Effects Of Anthocyanidins Research Articles

Effects of anthocyanidins on the conformational transition of Aβ(1-42) peptide: Insights from molecular docking and molecular dynamics simulations

Recent evidence from in vitro and in vivo studies has shown that anthocyanins and anthocyanidins can reduce and inhibit the amyloid beta (Aβ) species, one of the hallmarks of Alzheimer's disease (AD). However, their inhibition mechanisms on Aβ species at molecular details remain elusive. Therefore, in the present study, molecular modelling methods were employed to investigate their inhibitory mechanisms on Aβ(1-42) peptide. The results highlighted that anthocyanidins effectively inhibited the conformational transitions of helices into beta-sheet (β-sheet) conformation within Aβ(1-42) peptide by two different mechanisms: 1) the obstruction of two terminals from coming into contact due to the binding of anthocyanidins with residues of N- and second hydrophobic core (SHC)-C-terminals, and 2) the prevention of the folding process due to the binding of anthocyanidin with the central polar (Asp23 and Lys28) and native helix (Asp23, Lys28, and Leu34) residues. These new findings on the inhibition of β-sheet formation by targeting both N- and SHC-C-terminals, and the long-established target, D23-K28 salt bridge residues, not with the conventional central hydrophobic core (CHC) as reported in the literature, might aid in designing more potent inhibitors for AD treatment.

Effects of malvidin, cyanidin and delphinidin on human adipose mesenchymal stem cell differentiation into adipocytes, chondrocytes and osteocytes

BackgroundAnthocyanidins are plant phytochemicals found at high concentrations in berries, vegetables and flowers. Anthocyanidins have been extensively investigated due to their antioxidative, antidiabetic and anti-inflammatory effects. Few studies show that anthocyanidins decrease obesity and improve bone density. However, the effects of anthocyanidins on tissue regeneration have not been sufficiently clarified. Human mesenchymal stem cells (MSCs) are multipotent adult stem cells responsible for the regeneration of fat, bone and cartilage. Although MSCs are often used for screening of biologically active compounds, so far, the effect of anthocyanidins on MSC differentiation has not been addressed. PurposeThe aim of this study was to analyse the effect of anthocyanidins malvidin, cyanidin and delphinidin on adipose tissue-derived MSC differentiation into adipocytes, osteocytes and chondrocytes. Study design and methodsDifferentiation into adipocytes, osteocytes and chondrocytes was carried out in the defined cell culture conditions in the presence or absence of malvidin, cyanidin and delphinidin. The differentiation was confirmed by cytochemical staining and tissue-specific gene and protein expression. Antiobesity and anti-diabetes drug liraglutide was used as a reference drug in this study. ResultsDelphinidin inhibited MSC adipogenesis and downregulated FABP4 and adiponectin genes. Malvidin induced a significantly higher accumulation of calcium deposits in MSCs comparing to untreated MSCs, as well as upregulated the osteocyte-specific gene BMP-2 and Runx-2 expression and induced BMP-2 secretion. Cyanidin and delphinidin demonstrated a chondrogenesis stimulating effect by upregulation of Col2a1 and aggrecan. ConclusionAltogether, our data show that anthocyanidins malvidin, cyanidin and delphinidin exert favourable effects on MSC osteogenesis and chondrogenesis whereas delphinidin inhibits adipogenesis. These results suggest that anthocyanidin effects on tissue regeneration could be further analysed in depth in vivo.

Periostin, a signal transduction intermediate in TGF-β-induced EMT in U-87MG human glioblastoma cells, and its inhibition by anthocyanidins.

Periostin is a secreted protein that is highly expressed in glioblastoma cells as compared to normal brain tissue, and is therefore considered as a potential biomarker in therapeutic modalities. Its contribution in the cancer cells invasive phenotype is, however, poorly understood. This work investigates the role of periostin in U-87 MG glioblastoma cell invasion, cell migration and in Transforming Growth Factor β (TGF-β)-induced epithelial-mesenchymal transition (EMT). Periostin gene silencing, using small interfering RNA, decreased TGF-β-induced mesenchymal marker expression of fibronectin and vimentin, partly through reduced Smad2, Akt and Fak phosphorylation as well as U-87 MG cell invasion and migration. The effects of anthocyanidins, the most abundant diet-derived flavonoids, were examined on periostin-mediated downstream signaling pathways. Anthocyanidins were found to decrease periostin expression whether added under pre-, co- or post-treatment conditions along with TGF-β, and altered the Akt and Fak signaling pathways. These effects were similar to Galunisertib (LY2157299), a small molecule inhibitor of the TGF-β receptor I kinase. Taken together, our data demonstrate that periostin acts as a central element in TGF-β-induced EMT, which can be prevented by diet-derived anthocyanidins.

