International Journal of Molecular Sciences

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21 pages, 3881 KiB

Open AccessArticle

Kaempferia parviflora Extract Inhibits STAT3 Activation and Interleukin-6 Production in HeLa Cervical Cancer Cells

by Benjamart Suradej, Siriwoot Sookkhee, Jukreera Panyakaew, Pitchaya Mungkornasawakul, Nitwara Wikan, Duncan R. Smith, Saranyapin Potikanond and Wutigri Nimlamool

Int. J. Mol. Sci. 2019, 20(17), 4226; https://doi.org/10.3390/ijms20174226 - 29 Aug 2019

Cited by 30 | Viewed by 5502

Abstract

Kaempferia parviflora (KP) has been reported to have anti-cancer activities. We previously reported its effects against cervical cancer cells and continued to elucidate the effects of KP on inhibiting the production and secretion of interleukin (IL)-6, as well as its relevant signaling pathways [...] Read more.

Kaempferia parviflora (KP) has been reported to have anti-cancer activities. We previously reported its effects against cervical cancer cells and continued to elucidate the effects of KP on inhibiting the production and secretion of interleukin (IL)-6, as well as its relevant signaling pathways involved in cervical tumorigenesis. We discovered that KP suppressed epidermal growth factor (EGF)-induced IL-6 secretion in HeLa cells, and it was associated with a reduced level of Glycoprotein 130 (GP130), phosphorylated signal transducers and activators of transcription 3 (STAT3), and Mcl-1. Our data clearly showed that KP has no effect on nuclear factor kappa B (NF-κB) localization status. However, we found that KP inhibited EGF-stimulated phosphorylation of tyrosine 1045 and tyrosine 1068 of EGF receptor (EGFR) without affecting its expression level. The inhibition of EGFR activation was verified by the observation that KP significantly suppressed a major downstream MAP kinase, ERK1/2. Consistently, KP reduced the expression of Ki-67 protein, which is a cellular marker for proliferation. Moreover, KP potently inhibited phosphorylation of STAT3, Akt, and the expression of Mcl-1 in response to exogenous IL-6 stimulation. These data suggest that KP suppresses EGF-induced production of IL-6 and inhibits its autocrine IL-6/STAT3 signaling critical for maintaining cancer cell progression. We believe that KP may be a potential alternative anti-cancer agent for suppressing cervical tumorigenesis. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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16 pages, 5355 KiB

Open AccessArticle

Antitumor and Anti-Invasive Effect of Apigenin on Human Breast Carcinoma through Suppression of IL-6 Expression

by Hwan Hee Lee, Joohee Jung, Aree Moon, Hyojeung Kang and Hyosun Cho

Int. J. Mol. Sci. 2019, 20(13), 3143; https://doi.org/10.3390/ijms20133143 - 27 Jun 2019

Cited by 67 | Viewed by 5135

Abstract

Interleukin (IL)-6 plays a crucial role in the progression, invasion, and metastasis of breast cancer. Triple-negative breast cancer (TNBC) cell line MDA-MB-231 is known for its aggressive metastasis. Epithelial to mesenchymal transition (EMT) is a critical process in cancer metastasis. The positive correlation [...] Read more.

Interleukin (IL)-6 plays a crucial role in the progression, invasion, and metastasis of breast cancer. Triple-negative breast cancer (TNBC) cell line MDA-MB-231 is known for its aggressive metastasis. Epithelial to mesenchymal transition (EMT) is a critical process in cancer metastasis. The positive correlation between IL-6 and EMT in tumor microenvironment is reported. We found significantly upregulated IL-6 expression in MDA-MB-231 cells. A blockade of IL-6 expression decreased levels of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phosphorylated protein kinase B (pAkt), and cell cycle-related molecules, including cyclin-dependent kinases (CDKs) and cyclins in MDA-MB-231 cells. A short-hairpin RNA (shRNA)-mediated blockade of IL-6 expression inhibited migration and N-cadherin expression and induced E-cadherin expression in MDA-MB-231 cells. Growth rate was slower for the tumors derived from IL-6 shRNA-treated MDA-MB-231 cells than for those derived from control shRNA-treated MDA-MB-231 cells. The expression of pSTAT3, phosphorylated extracellular signal-regulated kinase (pERK), PI3K, pAkt, snail, vimentin, and N-cadherin was significantly lower in tumors from IL-6 shRNA-treated MDA-MB cells. In addition, apigenin treatment significantly inhibited the growth of MDA-MB-231-derived xenograft tumors along with the protein expressions of pSTAT3, pERK, IL-6, PI3K, pAkt, and N-cadherin. Our results demonstrate that the anti-invasive effect of apigenin in MDA-MB-231-derived xenograft tumors is mediated by the inhibition of IL-6-linked downstream signaling pathway. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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14 pages, 1547 KiB

