Antiangiogenic properties of natural polyphenols from red wine and green tea

Epidemiological studies have indicated that regular consumption of red wine and green tea is associated with a reduced risk of coronary heart disease and tumor progression. The development of tumors and of atherosclerosis lesions to advanced plaques, which are prone to rupture, is accelerated by the formation of new blood vessels. These new blood vessels provide oxygen and nutrients to neighboring cells. Therefore, recent studies have examined whether red wine polyphenolic compounds (RWPCs) and green tea polyphenols (GTPs) have antiangiogenic properties. In vitro investigations have indicated that RWPCs and GTPs are able to inhibit several key events of the angiogenic process such as proliferation and migration of endothelial cells and vascular smooth muscle cells and the expression of two major proangiogenic factors, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2, by both redox-sensitive and redox-insensitive mechanisms. Antiangiogenic properties of polyphenols have also been observed in the chick embryo chorioallantoic membrane since the local application of RWPCs and GTPs strongly inhibited the formation of new blood vessels. Moreover, intake of resveratrol or green tea has been shown to reduce corneal neovascularization induced by proangiogenic factors such as VEGF and fibroblast growth factor in mice. The ability of RWPCs and GTPs to prevent the formation of new blood vessels contributes, at least in part, to explain their beneficial effect on coronary heart disease and cancer. This review focuses on the antiangiogenic properties of natural polyphenols and examines underlying mechanisms.     

Dietary polyphenols and mechanisms of osteoarthritis

Osteoarthritis is a condition caused in part by injury, loss of cartilage structure and function, and an imbalance in inflammatory and anti-inflammatory pathways. It primarily affects the articular cartilage and subchondral bone of synovial joints and results in joint failure, leading to pain upon weight bearing including walking and standing. There is no cure for osteoarthritis, as it is very difficult to restore the cartilage once it is destroyed. The goals of treatment are to relieve pain, maintain or improve joint mobility, increase the strength of the joints and minimize the disabling effects of the disease. Recent studies have shown an association between dietary polyphenols and the prevention of osteoarthritis-related musculoskeletal inflammation. This review discusses the effects of commonly consumed polyphenols, including curcumin, epigallocatechin gallate and green tea extract, resveratrol, nobiletin and citrus fruits, pomegranate, as well as genistein and soy protein, on osteoarthritis with an emphasis on molecular antiosteoarthritic mechanisms.     

Antiangiogenic agents

Comment on: Conley SJ, et al. Proc Natl Acad Sci USA 2012; In press     

Neurological mechanisms of green tea polyphenols in Alzheimer's and Parkinson's diseases

Tea consumption is varying its status from a mere ancient beverage and a lifestyle habit, to a nutrient endowed with possible prospective neurobiological-pharmacological actions beneficial to human health. Accumulating evidence suggest that oxidative stress resulting in reactive oxygen species generation and inflammation play a pivotal role in neurodegenerative diseases, supporting the implementation of radical scavengers, transition metal (e.g., iron and copper) chelators, and nonvitamin natural antioxidant polyphenols in the clinic. These observations are in line with the current view that polyphenolic dietary supplementation may have an impact on cognitive deficits in individuals of advanced age. As a consequence, green tea polyphenols are now being considered as therapeutic agents in well controlled epidemiological studies, aimed to alter brain aging processes and to serve as possible neuroprotective agents in progressive neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. In particular, literature on the putative novel neuroprotective mechanism of the major green tea polyphenol, (-)-epigallocatechin-3-gallate, are examined and discussed in this review.     

Antiangiogenic agents

A greater understanding of the complex process of tumor-induced angiogenesis, coupled with the notion that tumors require a blood supply to both grow and metastasize, has fueled the search for agents that block or disrupt the angiogenic process. Because normal vascular endothelial cells (ECs) turn over so slowly, conventional wisdom suggests that an antiangiogenic approach to cancer therapy should offer improved efficacy and reduced toxicity, without the potential for drug resistance. Numerous reports have identified small molecules or antibodies that can interfere with one or more key steps in EC signaling, migration or differentiation. Three new compounds, ZD4190, SU6668 and PD 0173073, have been reported during the past year to have significant and selective antiangiogenic activity, as well as antitumor activity.     