Abstract 4316: Pharmacological targeting of the TGF-beta-induced epithelial-mesenchymal transition by anthocyanidins in glioblastoma

Abstract Introduction: Glioblastoma multiforme (GBM) is the most common primary brain tumor, known for its invasiveness and high resistance to standard treatments. Therefore, better understanding of the mechanisms that promote mesenchymal changes in GBM are of great clinical importance. Epithelial to mesenchymal transition (EMT) is a reversible biological process in which epithelial cells adopt mesenchymal properties. During EMT, migration, adhesion and cellular morphology are altered allowing benign tumor cells to infiltrate surrounding tissues and to metastasize to distant sites. Several growth factors have been shown to trigger EMT in tumor development; the Transforming Growth Factor-beta (TGF-b) is the most prominent inducer of EMT. Epidemiological studies have shown that diets rich in fruits and vegetables play an important role in preventing cancer due to their polyphenol content. Among polyphenols, the anthocyanidins, found in berries, red grapes, and other pigmented foods, plants and vegetables, have anti-inflammatory, cardioprotective, anti-angiogenic and anti-carcinogenic properties. Despite the well-known role of TGB-b in tumor progression, the impact of anthocyanidins on TGF-b-induced EMT remains misunderstood. Objectives: 1) Characterize the pharmacological effects of anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin and petunidin) on EMT, 2) identify the molecular targets leading to the inhibition of EMT modulated by anthocyanidins, and 3) characterize their effect on cellular activities involved in this tumor process. Methodology: The human U-87 glioblastoma (U-87 MG) cells were treated with anthocyanidins in pre-, co- and post-treatment with TGF-b. Results: Depending on the treatment, anthocyanidins affect differently the EMT induction by inhibiting U-87 MG cell migration. This inhibition resulted in a down-regulation of mesenchymal markers (fibronectin, snail), phosphorylation of Smad2 proteins and the mitogen-activated protein kinases (ERK, JNK) in a dose-dependent manner. Overall, delphinidin was the most potent inhibitor for all treatments. Conclusion: This study highlights a new antimetastatic action of anthocyanidins that supports the beneficial health and chemopreventive effects of dietary-based strategies against cancer. Citation Format: Amira Ouanouki, Evelyne Muhire, Sylvie Lamy, Borhane Annabi. Pharmacological targeting of the TGF-beta-induced epithelial-mesenchymal transition by anthocyanidins in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4316.

Effect of anthocyanidins on trascriptional activities of steroid and nuclear receptors

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Effects of anthocyanidins on myogenic differentiation and antioxidant defense in primary myogenic cells isolated from rainbow trout (Oncorhynchus mykiss)

There is increasing interest in using plant-derived extracts to promote growth and health in finfish species in recent years. Elucidating the effects of plant secondary metabolites on skeletal muscle growth signaling will contribute to an improved understanding of the effects of feeding carnivorous fish diets supplemented with plant extracts on fish somatic growth. Dietary intake of anthocyanins, a type of flavonoid widely distributed in plants, has long been associated with beneficial effects in both human and animal health; however, their effects in finfish are largely unknown. We conducted an experiment to test the effect of three doses (treatments A, B and C; 1×, 2.5× and 10×, respectively) of a mixture of three types of anthocyanidins (peonidin, cyanidin and pelargonidin chloride) on the expression of several genes in primary myogenic cells isolated from the skeletal muscle of rainbow trout (Oncorhynchus mykiss) after 24h of treatment. The genes of interest analyzed are involved in myogenic programing (pax7, myoD and myogenin), Notch signaling (her6 and hey2) and antioxidant enzymes (sod1, cat and gpx1). Significantly greater expression of pax7 in cells under treatment B compared with the untreated cells was detected. Although no differences in expression of myogenic regulatory factors, myoD and myogenin between test groups or the control were detected, a trend toward significantly lower expression in all groups tested compared with the control group was observed. Moreover, significantly higher expression levels of her6 and hey2 in cells under treatments A and B compared with untreated cells were detected. Although no significant differences in the expression of cat and sod1, significantly greater expression in gpx1 in all treated groups compared with the control group was detected. Collectively, we demonstrated that anthocyanidins enhance the expression of gpx1 in primary myogenic cells, thereby contributing to skeletal muscle tissue defense against oxidative stress in finfish species. Further, anthocyanidins appear to delay myogenic differentiation in primary myogenic cells by up-regulating the expression of pax7 while decreasing myogenic regulatory factors in a Notch signaling-dependent interaction. Whether this effect results a reduced growth performance and/or an increase in feed conversion ratio in fish fed diets supplemented with plant extracts rich in anthocyanins or anthocyanidins needs further study, and the need to better define the potential effects of different polyphenol classes in myogenic differentiation on primary myogenic cells from carnivorous fish is warranted. Statement of relevanceThe study contributes to increase our understanding regarding the effect of plant-derived secondary metabolites such as anthocyanidins on myogenic program and antioxidant enzyme defense in differentiating myogenic cells from carnivorous fish. We have demonstrated that anthocyanidins may delay the progress of the myogenic differentiation process and promote antioxidant defense expression in myogenic cells.