Open AccessArticle

Safety and Efficacy Assessment of Isoflavones from Pueraria (Kudzu) Flower Extract in Ovariectomised Mice: A Comparison with Soy Isoflavones

by Yuko Tousen, Jun Takebayashi, Takashi Kondo, Hiroyuki Fuchino, Noriaki Kawano, Takayuki Inui, Kayo Yoshimatsu, Nobuo Kawahara and Yoshiko Ishimi

Int. J. Mol. Sci. 2019, 20(12), 2867; https://doi.org/10.3390/ijms20122867 - 12 Jun 2019

Cited by 5 | Viewed by 4101

Abstract

Numerous Foods with Function Claims that contain the extract of Pueraria flower (kudzu) isoflavones (PFI) are available in the Japanese market. These are labelled with function claims of reducing visceral fat. However, these foods have not undergone proper safety assessment such as the [...] Read more.

Numerous Foods with Function Claims that contain the extract of Pueraria flower (kudzu) isoflavones (PFI) are available in the Japanese market. These are labelled with function claims of reducing visceral fat. However, these foods have not undergone proper safety assessment such as the evaluation of their oestrogenic activity and effects on drug-metabolising enzymes (cytochrome P-450: CYP) in the liver. This study evaluated the estrogenic effect and the hepatic CYP activity and mRNA expression in normal female mice as a safety assessment of PFI (Experiment 1). In addition, the bone mineral density and visceral fat weight in ovariectomised mice (OVX) compared to soy isoflavones (SI) was evaluated to assess the efficacy of PFI (Experiment 2). OVX control fed a control diet, OVX fed a PFI diet (the recommended human intake of PFI), OVX fed a PFI20 diet (20- times the recommended PFI), OVX fed an SI diet (the recommended human intake of SI), and OVX fed an SI20 diet (20 -times the recommended intake of SI) for 28 days in Experiment 2. Body, liver, and visceral fat weights were not affected by the PFI, PFI20, SI, or SI20 diets. The hepatic CYP1A and CYP3A activities were elevated by the SI20 treatment. Ovariectomy-induced bone loss was inhibited by the SI20 treatment, but not by the PFI20 treatment. These results suggest that (1) PFI intake in human doses had no oestrogenic properties and did not affect CYP activity in the liver; (2) there was no evidence that PFI affects the amount of visceral fat in OVX mice. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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15 pages, 3289 KiB

Open AccessArticle

Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes

by Ramona Palombo, Sabrina Caporali, Mattia Falconi, Federico Iacovelli, Blasco Morozzo Della Rocca, Alessandro Lo Surdo, Elena Campione, Eleonora Candi, Gerry Melino, Sergio Bernardini and Alessandro Terrinoni

Int. J. Mol. Sci. 2019, 20(11), 2689; https://doi.org/10.3390/ijms20112689 - 31 May 2019

Cited by 19 | Viewed by 4280

Abstract

Flavonoids have been demonstrated to affect the activity of many mammalian enzyme systems. Their functional phenolic groups are able to mediate antioxidant effects by scavenging free radicals. Molecules of this class have been found able to modulate the activity of kinases, phospholipase A2, [...] Read more.

