Apigenin protects from hepatorenal damage caused by lead acetate in rats

Exposure to lead (Pb) is associated with serious health problems including hepatorenal toxicity. Apigenin is a natural-sourced flavonoid with promising antioxidant and anti-inflammatory effects. In this research, we investigated the potential protective role of apigenin against lead acetate (PbAc)-induced hepatorenal damage. Thus, this experiment studied the exposure of male Wistar Albino rats to apigenin and/or PbAc and their effects in comparison to the control rats. Apigenin administration decreased the levels of Pb and prevented the histopathological deformations in liver and kidney tissues following PbAc exposure. This was confirmed by the normalized levels of liver and kidney function markers. Additionally, apigenin inhibited significantly oxidative reactions through upregulating Nrf2 and HO-1, and activating their downstreamed antioxidants accompanied by a marked depletion of pro-oxidants. Moreover, apigenin decreased the elevated pro-inflammatory cytokines and inhibited cell loss in liver and kidney tissues in response to PbAc intoxication in both tissues. The obtained results demonstrated that apigenin could be used to attenuate the molecular, biochemical, and histological alterations associated with Pb exposure due to its potent antioxidant, anti-inflammatory, and antiapoptotic effects.     

miR-34a-5p might have an important role for inducing apoptosis by down-regulation of SNAI1 in apigenin-treated lung cancer cells

Molecular Biology Reports - Apigenin is a flavonoid with antioxidant and anticancer effects. It has been reported that apigenin inhibits proliferation, migration, and invasion and induces apoptosis...     

Investigation of camomile fermentation

Summary The content of apigenin is an important factor of camomile spasmolytic activity. The hydrolysis of apigenin-7-O--glucoside into free aglycone in camomile ligulate flowers was possible using -glucosidase from almonds. The transformation of apigenin glucosides into apigenin has been achieved by autofermentation of camomile ligulate flowers and camomile flower heads. There is a significant increase of apigenin content, whereas the composition of other active components in camomile practically were not changed by autofermentation.     

The role of chalcone synthase in the regulation of flavonoid biosynthesis in developing oat primary leaves

The role of chalcone synthase in the regulation of flavonoid biosynthesis during organogenesis of oat primary leaves has been investigated at the level of enzyme activity and mRNA translation in vitro. Chalcone synthase was purified about 500-fold. The apparent Km values were 1.5 and 6.3 microM for 4-coumaroyl-CoA and malonyl-CoA, respectively. The end products of oat flavonoid biosynthesis, three C-glucosylflavones, did not inhibit the reaction at concentrations as measured up to 60 microM each. Apigenin (4',5,7-trihydroxyflavone), a stable structural analog of the reaction product, 2',4,4',6'-tetrahydroxychalcone, was found to be a strong competitive inhibitor of 4-coumaroyl-CoA binding and a strong noncompetitive inhibitor of malonyl-CoA binding. Although apigenin is not supposed to be an intermediate of C-glucosylflavone biosynthesis, this compound might be a valuable tool for future kinetic studies. To date, there is no indication of chalcone synthase regulation by feedback or similar mechanisms which modulate enzyme activity. Mathematical correlation of chalcone synthase activity and flavonoid accumulation during leaf development, however, indicates that chalcone synthase is the rate-limiting enzyme of the pathway. By in vitro translation studies using preparations of total RNA from different leaf stages, we could demonstrate for the first time that the translational activity of chalcone synthase mRNA undergoes marked daily changes. The high values found at the end of the dark phase suggest that light does not exert direct influence on flavonoid biosynthesis but probably functions by controlling the basic diurnal rhythm.     