Malvidin and delphinidin exhibit a dose‐dependent effect on cell viability and apoptosis in HT‐29 cells

Anthocyanidins (ANTH) induce apoptosis in some cancer cell lines, but studies describing the dose‐dependent effects of ANTH on cell populations are limited. The objective of this study was to evaluate the dose‐dependent response of malvidin (MAL) and delphinidin (DEL), ANTH with different chemical structures, on cell viability and apoptosis in HT‐29 cells in comparison with curcumin (CUR), a phenolic compound and a known inducer of apoptosis. Cells were treated with 0, 5, 10, 25, 50, 80, or 100 umol/L MAL or DEL or 40 or 80 umol/L CUR for 48 h at 37°C, 5% CO2, 95% air. Cells were treated with 250 umol/L tert‐butyl hydroperoxide for 2 h as a positive control. A significant ANTH concentration effect on cell proliferation and apoptosis was observed but MAL and DEL had similar effects on these measures. Lower concentrations of DEL (5 and 10 umol/L) and MAL (5 umol/L) increased cell viability by 12–16% compared to control, while higher concentrations of CUR, (80 umol/L), MAL (80 umol/L and 100 umol/L), and DEL (80 umol/L and 100 umol/L) decreased cell viability by 16–44%. Apoptosis was assessed by measuring caspase‐3 activity. Caspase‐3 activity only significantly increased with 80 umol/L MAL and DEL, by a fold increase of about 1.7. This data suggests MAL and DEL have comparable effects on HT‐29 cell viability and concentrations as high as 80 umol/L MAL and DEL are needed to induce apoptosis.

Inhibitory effect of anthocyanidins on hepatic glutathione S-transferase, UDP-glucuronosyltransferase and carbonyl reductase activities in rat and human

1. Anthocyanins and their aglycone anthocyanidins represent the most abundant flavonoids in human diet and popular constituents of various dietary supplements. The aim of this study was to evaluate inhibitory effect of four anthocyanidins (delphinidin, cyanidin, malvidin and pelargonidin) on three families of important drug-metabolizing enzymes: carbonyl reductases (CBRs), glutathione S-transferases (GSTs) and UDP-glucuronosyltransferases (UGT).2. Human or rat hepatic subcellular fractions were incubated with or without pure anthocyanidins (100 µM) and the activities of CBR, GST and UGT were assayed using menadione, 1-chloro-2,4-dinitrobenzene and p-nitrophenol as substrates, respectively. For the most potent inhibitors, half maximal inhibitory concentrations (IC50) were determined and the inhibition kinetics study was performed.3. Anthocyanidins inhibited weakly the activity of GST and moderately the activities of CBR and UGT. Cyanidin was the most potent inhibitor of human UGT with IC50 = 69 µM (at 200 µM substrate concentration) and competitive type of action. Delphinidin acted as significant non-competitive inhibitor of human CBR with IC50 = 16 µM (at substrate concentration 500 µM). The inhibitory potency of anthocyanidins differed in rat and human samples significantly.4. Anthocyanidins are able to inhibit CBR and UGT in vitro. Possible interference of anthocyanidins (in high-dose dietary supplements) with simultaneously administered drugs, which are UGT or CBR substrates, should be checked.

Abstract 3693: Berry anthocyanidins inhibit key events of lung cancer metastasis: Effects on miRNA and protein targets