Flavonoids have been demonstrated to affect the activity of many mammalian enzyme systems. Their functional phenolic groups are able to mediate antioxidant effects by scavenging free radicals. Molecules of this class have been found able to modulate the activity of kinases, phospholipase A2, cyclooxygenases, lipoxygenase, glutathione S-transferase, and many others. Recently, it has been demonstrated that luteolin, in the form of Luteolin-7-O-β-d-glucoside (LUT-7G) is able to induce the keratinocyte differentiation process in vitro. This flavonoid is able to counteract the proliferative effects of IL-22/IL6 pathway by the inhibition of STAT3 activity also in vivo in a psoriatic mouse model. Observations on energy metabolism changes of differentiating cells led us to perform a complete metabolomics analysis using human primary keratinocytes treated with LUT-7G. Our results show that LUT-7G, is not only able to impair the nuclear translocation of STAT3, but it also blocks the energy metabolism pathway, depressing the glycolytic and Krebs pathway by the inhibition of hexokinase 2 activity. These data confirm that LUT-7G can be proposed as a potential candidate for the treatment of inflammatory and proliferative diseases, but its role as a hexokinase 2 (HEK2) inhibitor opens new perspectives in nutritional science, and especially in cancer therapy, in which the inhibition of the Warburg effect could be relevant. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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9 pages, 1443 KiB

Open AccessArticle

Sexually Dimorphic Effect of Genistein on Hypothalamic Neuronal Differentiation in Vitro

by Marilena Marraudino, Alice Farinetti, Maria-Angeles Arevalo, Stefano Gotti, GianCarlo Panzica and Luis-Miguel Garcia-Segura

Int. J. Mol. Sci. 2019, 20(10), 2465; https://doi.org/10.3390/ijms20102465 - 18 May 2019

Cited by 11 | Viewed by 3111

Abstract

Developmental actions of estradiol in the hypothalamus are well characterized. This hormone generates sex differences in the development of hypothalamic neuronal circuits controlling neuroendocrine events, feeding, growth, reproduction and behavior. In vitro, estradiol promotes sexually dimorphic effects on hypothalamic neuritogenesis. Previous studies have [...] Read more.

Developmental actions of estradiol in the hypothalamus are well characterized. This hormone generates sex differences in the development of hypothalamic neuronal circuits controlling neuroendocrine events, feeding, growth, reproduction and behavior. In vitro, estradiol promotes sexually dimorphic effects on hypothalamic neuritogenesis. Previous studies have shown that developmental actions of the phytoestrogen genistein result in permanent sexually dimorphic effects in some behaviors and neural circuits in vivo. In the present study, we have explored if genistein, like estradiol, affects neuritogenesis in primary hypothalamic neurons and investigated the estrogen receptors implicated in this action. Hypothalamic neuronal cultures, obtained from male or female embryonic day 14 (E14) CD1 mice, were treated with genistein (0.1 µM, 0.5 µM or 1 µM) or vehicle. Under basal conditions, female neurons had longer primary neurites, higher number of secondary neurites and higher neuritic arborization compared to male neurons. The treatment with genistein increased neuritic arborization and the number of primary neurites and decreased the number of secondary neurites in female neurons, but not in male neurons. In contrast, genistein resulted in a significant increase in primary neuritic length in male neurons, but not in female neurons. The use of selective estrogen receptor antagonists suggests that estrogen receptor α, estrogen receptor β and G-protein-coupled estrogen receptors are involved in the neuritogenic action of genistein. In summary, these findings indicate that genistein exerts sexually dimorphic actions on the development of hypothalamic neurons, altering the normal pattern of sex differences in neuritogenesis. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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15 pages, 1446 KiB

Open AccessArticle

Green Tea Ameliorates Hyperglycemia by Promoting the Translocation of Glucose Transporter 4 in the Skeletal Muscle of Diabetic Rodents

by Manabu Ueda-Wakagi, Hironobu Nagayasu, Yoko Yamashita and Hitoshi Ashida

Int. J. Mol. Sci. 2019, 20(10), 2436; https://doi.org/10.3390/ijms20102436 - 16 May 2019

Cited by 42 | Viewed by 4919

Abstract

It is known that green tea helps prevent obesity and diabetes mellitus. In this study, we aimed to determine whether green tea ameliorates hyperglycemia and the mechanism involved in diabetic rodents. Green tea consumption reduced blood glucose and ameliorated glucose intolerance, which was [...] Read more.