The growth,flower properties and demography of Anthemis arvensis exposed to enhanced UV-B radiation

The winter annual species Anthemis arvensis L. (Asteraceae) was grown for 3.5 months in the field under ambient or ambient plus supplemental UV-B radiation, simulating a 15% ozone depletion over Patras (38.3° N, 29.1° E). Enhanced UV-B radiation had no effect on the methanol extractable UV-B absorbing capacity of leaves, phenological and morphometric parameters of anthesis (flowering time, anthesis duration, head life span, number of heads per plant, number of tubular and ligulate florets per head, area per ligulate floret). Concerning the optical properties of heads, enhanced UV-B radiation had no significant effect on the extractable absorbance of both floret types nor on the spectral reflectance of the tubular florets. However, under UV-B supplementation the white ligulate florets exhibited a slight, statistically significant decrease of reflectance in the visible region of the spectrum. This may be due to structural changes of the floret surface, since microscopic examination under SEM revealed the papillae of the adaxial epidermal cells to be swollen. The above ground dry mass measured at plant harvest was not affected but a significant increase in root biomass (and accordingly in root/shoot ratio) was observed. We conclude that Anthemis arvensis is resistant against UV-B radiation damage. The possible consequences of UV-B induced structural changes on floret epidermis are discussed.     

Apigenin up-regulates transgelin and inhibits invasion and migration of colorectal cancer through decreased phosphorylation of AKT

Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world. Apigenin is a flavonoid that possesses various clinically relevant properties such as anti-tumour, anti-platelet and anti-inflammatory activities. Our results showed that apigenin has anti-proliferation, anti-invasion and anti-migration effects in three kinds of colorectal adenocarcinoma cell lines, namely SW480, DLD-1 and LS174T. Proteomic analysis with SW480 indicated that apigenin up-regulated the expression of transgelin (TAGLN) in mitochondria to exert its anti-tumour growth and anti-metastasis effects. Real-time quantitative polymerase chain reaction (RQ-PCR) and western blot confirm the up-regulation in all the three colorectal adenocarcinoma cells. An inverse correlation was observed between TAGLN expression and CRC metastasis in tissue microarray staining. TAGLN siRNA increased the viability of SW480. Apigenin decreased the expression of MMP-9 in a dose-dependent manner. Transfection of three truncated forms of TAGLN and wild type has identified TAGLN as a repressor of MMP-9 expression. A synergetic effect was observed in overexpression of TAGLN wild type and apigenin treatment which manifested as lowered phosphorylation of AKT Ser473 and ATK Thr308. In an orthotopic CRC model, apigenin inhibited tumour growth and metastasis to liver and lung. In conclusion, our research provided direct evidence that apigenin inhibited tumour growth and metastasis both in vitro and in vivo. Apigenin up-regulated TAGLN and hence down-regulated MMP-9 expression through decreasing phosphorylation of Akt at Ser473 and in particular Thr308 to prevent cell proliferation and migration.     

Flavonoid Apigenin Inhibits Lipopolysaccharide-Induced Inflammatory Response through Multiple Mechanisms in Macrophages

Background

Apigenin is a non-toxic natural flavonoid that is abundantly present in common fruits and vegetables. It has been reported that apigenin has various beneficial health effects such as anti-inflammation and chemoprevention. Multiple studies have shown that inflammation is an important risk factor for atherosclerosis, diabetes, sepsis, various liver diseases, and other metabolic diseases. Although it has been long realized that apigenin has anti-inflammatory activities, the underlying functional mechanisms are still not fully understood.

Methodology and Principal Findings

In the present study, we examined the effect of apigenin on LPS-induced inflammatory response and further elucidated the potential underlying mechanisms in human THP-1-induced macrophages and mouse J774A.1 macrophages. By using the PrimePCR array, we were able to identify the major target genes regulated by apigenin in LPS-mediated immune response. The results indicated that apigenin significantly inhibited LPS-induced production of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α through modulating multiple intracellular signaling pathways in macrophages. Apigenin inhibited LPS-induced IL-1β production by inhibiting caspase-1 activation through the disruption of the NLRP3 inflammasome assembly. Apigenin also prevented LPS-induced IL-6 and IL-1β production by reducing the mRNA stability via inhibiting ERK1/2 activation. In addition, apigenin significantly inhibited TNF-α and IL-1β-induced activation of NF-κB.

Conclusion and Significance

Apigenin Inhibits LPS-induced Inflammatory Response through multiple mechanisms in macrophages. These results provided important scientific evidences for the potential application of apigenin as a therapeutic agent for inflammatory diseases.     