Rational identification of diet-derived postbiotics for improving intestinal microbiota function

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Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals

Nanotechnology is an innovative approach that has potential applications in nutraceutical research. Phytochemicals have promising potential for maintaining and promoting health, as well as preventing and potentially treating some diseases. However, the generally low solubility, stability, bioavailability and target specificity, together with the side effects seen when used at high levels, have limited their application. Indeed, nanoparticles can increase solubility and stability of phytochemicals, enhance their absorption, protect them from premature degradation in the body and prolong their circulation time. Moreover, these nanoparticles exhibit high differential uptake efficiency in the target cells (or tissue) over normal cells (or tissue) through preventing them from prematurely interacting with the biological environment, enhanced permeation and retention effect in disease tissues and improving their cellular uptake, resulting in decreased toxicity, In this review, we outline the commonly used biocompatible and biodegradable nanoparticles including liposomes, emulsions, solid lipid nanoparticles, nanostructured lipid carriers, micelles and poly(lactic-co-glycolic acid) nanoparticles. We then summarize studies that have used these nanoparticles as carriers for epigallocatechin gallate, quercetin, resveratrol and curcumin administration to enhance their aqueous solubility, stability, bioavailability, target specificity and bioactivities.     

Inhibitory mechanisms of tea polyphenols on the ultraviolet B-activated phosphatidylinositol 3-kinase-dependent pathway

In this study, we investigated the effect of tea polyphenols, (-)-epigallocatechin-3-gallate or theaflavins, on UVB-induced phosphatidylinositol 3-kinase (PI3K) activation in mouse epidermal JB6 Cl 41 cells. Pretreatment of cells with these polyphenols inhibited UVB-induced PI3K activation. Furthermore, UVB-induced activation of Akt and ribosomal p70 S6 kinase (p70 S6-K), PI3K downstream effectors, were also attenuated by the polyphenols. In addition to LY294002, a PI3K inhibitor, pretreatment with a specific mitogen-activated protein/extracellular signal-regulated protein kinases (Erks) kinase 1 inhibitor, U0126, or a specific p38 kinase inhibitor, SB202190, blocked UVB-induced activation of both Akt and p70 S6-K. Pretreatment with LY294002 restrained UVB-induced phosphorylation of Erks, suggesting that in UVB signaling, the Erk pathway is mediated by PI3K. Moreover, pretreatment with rapamycin, an inhibitor of p70 S6-K, inhibited UVB-induced activation of p70 S6-K, but UVB-induced activation of Akt did not change. Interestingly, UVB-induced p70 S6-K activation was directly blocked by the addition of (-)-epigallocatechin-3-gallate or theaflavins, whereas these polyphenols showed only a weak inhibition on UVB-induced Akt activation. Because PI3K is an important factor in carcinogenesis, the inhibitory effect of these polyphenols on activation of PI3K and its downstream effects may further explain the anti-tumor promotion action of these tea constituents.     

Antiangiogenic activity of 2-deoxy-D-glucose

Background

During tumor angiogenesis, endothelial cells (ECs) are engaged in a number of energy consuming biological processes, such as proliferation, migration, and capillary formation. Since glucose uptake and metabolism are increased to meet this energy need, the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on in vitro and in vivo angiogenesis were investigated.

Methodology/Principal Findings

In cell culture, 2-DG inhibited EC growth, induced cytotoxicity, blocked migration, and inhibited actively forming but not established endothelial capillaries. Surprisingly, 2-DG was a better inhibitor of these EC properties than two more efficacious glycolytic inhibitors, 2-fluorodeoxy-D-glucose and oxamate. As an alternative to a glycolytic inhibitory mechanism, we considered 2-DG''s ability to interfere with endothelial N-linked glycosylation. 2-DG''s effects were reversed by mannose, an N-linked glycosylation precursor, and at relevant concentrations 2-DG also inhibited synthesis of the lipid linked oligosaccharide (LLO) N-glycosylation donor in a mannose-reversible manner. Inhibition of LLO synthesis activated the unfolded protein response (UPR), which resulted in induction of GADD153/CHOP and EC apoptosis (TUNEL assay). Thus, 2-DG''s effects on ECs appeared primarily due to inhibition of LLOs synthesis, not glycolysis. 2-DG was then evaluated in two mouse models, inhibiting angiogenesis in both the matrigel plug assay and the LH_BETAT_AG transgenic retinoblastoma model.

Conclusions/Significance

In conclusion, 2-DG inhibits endothelial cell angiogenesis in vitro and in vivo, at concentrations below those affecting tumor cells directly, most likely by interfering with N-linked glycosylation rather than glycolysis. Our data underscore the importance of glucose metabolism on neovascularization, and demonstrate a novel approach for anti-angiogenic strategies.     

Antiangiogenic activity of chemopreventive drugs

Tumors growing within the host form dynamic aberrant tissue that consists of host components, including the stroma, an expanding vasculature and often chronic inflammation, in addition to the tumor cells themselves. These host components can contribute to, rather than limit, tumor expansion, whereas deprivation of vessel formation has the potential to confine tumors in small, clinically silent foci. Therapeutic inhibition of vessel formation could be best suited to preventive strategies aimed at the suppression of angiogenesis in primary tumors in subjects at risk, or of micrometastases after surgical removal of a primary tumor. Our analysis of potential cancer chemopreventive molecules including N-acetylcysteine, green tea flavonoids and 4-hydroxyphenyl-retinamide has identified antiangiogenic activities that could account--at least in part--for the tumor prevention effects observed with these compounds. These drugs appear to target common mechanisms of tumor angiogenesis that may permit identification of critical targets for antiangiogenic therapy and antiangiogenic chemoprevention.     