It is known that green tea helps prevent obesity and diabetes mellitus. In this study, we aimed to determine whether green tea ameliorates hyperglycemia and the mechanism involved in diabetic rodents. Green tea consumption reduced blood glucose and ameliorated glucose intolerance, which was assessed using an oral glucose tolerance test in both streptozotocin-induced type 1 diabetic rats and type 2 diabetic KK-A^y mice. Green tea also reduced the plasma fructosamine and glycated hemoglobin concentrations in both models. Furthermore, it increased glucose uptake into the skeletal muscle of both model animals, which was accompanied by greater translocation of glucose transporter 4 (GLUT4). Moreover, epigallocatechin gallate (EGCG), the principal catechin in green tea, also ameliorated glucose intolerance in high-fat diet-induced obese and diabetic mice. These results suggest that green tea can ameliorate hyperglycemia in diabetic rodents by stimulating GLUT4-mediated glucose uptake in skeletal muscle, and that EGCG is one of the effective compounds that mediate this effect. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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13 pages, 1105 KiB

Open AccessArticle

Antioxidant and Photoprotective Activity of Apigenin and its Potassium Salt Derivative in Human Keratinocytes and Absorption in Caco-2 Cell Monolayers

by Noelia Sánchez-Marzo, Almudena Pérez-Sánchez, Verónica Ruiz-Torres, Adrián Martínez-Tébar, Julián Castillo, María Herranz-López and Enrique Barrajón-Catalán

Int. J. Mol. Sci. 2019, 20(9), 2148; https://doi.org/10.3390/ijms20092148 - 30 Apr 2019

Cited by 51 | Viewed by 5694

Abstract

Ultraviolet (UV) radiation, especially types A (UVA) and B (UVB), is one of the main causes of skin disorders, including photoaging and skin cancer. Ultraviolent radiation causes oxidative stress, inflammation, p53 induction, DNA damage, mutagenesis, and oxidation of various molecules such as lipids [...] Read more.

Ultraviolet (UV) radiation, especially types A (UVA) and B (UVB), is one of the main causes of skin disorders, including photoaging and skin cancer. Ultraviolent radiation causes oxidative stress, inflammation, p53 induction, DNA damage, mutagenesis, and oxidation of various molecules such as lipids and proteins. In recent decades, the use of polyphenols as molecules with an antioxidant and anti-inflammatory capacity has increased. However, some of these compounds are poorly soluble, and information regarding their absorption and bioavailability is scarce. The main objective of this study was to compare the intestinal absorption and biological activity of apigenin and its more soluble potassium salt (apigenin-K) in terms of antioxidant and photoprotective capacity. Photoprotective effects against UVA and UVB radiation were studied in human keratinocytes, and antioxidant capacity was determined by different methods, including trolox equivalent antioxidant capacity (TEAC), ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Finally, the intestinal absorption of both apigenins was determined using an in vitro Caco-2 cell model. Apigenin showed a slightly higher antioxidant capacity in antioxidant activity assays when compared with apigenin-K. However, no significant differences were obtained for their photoprotective capacities against UVA or UVB. Results indicated that both apigenins protected cell viability in approximately 50% at 5 J/m² of UVA and 90% at 500 J/m² of UVB radiation. Regarding intestinal absorption, both apigenins showed similar apparent permeabilities (P_app), 1.81 × 10⁻⁵ cm/s and 1.78 × 10⁻⁵ cm/s, respectively. Taken together, these results suggest that both apigenins may be interesting candidates for the development of oral (nutraceutical) and topical photoprotective ingredients against UVA and UVB-induced skin damage, but the increased water solubility of apigenin-K makes it the best candidate for further development. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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12 pages, 2740 KiB

Open AccessArticle

Quercetin Potentiates Docosahexaenoic Acid to Suppress Lipopolysaccharide-induced Oxidative/Inflammatory Responses, Alter Lipid Peroxidation Products, and Enhance the Adaptive Stress Pathways in BV-2 Microglial Cells

by Grace Y. Sun, Runting Li, Bo Yang, Kevin L. Fritsche, David Q. Beversdorf, Dennis B. Lubahn, Xue Geng, James C. Lee and C. Michael Greenlief

Int. J. Mol. Sci. 2019, 20(4), 932; https://doi.org/10.3390/ijms20040932 - 21 Feb 2019

Cited by 20 | Viewed by 6902

Abstract

High levels of docosahexaenoic acid (DHA) in the phospholipids of mammalian brain have generated increasing interest in the search for its role in regulating brain functions. Recent studies have provided evidence for enhanced protective effects when DHA is administered in combination with phytochemicals, [...] Read more.