Apigenin inhibits growth and motility but increases gap junctional coupling intensity in rat prostate carcinoma (MAT-LyLu) cell populations

Apigenin (4',5,7,-trihydroxyflavone) is a flavonoid abundant in the common fruits, herbs and vegetables constituting the bulk of the human diet. This study was aimed at quantifying the effects of apigenin on the basic cellular traits determining cancer development, i.e. cell proliferation, gap junctional coupling, and motility, using the Dunning rat prostate MAT-LyLu cell model. We demonstrated that apigenin considerably inhibits MAT-LyLu cell proliferation and significantly enhances the intensity of connexin43-mediated gap junctional coupling. This effect correlates with an increased abundance of Cx43-positive plaques at the cell-to-cell borders seen in apigenin-treated variants. Moreover, we observed an inhibitory effect of apigenin on the motility of MAT-LyLu cells. The basic parameters characterising MAT-LyLu cell motility, especially the rate of cell displacement, considerably decreased upon apigenin administration. This in vitro data indicates that apigenin may affect cancer development in general, and prostate carcinogenesis in particular, via its influence on cellular activities decisive for both cancer promotion and progression, including cell proliferation, gap junctional coupling and cell motility and invasiveness.     

Oxidation pathways underlying the pro-oxidant effects of apigenin

Apigenin, a natural flavone, is emerging as a promising compound for the treatment of several diseases. One of the hallmarks of apigenin is the generation of intracellular reactive oxygen species (ROS), as judged by the oxidation of reduced dichlorofluorescein derivatives seen in many cell types. This study aimed to reveal some mechanisms by which apigenin can be oxidized and how apigenin-derived radicals affect the oxidation of 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein (H₂DCF), a probe usually employed to detect intracellular ROS. Apigenin induced a rapid oxidation of H₂DCF in two different immortalized cell lines derived from rat and human hepatic stellate cells. However, apigenin did not generate ROS in these cells, as judged by dihydroethidium oxidation and extracellular hydrogen peroxide production. In cell-free experiments we found that oxidation of apigenin leads to the generation of a phenoxyl radical, which directly oxidizes H₂DCF with catalytic amounts of hydrogen peroxide. The net balance of the reaction was the oxidation of the probe by molecular oxygen due to redox cycling of apigenin. This flavonoid was also able to deplete NADH and glutathione by a similar mechanism. Interestingly, H₂DCF oxidation was significantly accelerated by apigenin in the presence of horseradish peroxidase and xanthine oxidase, but not with other enzymes showing peroxidase-like activity, such as cytochrome c or catalase. We conclude that in cells treated with apigenin oxidation of reduced dichlorofluorescein derivatives does not measure intracellular ROS and that pro- and antioxidant effects of flavonoids deduced from these experiments are inconclusive and must be confirmed by other techniques.     

Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells

Agents that are capable of inducing selective apoptosis of cancer cells are receiving considerable attention in developing novel cancer-preventive approaches. In the present study, employing normal human prostate epithelial cells (NHPE), virally transformed normal human prostate epithelial cells (PZ-HPV-7), and human prostate adenocarcinoma (CA-HPV-10) cells, we evaluated the growth-inhibitory effects of apigenin, a flavonoid abundantly present in fruits and vegetables. Apigenin treatment to NHPE and PZ-HPV-7 resulted in almost similar growth inhibitory responses of low magnitude. In sharp contrast, apigenin treatment resulted in a significant decrease in cell viability of CA-HPV-10 cells. Similar selective growth inhibitory effects were also observed for human epidermoid carcinoma A431 cells compared to normal human epidermal keratinocytes. Apigenin treatment resulted in significant apoptosis of CA-HPV-10 cells as evident from (i) DNA ladder assay, (ii) fluorescence microscopy, and (iii) TUNEL assay, whereas the NHPE and PZ-HPV-7 cells did not undergo apoptosis but showed exclusive necrotic staining only at a high dose of 40 microM. Apigenin (1-10 microM) also resulted in a dose-dependent G2-M phase cell cycle arrest of CA-HPV-10 cells but not of PZ-HPV-7 cells. The growth-inhibitory and apoptotic potential of apigenin was also observed in a variety of prostate carcinoma cells representing different stage and androgen responsiveness. Apigenin may be developed as a promising chemopreventive and/or chemotherapeutic agent against prostate cancer.     

