Angiogenesis and current approaches to deal with its misregulation in related diseases

Abstract: Angiogenesis, which is the formation of blood vessels from pre-existing vessels, normally supply nutrition and oxygen to cells and tissues. In medicine point of view, regulation of angiogenesis is disrupted in many diseases such as cancers, psoriasis, age related macular degeneration, diabetes, proliferative retinopathies and rheumatoid arthritis. How to suppress, control and regulate the angiogenesis have been very challenging tasks in order to provide better and more effective treatments for related patients. With this regard, anti-angiogenic therapy has been considered as a potential approach to do so. However, anti-angiogenic agents are not completely safe and present side effects. Therefore, many attentions have been paid to understand more about molecular and cellular mechanisms involved in angiogenesis in order to prevent many life-threating side effects of anti-angiogenic agents. It may lead to discovering more desirable drugs to tackle angiogenesis. This review aims to give an overview about what angiogenesis is as well as present the most important factors involved in angiogenesis. It also attempts to describe current approaches and challenges in controlling angiogenesis

Angiogenesis and current approaches to deal with its misregulation in related diseases

Abstract: Angiogenesis, which is the formation of blood vessels from pre-existing vessels, normally supply nutrition and oxygen to cells and tissues. In medicine point of view, regulation of angiogenesis is disrupted in many diseases such as cancers, psoriasis, age related macular degeneration, diabetes, proliferative retinopathies and rheumatoid arthritis. How to suppress, control and regulate the angiogenesis have been very challenging tasks in order to provide better and more effective treatments for related patients. With this regard, anti-angiogenic therapy has been considered as a potential approach to do so. However, anti-angiogenic agents are not completely safe and present side effects. Therefore, many attentions have been paid to understand more about molecular and cellular mechanisms involved in angiogenesis in order to prevent many life-threating side effects of anti-angiogenic agents. It may lead to discovering more desirable drugs to tackle angiogenesis. This review aims to give an overview about what angiogenesis is as well as present the most important factors involved in angiogenesis. It also attempts to describe current approaches and challenges in controlling angiogenesis

La Russia e il Caucaso: alle origini di un problema insoluto

Interactions between cancer cells and stromal cells in the tumour microenvironment play a key role in the control of invasiveness, metastasis and angiogenesis. Macrophages display a range of activation states in specific pathological contexts and alternatively activated (M2) macrophages can promote tumour aggressiveness. Opioids are able to modulate tumour growth and metastasis. We tested whether morphine modulates the activation of macrophages induced by (i) interleukin-4 (IL-4), the prototypical M2 polarization-inducing cytokine, or (ii) coculture with breast cancer cells. We showed that IL-4 causes increased MMP-9 production and expression of the alternative activation markers arginase-1 and MRC-1. Morphine prevented IL-4-induced increase in MMP-9 in a naloxone- and methylnaltrexone-reversible fashion. Morphine also prevented IL-4-elicited alternative activation of RAW264.7 macrophages. Expression of MMP-9 and arginase-1 were increased when RAW264.7 were subjected to paracrine activation by 4T1 cells, and this effect was prevented by morphine via an opioid receptor-mediated mechanism. Morphine further decreased 4T1 breast cancer cell invasion elicited by co-culture with RAW264.7. Reduction of MMP-9 expression and alternative activation of macrophages by morphine was confirmed using mouse bone marrow-derived macrophages. Taken together, our results indicate that morphine may modulate tumour aggressiveness by regulating macrophage protease production and M2 polarization within the tumour microenvironment.journal articleresearch support, non-u.s. gov't2015 Jun 162015 06 16importe

Morphine decreases the pro-angiogenic interaction between breast cancer cells and macrophages in vitro

Interactions between the various cell types that constitute a solid tumour are essential to the biology of the tumour. We evaluated the effect of morphine on the proangiogenic interaction taking place between macrophages and breast cancer cells in vitro. The conditioned medium (CM) from breast cancer cells co-cultured with macrophages elicited endothelial cell proliferation and tube formation. This effect was inhibited if the co-culture occurred in the presence of morphine. The CM from breast cancer cells or macrophages grown individually, whether or not prepared in the presence of morphine, was ineffective in stimulating EC proliferation or tube formation. Using a mouse antibody array, we identified several angiogenesis-regulating factors differentially expressed in the CM of co-cultured cells prepared in the presence or absence of morphine, amongst which interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and vascular endothelial growth factor (VEGF)-A. VEGF was induced in both cell types by the co-culture and this was prevented by morphine in a non-naloxone reversible fashion. The effect of CM from co-cultured cells on endothelial tube formation, but not proliferation, was prevented by anti-VEGF neutralizing antibody. Our results indicate that morphine prevents, in part via modulating VEGF-A expression, the pro-angiogenic interaction between macrophages and breast cancer cells

The TLR4-active morphine metabolite morphine-3-glucuronide does not elicit macrophage classical activation in vitro