High levels of docosahexaenoic acid (DHA) in the phospholipids of mammalian brain have generated increasing interest in the search for its role in regulating brain functions. Recent studies have provided evidence for enhanced protective effects when DHA is administered in combination with phytochemicals, such as quercetin. DHA and quercetin can individually suppress lipopolysaccharide (LPS)–induced oxidative/inflammatory responses and enhance the antioxidative stress pathway involving nuclear factor erythroid-2 related factor 2 (Nrf2). However, studies with BV-2 microglial cells indicated rather high concentrations of DHA (IC₅₀ in the range of 60–80 µM) were needed to produce protective effects. To determine whether quercetin combined with DHA can lower the levels of DHA needed to produce protective effects in these cells is the goal for this study. Results showed that low concentrations of quercetin (2.5 µM), in combination with DHA (10 µM), could more effectively enhance the expression of Nrf2 and heme oxygenase 1 (HO-1), and suppress LPS–induced nitric oxide, tumor necrosis factor-α, phospho-cytosolic phospholipase A₂, reactive oxygen species, and 4-hydroxynonenal, as compared to the same levels of DHA or quercetin alone. These results provide evidence for the beneficial effects of quercetin in combination with DHA, and further suggest their potential as nutraceuticals for improving health. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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Review

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14 pages, 5734 KiB

Open AccessReview

The Effect of Polyphenols on Hypercholesterolemia through Inhibiting the Transport and Expression of Niemann–Pick C1-Like 1

by Shoko Kobayashi

Int. J. Mol. Sci. 2019, 20(19), 4939; https://doi.org/10.3390/ijms20194939 - 6 Oct 2019

Cited by 33 | Viewed by 6545

Abstract

The Niemann–Pick C1-like 1 (NPC1L1) protein is a cholesterol transporter that is expressed in the small intestine. This report describes the discovery of NPC1L1, its transport properties, and the inhibitory effects of polyphenols on NPC1L1. NPC1L1 was identified in 2004 while searching for [...] Read more.

The Niemann–Pick C1-like 1 (NPC1L1) protein is a cholesterol transporter that is expressed in the small intestine. This report describes the discovery of NPC1L1, its transport properties, and the inhibitory effects of polyphenols on NPC1L1. NPC1L1 was identified in 2004 while searching for ezetimibe molecular targets. Excessive synthesis of cholesterol results in hyperlipidemia, which increases the amount of bile cholesterol excreted into the duodenum. The inhibition of NPC1L1 decreases blood cholesterol because food and bile cholesterol are also absorbed from NPC1L1 in the intestine. Some polyphenols, particularly luteolin, have been reported as NPC1L1-mediated anti-dyslipidemia constituents. Luteolin affects NPC1L1 through two mechanisms. Luteolin directly inhibits NPC1L1 by binding to it, which occurs in a short timeframe similar to that for ezetimibe. The other mechanism is the inhibition of NPC1L1 expression. Luteolin reduced the binding of Sterol-regulatory element-binding protein 2 (SREBP2) in the promoter region of the NPC1L1 gene and decreased mRNA levels of SREBP2 and hepatocyte nuclear factor 4α. These data suggest that luteolin decreases the expression of NPC1L1 through regulation of transcription factors. This review also explores the effect of other polyphenols on NPC1L1 and hypercholesterolemia. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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19 pages, 1466 KiB

Open AccessReview

Progress in Research on the Role of Flavonoids in Lung Cancer

by Oana Zanoaga, Cornelia Braicu, Ancuta Jurj, Alexandru Rusu, Rares Buiga and Ioana Berindan-Neagoe

Int. J. Mol. Sci. 2019, 20(17), 4291; https://doi.org/10.3390/ijms20174291 - 2 Sep 2019

Cited by 57 | Viewed by 5415

Abstract

Lung cancer is the leading cause of cancer deaths worldwide. Therefore, for the prevention, diagnosis, prognosis and treatment of lung cancer, efficient preventive strategies and new therapeutic strategies are needed to face these challenges. Natural bioactive compounds and particular flavonoids compounds have been [...] Read more.