Antiangiogenic potential of 10-hydroxycamptothecin

To investigate the antiangiogenic potential of 10-hydroxycamptothecin (HCPT), the proliferation of human microvascular endothelial cells (HMEC) and seven human tumor cell lines were detected by SRB assay, and the endothelial cell migration and tube formation were assessed using two in vitro model systems. Also, inhibition of angiogenesis was determined with a modification of the chick embryo chorioallantoic membrane (CAM) assay in vivo. Morphological assessment of apoptosis was performed by fluorescence microscope. HCPT 0.313-5 micromol x L(-1) treatment resulted in a dose-dependent inhibition of proliferation, migration and tube formation in HMEC cells, and HCPT 6.25-25 nmol x egg(-1) inhibited angiogenesis in CAM assay. HCPT 1.25-5 micromol x L(-1) elicited typical morphological changes of apoptosis including condensed chromatin, nuclear fragmentation, and reduction in volume in HMEC cells. HCPT significantly inhibited angiogenesis both in vitro and in vivo at relatively low concentrations, and this effect was related with induction of apoptosis in HMEC cells. These results taken collectively suggest that HCPT may be a potent antiangiogenetic and cytotoxic drug and further investigation is warranted.     

Antiangiogenic and radiotherapy for cancer treatment

Tumor growth and progression depends on tumor angiogenesis, the growth of tumor blood vessels, therefore, targeting tumor angiogenesis is a very promising approach for controlling tumor growth and/or causing regression. Tumor blood vessels have been recognized as a critical component of radiation response to the point of being independent of tumor oxygenation during radiation. An anti-angiogenic approach has been considered less likely to develop drug resistance. But recent findings suggest that anti-angiogenesis causes hypoxia that selects tumor cells (due to genetic instability) that are less dependent on blood supply and leads to drug resistance. The approach of combination of anti-angiogenesis with ionizing radiation by targeting both endothelial and tumor cells should minimize this possibility. The combination may produce a synergistic anti-tumor effect.     

Antiangiogenic and antitumor activities of IL-27

IL-27 is a novel IL-6/IL-12 family cytokine playing an important role in the early regulation of Th1 responses. We have recently demonstrated that IL-27 has potent antitumor activity, which is mainly mediated through CD8(+) T cells, against highly immunogenic murine colon carcinoma. In this study, we further evaluated the antitumor and antiangiogenic activities of IL-27, using poorly immunogenic murine melanoma B16F10 tumors, which were engineered to overexpress single-chain IL-27 (B16F10 + IL-27). B16F10 + IL-27 cells exerted antitumor activity against not only s.c. tumor but also experimental pulmonary metastasis. Similar antitumor and antimetastatic activities of IL-27 were also observed in IFN-gamma knockout mice. In NOD-SCID mice, these activities were decreased, but were still fairly well-retained, suggesting that different mechanisms other than the immune response are also involved in the exertion of these activities. Immunohistochemical analyses with Abs against vascular endothelial growth factor and CD31 revealed that B16F10 + IL-27 cells markedly suppressed tumor-induced neovascularization in lung metastases. Moreover, B16F10 + IL-27 cells clearly inhibited angiogenesis by dorsal air sac method, and IL-27 exhibited dose-dependent inhibition of angiogenesis on chick embryo chorioallantoic membrane. IL-27 was revealed to directly act on HUVECs and induce production of the antiangiogenic chemokines, IFN-gamma-inducible protein (IP-10) and monokine induced by IFN-gamma. Finally, augmented mRNA expression of IP-10 and monokine induced by IFN-gamma was detected at the s.c. B16F10 + IL-27 tumor site, and antitumor activity of IL-27 was partially inhibited by the administration of anti-IP-10. These results suggest that IL-27 possesses potent antiangiogenic activity, which plays an important role in its antitumor and antimetastatic activities.     

抗血管生成蛋白与多肽研究进展

多项动物实验和临床实啦已经充分证实,抗血管生成疗法可以抑制肿瘤生长。在可抑制肿瘤生长的分子中,许多是蛋白与多肽,包括细胞因子、趋化因子、血管内皮生长因子及其受体的抗体、可溶性受体、胞外基质蛋白片段及小分子合成多肽等。简要综述其中部分分子的作用机理及临床应用情况。