Chromosome number and flavonoid synthesis in Briza L. (Gramineae)

Following a recent reidentification of the apigenin C-glycosides in diploid Briza media, the luteolin C-glycosides were reexamined and three acylated derivatives of a luteolin C-glycoside were found. In an attempt to identify the chromosome or group of chromosomes responsible for the change in flavonoid synthesis from 4'-hydroxy- in diploid plants to 3',4'-dihydroxyflavone C-glycosides in autotetraploid plants, leaf flavonoids of artificially produced aneuploids of B. media were examined. Among these plants three different leaf flavonoid profiles were recognized: diploid, tetraploid, and a "modified" tetraploid pattern. All the aneuploids with the normal or "modified" tetraploid pattern were trisomic for one of the small acrocentric chromosomes. Induced polyploids of other Briza species were usually found to have similar flavonoid patterns in the two chromosome races. Flavonoid sulfates were found in three South American species but are absent from all the European species.     

Apigenin 7-glucoside from Stachys tibetica Vatke and its anxiolytic effect in rats

BackgroundStachys tibetica Vatke (Himalayan or mountain tea) grows abundantly in the tropical and subtropical locations of the world including India, Tibet and China. The traditional healers of Kargil and adjoining areas in Ladakh, Jammu and Kashmir in India use the drug to treat fever, cough, phobias and various mental disorders etc. in the form of a decoction or as a tea. Flavonoids are important components in most herbal teas and play an important role in the management of various brain disorders via mimicking the action of benzodiazepines or through benzodiazepine receptors.Aim of the studyThe present study aimed to isolate flavonoids from S. tibetica and to evaluate their anxiolytic potential in comparison to reference synthetic (diazepam) and natural (apigenin) molecules.Materials and methodsS. tibetica root powder was extracted with 95% methanol for about 72 h using a soxhlet apparatus and the resultant extract was subjected to isolation procedures, resulting in the isolation of apigenin 7-glucoside and characterisation by various physical and spectrometric analyses. Apigenin 7-glucoside was evaluated for anxiolytic activity in rats in comparison with the reference compounds diazepam and apigenin using the elevated plus maze (EPM) model.ResultsPhytochemical investigations of S. tibetica revealed the presence of tannins, phenolics, flavonoids, saponins, glycosides and carbohydrates. A flavonoid glucoside, apigenin 7-glucoside was isolated for the first time from the roots of S. tibetica Vatke. The percentage of time spent and arm entries in the open arms was increased while the arms entries and duration of time spent in closed arms were decreased in the groups treated with apigenin 7-glucoside (which dose). In a similar fashion, diazepam and apigenin also exhibited anxiolytic activity (*p < 0.05, **p < 0.01). Apigenin 7-glucoside significantly decreased the percentage of head dips in EPM. Apigenin 7-glucoside showed anxiolytic potential comparable to the reference drugs apigenin and diazepam.ConclusionApigenin 7-glucoside could be an important molecule for the treatment of anxiety and further studies are required to elucidate its possible mechanism of action.     

Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy

Natural-food-based compounds show substantial promise for prevention and biotherapy of cancers including leukemia. In general, their mechanism of action remains unclear, hampering rational use of these compounds. Herein we show that the common dietary flavonoid apigenin has anticancer activity, but also may decrease chemotherapy sensitivity, depending on the cell type. We analyzed the molecular consequences of apigenin treatment in two types of leukemia, the myeloid and erythroid subtypes. Apigenin blocked proliferation in both lineages through cell-cycle arrest in G₂/M phase for myeloid HL60 and G₀/G₁ phase for erythroid TF1 cells. In both cell lines the JAK/STAT pathway was one of major targets of apigenin. Apigenin inhibited PI3K/PKB pathway in HL60 and induced caspase-dependent apoptosis. In contrast, no apoptosis was detected in TF1 cells, but initiation of autophagy was observed. The block in cell cycle and induction of autophagy observed in this erythroleukemia cell line resulted in a reduced susceptibility toward the commonly used therapeutic agent vincristine. Thus, this study shows that although apigenin is a potential chemopreventive agent due to the induction of leukemia cell-cycle arrest, caution in dietary intake of apigenin should be taken during disease as it potentially interferes with cancer treatment.     