Macrophages are abundant in the tumor microenvironment where they adopt a pro-tumor phenotype following alternative polarization induced by paracrine factors from cancer and stromal cells. In contrast, classically activated macrophages have tumoricidal activities, such that the polarization of tumor-associated macrophages has become a novel therapeutic target. Toll-like receptor 4 engagement promotes classical activation of macrophages, and recent literature suggests TLR4 agonism to prevent metastasis and promote survival in experimental metastasis models. A growing number of studies indicate that TLR4 can respond to opioids, including the opioid receptor-inactive morphine metabolite morphine-3-glucuronide (M3G). We measured the activation of TLR4 in a reporter cell line exogenously expressing TLR4 and TLR4 co-receptors, and confirmed that M3G weakly but significantly activates TLR4. We hypothesized that M3G would promote the expression of classical activation signature genes in macrophages in vitro. We exposed mouse and human macrophage cell lines to M3G or the TLR4 activator lipopolysaccharide (LPS), alone or in combination with interferon gamma (IFN-gamma). The classical macrophage activation markers tested were iNOS, CD86, IL-6, or TNF-alpha in RAW 264.7 cells and IL-6, IL-12, IL-23, TNF-alpha, CXCL10, and CXCL11 in THP1 cells. Our results show that despite exhibiting TLR4-activation ability, M3G does not elicit the expression of classical activation markers in LPS-responsive macrophages

Effect of the Biphenyl Neolignan Honokiol on Aβ42-Induced Toxicity in Caenorhabditis elegans, Aβ42 Fibrillation, Cholinesterase Activity, DPPH Radicals, and Iron(II) Chelation

The biphenyl neolignan honokiol is a neuroprotectant which has been proposed as a treatment for central nervous system disorders such as Alzheimer's disease (AD). The death of cholinergic neurons in AD is attributed to multiple factors, including accumulation and fibrillation of amyloid beta peptide (Aβ) within the brain; metal ion toxicity; and oxidative stress. In this study, we used a transgenic Caenorhabditis elegans model expressing full length Aβ as a convenient in vivo system for examining the effect of honokiol against Aβ-induced toxicity. Furthermore, honokiol was evaluated for its ability to inhibit Aβ oligomerization and fibrillation; inhibit acetylcholinesterase and butyrylcholinesterase; scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals; and chelate iron(II). Honokiol displayed activity similar to that of resveratrol and (-)-epigallocatechin gallate (EGCG) in delaying Aβ-induced paralysis in C. elegans, and it exhibited moderate-to-weak ability to inhibit Aβ on-pathway aggregation, inhibit cholinesterases, scavenge DPPH radicals, and chelate iron(II). Moreover, honokiol was found to be chemically stable relative to EGCG, which was highly unstable. Together with its good drug-likeness and brain availability, these results suggest that honokiol may be amenable to drug development and that the synthesis of honokiol analogues to optimize these properties should be considered

Flavonoid genistein protects bone marrow sinusoidal blood vessels from damage by methotrexate therapy in rats

Cancer chemotherapy can cause significant damage to the bone marrow (BM) microvascular (sinusoidal) system. Investigations must now address whether and how BM sinusoidal endothelial cells (SECs) can be protected during chemotherapy. Herein we examined the potential protective effects of genistein, a soy-derived flavonoid, against BM sinusoidal damage caused by treatment with methotrexate (MTX). The groups of young adult rats were gavaged daily with genistein (20 mg/kg) or placebo. After 1 week, rats also received daily injections of MTX (0.75 mg/kg) or saline for 5 days and were killed after a further 4 days. Histological analyses showed that BM sinusoids were markedly dilated ( p < 0.001) in the MTX-alone group but were unaffected or less dilated in the genistein+MTX group. In control rats, genistein significantly enhanced expression of vascular endothelial growth factor (VEGF; p < 0.01), particularly in osteoblasts, and angiogenesis marker CD31 ( p < 0.001) in bone. In MTX-treated rats, genistein suppressed MTX-induced apoptosis of BM SECs ( p < 0.001 vs MTX alone group) and tended to increase expression of CD31 and VEGF ( p < 0.05). Our in vitro studies showed that genistein in certain concentrations protected cultured SECs from MTX cytotoxic effects. Genistein enhanced tube formation of cultured SECs, which is associated with its ability to induce expression of endothelial nitric oxide synthase and production of nitric oxide. These data suggest that genistein can protect BM sinusoids during MTX therapy, which is associated, at least partially, with its indirect effect of promoting VEGF expression in osteoblasts and its direct effect of enhancing nitric oxide production in SECs

Effect of the Biphenyl Neolignan Honokiol on Aβ₄₂-Induced Toxicity in <i>Caenorhabditis elegans</i>, Aβ₄₂ Fibrillation, Cholinesterase Activity, DPPH Radicals, and Iron(II) Chelation

The biphenyl neolignan honokiol is a neuroprotectant which has been proposed as a treatment for central nervous system disorders such as Alzheimer’s disease (AD). The death of cholinergic neurons in AD is attributed to multiple factors, including accumulation and fibrillation of amyloid beta peptide (Aβ) within the brain; metal ion toxicity; and oxidative stress. In this study, we used a transgenic <i>Caenorhabditis elegans</i> model expressing full length Aβ₄₂ as a convenient <i>in vivo</i> system for examining the effect of honokiol against Aβ-induced toxicity. Furthermore, honokiol was evaluated for its ability to inhibit Aβ₄₂ oligomerization and fibrillation; inhibit acetylcholinesterase and butyrylcholinesterase; scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals; and chelate iron­(II). Honokiol displayed activity similar to that of resveratrol and (−)-epigallocatechin gallate (EGCG) in delaying Aβ₄₂-induced paralysis in <i>C. elegans</i>, and it exhibited moderate-to-weak ability to inhibit Aβ₄₂ on-pathway aggregation, inhibit cholinesterases, scavenge DPPH radicals, and chelate iron­(II). Moreover, honokiol was found to be chemically stable relative to EGCG, which was highly unstable. Together with its good drug-likeness and brain availability, these results suggest that honokiol may be amenable to drug development and that the synthesis of honokiol analogues to optimize these properties should be considered