in vitro e in silico. Antecedentes: La depresión es un trastorno relacionado con cambios neuroquímicos. Existe relación entre la depresión y la alteración de la neurotransmisión serotoninérgica y noradrenérgica. Recientemente, se buscan fármacos para el tratamiento de la depresión. La principal fuente para la obtención de fármacos son las plantas medicinales. En México, el uso de Agastache mexicana, ha demostrado efecto ansiolítico relacionado a interacción con el receptor a benzodiazepinas GABAA, así como efecto de liberación de serotonina in vitro. Estos efectos son atribuidos a tilianina, un flavonoide presente en dicha especie. Métodos: Tilianina se obtuvo por maceración exhaustiva a partir de A. mexicana, colectada en Tlalnepantla, Morelos, México. La purificación se realiza a través de columna cromatográfica (abierta) fase normal. El efecto de tilianina a dosis de 16, 50 y 156.6 mg/kg fue evaluado 30min después de su administración intraperitoneal en ratas macho de la cepa Wistar de 240g, mismas que fueron sometidas a pruebas de nado forzado. A partir de hipocampo y corteza se cuantificó la actividad monoaminooxidasa (MAO). Complementado los estudios con la evaluación in silico de acoplamiento molecular de tilianina con el sitio de acción de MAO-A mediante AutoDockTools. Núm. de registro del protocolo: 32/22 Resultados: A partir de 500g de planta se aisló y purificó tilianina con un rendimiento de 0.2%. Tilianina mostró diferencia estadísticamente significativa en la disminución del tiempo de inmovilidad a dosis de 16 (P=0.0005) y 50 (P=0.0011) mg/kg, así como en el aumento del tiempo de nado en ambas dosis (P=0.0020 y P=0.0005 respectivamente). En los ensayos in vitro, la tilianina presentó un efecto inhibidor estadísticamente significativo sobre MAO-A a 16 (P=0.0194) y 50 (P=0.0064) mg/kg y MAO-B a 16 (P=0.0061), 50 (P=0.0048) y 156.2 (P=0.0191) mg/kg. Los ensayos de acoplamiento molecular in silico sugieren una interacción entre la tilianina y el sitio activo de MAO-A (ΔG= -7.40±0.04 Kcal/mol, Ki= 3.75±0.24 µM). Conclusiones: Tilianina posee un efecto sobre la conducta de nado en ratas que se relaciona con la actividad inhibitoria de MAO-A y MAO B, así como lo observado en los ensayos in silico de acoplamiento molecular, por lo que tilianina es una potencial molécula para desarrollarse como un posible fármaco para el tratamiento de la depresión. [ABSTRACT FROM AUTHOR]

In the search for potential new antiasthmatic drugs, the ex vivo relaxing effect and structural activity relationship (SAR) studies of a series of ten structurally related flavonoids were established. Also, glycosylated and prenylated flavonoids were included in this study in order to explore their relaxant effect. All flavonoids studied showed a significant relaxant effect on the contraction induced by carbachol (CCh) 1 µM on tracheal rat rings, with the exception of isoprenylated and glycosylated derivatives. Results indicated that the flavone scaffold or their 6-substituted or 7-substituted positions, exhibited best relaxant activity, being flavone ( 1), 6-hydroxyflavone ( 2), 6-aminoflavone ( 3), and 7-hydroxyflavone ( 6) the most active compounds, even more than the positive control (Theophylline). On the other hand, SAR analysis suggested that the presence of hydrogen-bond donor and acceptor substituents in position 6- or 7- in the flavone core, or the 2 and 3 double bond, and the increasing presence of hydroxyl groups in positions 4′-, 5′-, 6′-, and 6- could enhance the ex vivo relaxant effect of the flavonoids studied. Derived from SAR analysis, a pharmacophore mapping was proposed, taking into account the structure of 6-hydroxyflavone, in order to have the scaffold to show the best ex vivo relaxant activity. [ABSTRACT FROM AUTHOR]

Abstract: β-eudesmol (1), cryptomeridiol (2), ilicic acid (3), 5,7-dihydroxyflavone (chrysin, 4) and 7-O-methyl-chrysin (tectochrysin, 5) were isolated as the major constituents from the acetone extract of the aerial parts of Flourensia resinosa S.F. Blake (Asteraceae), along with flourensiadiol (6), spathulenol (7), p-acetophenol (8), lupeol (9), β-sitosterol (10), triacontanol (11) and squalene (12). Based on previous studies, this chemical composition for F. resinosa is in accordance with the chemical profile of other species of Flourensia. The profile of flavonoids, sesquiterpenes and benzofurans may have chemotaxonomic significance within this genus. [Copyright &y& Elsevier]

Abstract: The aim of the current study was to investigate the oral antidiabetic activity of six structurally related flavonoids: flavone (1), 3-hydroxyflavone (2), 6-hydroxyflavone (3), 7-hydroxyflavone (4), chrysin (5) and quercetin (6). Normoglycemic and STZ-nicotinamide diabetic rats were treated with these flavonoids (50mg/kg) and the hypoglycemic and antidiabetic effects in acute and sub acute (five days of treatment) experiments were determined. Compounds 1, 5 and 6 were found most active in both experiments in comparison with control group (p <0.05). After five days of administration to STZ-nicotinamide diabetic rats, flavonoids induced a significantly diminishing of total cholesterol, TG and LDL and an augment of HDL compared with the control group (p <0.05). The in vitro inhibitory activity of the compounds against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was also evaluated. Quercetin, the most active compound, was docked into the crystal structure of 11β-HSD1. Docking results indicate potential hydrogen bond interactions with hydroxyl groups of catalytic amino acid residues. [Copyright &y& Elsevier]