Lung cancer is the leading cause of cancer deaths worldwide. Therefore, for the prevention, diagnosis, prognosis and treatment of lung cancer, efficient preventive strategies and new therapeutic strategies are needed to face these challenges. Natural bioactive compounds and particular flavonoids compounds have been proven to have an important role in lung cancer prevention and of particular interest is the dose used for these studies, to underline the molecular effects and mechanisms at a physiological concentration. The purpose of this review was to summarize the current state of knowledge regarding relevant molecular mechanisms involved in the pharmacological effects, with a special focus on the anti-cancer role, by regulating the coding and non-coding genes. Furthermore, this review focused on the most commonly altered and most clinically relevant oncogenes and tumor suppressor genes and microRNAs in lung cancer. Particular attention was given to the biological effect in tandem with conventional therapy, emphasizing the role in the regulation of drug resistance related mechanisms. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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19 pages, 360 KiB

Open AccessReview

The Anti-Cancer Effect of Quercetin: Molecular Implications in Cancer Metabolism

by Marjorie Reyes-Farias and Catalina Carrasco-Pozo

Int. J. Mol. Sci. 2019, 20(13), 3177; https://doi.org/10.3390/ijms20133177 - 28 Jun 2019

Cited by 386 | Viewed by 23359

Abstract

Cancer is a problem with worldwide importance and is the second leading cause of death globally. Cancer cells reprogram their metabolism to support their uncontrolled expansion by increasing biomass (anabolic metabolism—glycolysis) at the expense of their energy (bioenergetics-mitochondrial function) requirements. In this aspect, [...] Read more.

Cancer is a problem with worldwide importance and is the second leading cause of death globally. Cancer cells reprogram their metabolism to support their uncontrolled expansion by increasing biomass (anabolic metabolism—glycolysis) at the expense of their energy (bioenergetics-mitochondrial function) requirements. In this aspect, metabolic reprogramming stands out as a key biological process in understanding the conversion of a normal cell into a neoplastic precursor. Quercetin is the major representative of the flavonoid subclass of flavonols. Quercetin is ubiquitously present in fruits and vegetables, being one of the most common dietary flavonols in the western diet. The anti-cancer effects of quercetin include its ability to promote the loss of cell viability, apoptosis and autophagy through the modulation of PI3K/Akt/mTOR, Wnt/β-catenin, and MAPK/ERK1/2 pathways. In this review, we discuss the role of quercetin in cancer metabolism, addressing specifically its ability to target molecular pathways involved in glucose metabolism and mitochondrial function. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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16 pages, 2080 KiB

Open AccessReview

Synthetic Flavonoids as Novel Modulators of Platelet Function and Thrombosis

by Thomas M. Vallance, Divyashree Ravishankar, Dina A. I. Albadawi, Helen M. I. Osborn and Sakthivel Vaiyapuri

Int. J. Mol. Sci. 2019, 20(12), 3106; https://doi.org/10.3390/ijms20123106 - 25 Jun 2019

Cited by 17 | Viewed by 5055

Abstract

Cardiovascular diseases represent a major cause of mortality and morbidity in the world, and specifically, thrombotic conditions such as heart attacks and strokes are caused by unwarranted activation of platelets and subsequent formation of blood clots (thrombi) within the blood vessels during pathological [...] Read more.