Abstract Lung cancer continues to represent the largest cause of mortality in the world claiming over 1.3 million lives every year. The majority of patients who succumb to lung cancer die from cancer relapse and/or metastatic disease progression making the search for new anti-cancer and anti-metastasis agents imperative. Berry phytochemicals have received increasing attention lately for their various biological effects. We previously demonstrated notable synergistic anti-tumor effects of blueberry anthocyanidins (cyanidin, malvidin, peonidin, petunidin and delphinidin) against human lung cancer cells in culture and in vivo in nude mouse model. Herein, we show the anti-metastatic effects of all the 5 anthocyanidins individually and in combination in the highly aggressive and invasive human NSCLC H1299 cells. Using wound-healing and Boyden chamber assays, all the five anthocyanidins (25 µM each) were found to exhibit varied inhibitory effects on H1299 cell migration and invasion. However, an equimolar mixture containing either 3.125 or 6.25 µM of each anthocyanidin elicited similar inhibition of H1299 cell migration and invasion indicating a synergistic effect. Given the multi-complexity of the metastasis process, the effect of anthocyanidins on a plethora of molecular targets mediating of the metastatic process was analyzed by western blotting. We found that berry anthocyanidins decreased the expression of several metastatic and angiogenic mediators, viz; matrix metalloproteinases (MMP-2 and MMP-9), vascular endothelial growth factor (VEGF), c-MYC, NOTCH-1, WNT1. Furthermore, the anthocyanidins effectively inhibited TNF-α-induced NF-κB activation and suppressed of ERK-1/2 activation, which could further explain their anti-invasive capabilities. Recently, emerging evidence also suggests the involvement of miRNAs in regulating various processes of cancer cell invasion and metastasis. Effect of anthocyanidins on four such miRNAs frequently downregulated in NSCLC and implicated in lung cancer invasion and metastasis (miR-126, miR125a-5p, miR200c) and lung cancer relapse (miR-34a) was analyzed by qPCR. We observed a significant increase in the expression of all the four miRNAs by the anthocyanidins. Target prediction scan for gene targets revealed several angiogenic signaling molecules to be regulated by these miRNA's. Our results thus establish that protective properties of anthocyanidins may arise, at least, in part, from its capability to manipulate some distinct and some overlapping miRNA and protein targets that may potentiate the anti-cancer and anti-metastatic effects of the berry anthocyanidins. Collectively, our data suggest that berry anthocyanidins may provide a safe, effective, unconventional and user-friendly approach to prevent or delay the onset of lung cancer recurrence and metastasis (Supported from KLCRP and Agnes Brown Duggan Endowment). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3693. doi:10.1158/1538-7445.AM2011-3693

Evidence for the efficacy of complementary and alternative medicines in the management of fibromyalgia: a systematic review

To critically evaluate the evidence regarding complementary and alternative medicines (CAMs) taken orally or applied topically for the treatment of FM. Randomized controlled trials of FM using CAMs, in comparison with other treatments or placebo, published in English up to March 2009, were eligible for inclusion. They were identified using systematic searches of bibliographic databases and manual searching of reference lists. Information was extracted on outcomes, and statistical significance, in comparison with alternative treatment or placebo, and side effects were reported. The methodological quality of the primary studies was determined. Single studies on four CAMs, and three on different approaches to homeopathic care were identified. Their methodological quality was moderate. The homeopathy studies were small, but each reported an improvement in pain. The effects of anthocyanidins, capsaicin and S-adenosylmethionine each showed at least one statistically significant improved outcome compared with placebo. However, the studies of anthocyanidins and capsaicin only demonstrated an improvement in a single outcome, sleep disturbance and tenderness, respectively, of several outcomes considered. No evidence of efficacy was found regarding Soy in a single study. Most of these CAMs were free of major adverse effects and usually associated with only minor adverse effects such as dizziness, nausea and stomach upsets. There is insufficient evidence on any CAM, taken orally or applied topically, for FM. The small number of positive studies lack replication. Further high-quality trials are necessary to determine whether these initial findings can be supported by a larger evidence base.

Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: Structure–activity relationship and molecular mechanisms involved

The effects of anthocyanidins, the aglycon nucleuses of anthocyanins widely occurring in reddish fruits and vegetables, on the expression of cyclooxygenase-2 (COX-2) were investigated in lipopolysaccharide (LPS)-activated murine macrophage RAW264 cells. Of five anthocyanidins, delphinidin and cyanidin inhibited LPS-induced COX-2 expression, but pelargonidin, peonidin and malvidin did not. The structure–activity relationship suggest that the ortho-dihydroxyphenyl structure of anthocyanidins on the B-ring appears to be related with the inhibitory actions. Delphinidin, the most potent inhibitor, caused a dose-dependent inhibition of COX-2 expression at both mRNA and protein levels. Western blotting analysis indicated that delphinidin inhibited the degradation of IκB-α, nuclear translocation of p65 and CCAAT/enhancer-binding protein (C/EBP)δ and phosphorylation of c-Jun, but not CRE-binding protein (CREB). Moreover, delphinidin suppressed the activations of mitogen-activated protein kinase (MAPK) including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 kinase. MAPK inhibitors (U0126 for MEK1/2, SB203580 for p38 kinase and SP600125 for JNK) specifically blocked LPS-induced COX-2 expression. Thus, our results demonstrated that LPS-induced COX-2 expression by activating MAPK pathways and delphinidin suppressed COX-2 by blocking MAPK-mediated pathways with the attendant activation of nuclear factor-κB (NF-κB), activator protein-1 (AP-1) and C/EBPδ. These findings provide the first molecular basis that anthocyanidins with ortho-dihydroxyphenyl structure may have anti-inflammatory properties through the inhibition of MAPK-mediated COX-2 expression.