Neuroprotective Effect of Apigenin on Depressive-Like Behavior: Mechanistic Approach

Apigenin, as a natural flavonoid present in several plants is characterized with potential anticancer, antioxidant, and anti-inflammatory properties. Recent studies proposed that apigenin affects depression disorder through unknown mechanistic pathways. The effects of apigenin’s anti-depressive properties on streptozocin-mediated depression have been investigated through the evaluation of behavioral tests, oxidative stress, cellular energy homeostasis and inflammatory responses. The results demonstrated anti-depressive properties of apigenin in behavioral test including forced swimming and splash tests and oxidative stress biomarkers such as reduced glutathione, lipid peroxidation, total antioxidant power and coenzyme Q₁₀ levels. Apigenin, also, demonstrated its regulatory potency in cellular energy homeostasis and immune system gene expression through inhibiting Nlrp3 and Tlr4 overexpression. Furthermore, failure in energy production as the key factor in various psychiatric disorders was reversed by apigenin modulating effect on AMPK gene expression. Overall, 20 mg/kg of apigenin was recognized as the dose suitable for minimizing the undesirable adverse effects in the STZ-mediated depression model proposed in this study. Our data suggested that apigenin could be able to adjust behavioral dysfunction, biochemical biomarkers and recovered cellular antioxidant level in depressed animals. The surprising results were achieved by raise in COQ₁₀ level, which could regulate the overexpression of the AMPK gene in stressful conditions. The regulatory effect of apigenin in inflammatory signaling pathways such as Nlrp3, and Tlr4 gene expression was studied at the surface part of the hippocampus.

     

Exudate flavonoid aglycones of Veronica: Ecological and systematic implications

A survey on the distribution of surface flavonoid aglycones in 52 samples of 29 species of Veronica resulted in detection of eight flavone aglycones. Apigenin and luteolin were the most common constituents of the studied exudates, followed by the methylated derivatives apigenin 4′-methyl ether, apigenin 7,4′-dimethyl ether and luteolin 3′-methyl ether. Some intraspecific variations and the main ecological trends of flavonoid aglycone accumulation in Veronica were discussed. The observed exudate profiles appeared to be characteristic for some related groups within the genus, in agreement with the morphological, karyological, molecular and other chemical data.     

Apigenin-induced apoptosis of leukemia cells is mediated by a bimodal and differentially regulated residue-specific phosphorylation of heat-shock protein�C27

Apigenin, a natural plant flavonoid with antiproliferative activity, is emerging as a promising compound for cancer prevention and therapy, but its mechanism of action remains unclear. High expression of the small heat-shock protein-27 (Hsp27) in leukemia contributes to the resistance of these cells to cancer treatments. Changes in Hsp27 phosphorylation have been associated with heat and metabolic stress, but its role in flavonoid anticancer activity has not been investigated. In this study, we examined the effect of apigenin in the regulation of Hsp27 on leukemia. We showed that apigenin does not affect Hsp27 expression but induces a bimodal phosphorylation on Ser78 and Ser82. The phosphorylation at early times was regulated by p38. At later times, Hsp27 phosphorylation was dependent on p38 activity and for some residues on PKCδ. Silencing of p38 expression reduced apigenin-induced phosphorylation on Ser15, Ser78, and Ser82, whereas silencing of PKCδ expression reduced the phosphorylation on Ser15 and Ser82 without affecting Ser78. In addition, we found that apigenin-induced PKCδ activity is mediated by p38. We also showed that the phosphorylation of Hsp27 significantly increased the susceptibility of leukemia cells to apigenin-induced apoptosis. Together, these results identify a complex signaling network regulating the cytotoxic effect of apigenin through Hsp27 phosphorylation.