Cardiovascular diseases represent a major cause of mortality and morbidity in the world, and specifically, thrombotic conditions such as heart attacks and strokes are caused by unwarranted activation of platelets and subsequent formation of blood clots (thrombi) within the blood vessels during pathological circumstances. Therefore, platelets act as a primary therapeutic target to treat and prevent thrombotic conditions. Current treatments are limited due to intolerance, and they are associated with severe side effects such as bleeding complications. Hence, the development of novel therapeutic strategies for thrombotic diseases is an urgent priority. Flavonoids are naturally occurring plant-derived molecules that exert numerous beneficial effects in humans through modulating the functions of distinct cell types. However, naturally occurring flavonoids suffer from several issues such as poor solubility, lipophilicity, and bioavailability, which hinder their efficacy and potency. Despite these, flavonoids act as versatile templates for the design and synthesis of novel molecules for various therapeutic targets. Indeed, several synthetic flavonoids have recently been developed to improve their stability, bioavailability, and efficacy, including for the modulation of platelet function. Here, we provide insight into the actions of certain natural flavonoids along with the advantages of synthetic flavonoids in the modulation of platelet function, haemostasis, and thrombosis. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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17 pages, 1224 KiB

Open AccessReview

Quercetin Regulates the Integrated Stress Response to Improve Memory

by Toshiyuki Nakagawa and Kazunori Ohta

Int. J. Mol. Sci. 2019, 20(11), 2761; https://doi.org/10.3390/ijms20112761 - 5 Jun 2019

Cited by 26 | Viewed by 9939

Abstract

The initiation of protein synthesis is suppressed under several stress conditions, inducing phosphorylation of the α-subunit of the eukaryotic initiation factor 2 (eIF2α), thereby inactivating the GTP-GDP recycling protein eIF2B. By contrast, the mammalian activating transcription factor 4 (ATF4, also known as cAMP [...] Read more.

The initiation of protein synthesis is suppressed under several stress conditions, inducing phosphorylation of the α-subunit of the eukaryotic initiation factor 2 (eIF2α), thereby inactivating the GTP-GDP recycling protein eIF2B. By contrast, the mammalian activating transcription factor 4 (ATF4, also known as cAMP response element binding protein 2 (CREB2)) is still translated under stress conditions. Four protein kinases (general control nonderepressible-2 (GCN2) kinase, double-stranded RNA-activated protein kinase (PKR), PKR-endoplasmic reticulum (ER)-related kinase (PERK), and heme-regulated inhibitor kinase (HRI)) phosphorylate eIF2α in the presence of stressors such as amino acid starvation, viral infection, ER stress, and heme deficiency. This signaling reaction is known as the integrated stress response (ISR). Here, we review ISR signaling in the brain in a mouse model of Alzheimer’s disease (AD). We propose that targeting ISR signaling with quercetin has therapeutic potential, because it suppresses amyloid-β (Aβ) production in vitro and prevents cognitive impairments in a mouse model of AD. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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18 pages, 473 KiB

Open AccessReview

Molecular Targets of Genistein and Its Related Flavonoids to Exert Anticancer Effects

by Hee-Sung Chae, Rong Xu, Jae-Yeon Won, Young-Won Chin and Hyungshin Yim

Int. J. Mol. Sci. 2019, 20(10), 2420; https://doi.org/10.3390/ijms20102420 - 16 May 2019

Cited by 65 | Viewed by 7434

Abstract

Increased health awareness among the public has highlighted the health benefits of dietary supplements including flavonoids. As flavonoids target several critical factors to exert a variety of biological effects, studies to identify their target-specific effects have been conducted. Herein, we discuss the basic [...] Read more.

Increased health awareness among the public has highlighted the health benefits of dietary supplements including flavonoids. As flavonoids target several critical factors to exert a variety of biological effects, studies to identify their target-specific effects have been conducted. Herein, we discuss the basic structures of flavonoids and their anticancer activities in relation to the specific biological targets acted upon by these flavonoids. Flavonoids target several signaling pathways involved in apoptosis, cell cycle arrest, mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/AKT kinase, and metastasis. Polo-like kinase 1 (PLK1) has been recognized as a valuable target in cancer treatment due to the prognostic implication of PLK1 in cancer patients and its clinical relevance between the overexpression of PLK1 and the reduced survival rates of several carcinoma patients. Recent studies suggest that several flavonoids, including genistein directly inhibit PLK1 inhibitory activity. Later, we focus on the anticancer effects of genistein through inhibition of PLK1. Full article

(This article belongs to the Special Issue Perspectives on the Health Benefits of Flavonoids)

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