Miguel Ángel Medina

Monocyte chemoattractant protein-1: a key mediator in inflammatory processes.

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant for monocytes and macrophages to areas of inflammation. MCP-1 is a prototypical chemokine subject to coordinated regulation by immunomodulatory agents. Since MCP-1 is implicated in multiple inflammatory diseases, it is a potential target for the treatment of these disorders. In this review, we will provide background information and summarize the MCP-1 structure and signaling pathways. Its involvement in multiple diseases, such as tumour development, atherogenesis and rare autoimmune diseases is also revised.

Relevance of glutamine metabolism to tumor cell growth

Tumor cells are characterized as rapidly dividing cells, and consequently they need a constant supply of both energy and nitrogen substrates. To resolve their energy requirements, they are able to use virtually any substrate: glucose [see 1 for a review; 2-4], lipids [5-7], ketone bodies [3], even amino acids [2-4, 8-10]. Nevertheless, the glucose and amino acid consumption by malignant tumor cells overcomes their own needs for their metabolic requirements; thus, tumor cells apparently waste glucose and amino acids without any profit [1, ll]. In this context, tumor has been described as a trap for glucose and nitrogen [12-13]. Tumors compete with the host for glucose [13-14]; this competence results in a progressive hypoglycemia [15] and host hepatic glycogen depletion [13]. In the same way, tumors compete for nitrogen compounds; this process produces in the host a negative nitrogen balance and a characteristic weight loss, and in the tumor a reciprocal nitrogen increase. The biochemical mechanisms underlying these phenomena still remain unclear. There is consensus that tumors increase protein degradation and reduce protein synthesis in the host tissues [16]. Alanine and glutamine are two efficient vehicles for the transport of nitrogen and carbon-skeletons between the different tissues in the living organism [17-18]. When a tumor develops, there is a net flux of amino acids from host tissues to the tumor [19]. Since ammonium ions are very toxic for most of the cells, glutamine is the physiological non-toxic ammonium vehicle between different mammalian tissues; therefore, glutamine is the main source of nitrogen for tumor cells [2, 20-21]. Thus, the presence of a tumor must produce great changes in the metabolism of glutamine in host tissues in such a way that host nitrogen metabolism is accomodated to tumor enhanced requirements of glutamine. To be used, glutamine must be transported into tumor mitochondria, where it is metabolized [21]. This implies two transport processes: the transport of glutamine across the plasma membrane and across the inner mitochondrial membrane. Once glutamine has been incorporated into tumor cells, this amino acid is quickly metabolized [12, 16, 19].

Biogenic amines and polyamines: Similar biochemistry for different physiological missions and biomedical applications

Biogenic amines are organic polycations derived from aromatic or cationic amino acids. All of them have one or more positive charges and a hydrophobic skeleton. Nature has evolved these molecules to play different physiological roles in mammals, but maintains similar patterns for their metabolic and intracellular handling. As deduced from this review, many questions still remain to be solved around their biochemistry and molecular biology, blocking our aims to control the relevant pathologies in which they are involved (cancer and immunological, neurological, and gastrointestinal diseases). Advances in this knowledge are dispersed among groups working on different biomedical areas. In these pages, we put together the most relevant information to remark how fruitful it can be to learn from Nature and to take advantage of the biochemical similarities (keyprotein structures and their regulation data on metabolic interplays and binding properties) to generate new hypothesis and develop different biomedical strategies based on biochemistry and molecular biology of these compounds.

Antiangiogenic activity of aeroplysinin-1, a brominated compound isolated from a marine sponge

(+)‐Aeroplysinin‐1, an antibacterial brominated compound produced by certain sponges, was selected during a blind high‐throughput screening for new potential antiangiogenic compounds obtained from marine organisms. In a variety of experimental systems, representing the sequential events of the angiogenic process, aeroplysinin‐1 treatment of endothelial cells resulted in strong inhibitory effects. Aeroplysinin‐1 inhibited the growth of endothelial cells in culture and induced endothelial cell apoptosis. Capillary tube formation on Matrigel was completely abrogated by addition of aeroplysinin‐1 at the low micromolar range. Aeroplysinin‐1 also exhibited a clear inhibitory effect on the migration capabilities of endothelial cells. Zymographic assays showed that aeroplysinin‐1 treatment produced a decrease in the concentration of matrix metalloproteinase‐2 and urokinase in conditioned medium from endothelial cells. Finally, aeroplysinin‐1 exhibited a dose‐dependent inhibitory effect on the in vivo chorioallantoic membrane assay, showing potent apoptosis‐inducing activity in the developing endothelium. The in vivo inhibition of angiogenesis by aeroplysinin‐1 was confirmed by the Matrigel plug assay. Together, our data indicate that aeroplysinin‐1 is a compound that interferes with key events in angiogenesis, making it a promising drug for further evaluation in the treatment of angiogenesis‐related pathologies.

Fourier transform Raman study of the structural specificities on the interaction between DNA and biogenic polyamines.

Biogenic polyamines putrescine, spermidine, and spermine are essential molecules for proliferation in all living organisms. Direct interaction of polyamines with nucleic acids has been proposed in the past based on a series of experimental evidences, such as precipitation, thermal denaturation, or protection. However, binding between polyamines and nucleic acids is not clearly explained. Several interaction models have also been proposed, although they do not always agree with one another. In the present work, we make use of the Raman spectroscopy to extend our knowledge about polyamine-DNA interaction. Raman spectra of highly polymerized calf-thymus DNA at different polyamine concentrations, ranging from 1 to 50 mM, have been studied for putrescine, spermidine, and spermine. Both natural and heavy water were used as solvents. Difference Raman spectra have been computed by subtracting the sum of the separated component spectra from the experimental spectra of the complexes. The analysis of the Raman data has supported the existence of structural specificities in the interactions, at least under our experimental conditions. These specificities lead to preferential bindings through the DNA minor groove for putrescine and spermidine, whereas spermine binds by the major groove. On the other hand, spermine and spermidine present interstrand interactions, whereas putrescine presents intrastrand interactions in addition to exo-groove interactions by phosphate moieties.

Histamine, polyamines, and cancer

Mammalian ornithine decarboxylase and histidine decarboxylase present common structural and functional features, and their products also share pharmacological and physiological properties. Although accumulated evidence pointed for years to a direct involvement of polyamines and histamine in tumour growth, it has been only in the last few years that new molecular data have contributed to the clarification of this topic. The aim of this commentary is to review the molecular grounds of the role of histamine and polyamines in cancer and to point to possible directions for future research in emerging areas of interest.

Nitrogen Metabolism in Tumor Bearing Mice

In experiments with whole animals infested with a highly malignant strain of Ehrlich ascites tumor cells, serial concentrations of amino acids were determined for host plasma, ascitic fluid, and tumor cells, throughout tumor development. Concentration gradients of glutamine, asparagine, valine, leucine, isoleucine, phenylalanine, tyrosine, histidine, tryptophan, arginine, serine, methionine, and taurine from the host plasma toward the ascitic liquid were established; while on the other hand, concentration gradients from the ascitic liquid toward the plasma were established for glutamate, aspartate, glycine, alanine, proline, and threonine. With the exception of aspartate the concentrations of these amino acids were highest inside the cells. Arginine was the only amino acid not detected in tumor cells. In vitro incubations of tumor cells in the presence of glutamine and/or glucose, as the energy and nitrogen sources, confirmed the amino acid fluxes previously deduced from the observed relative concentrations of amino acids in plasma, ascitic liquid, and tumor cells, suggesting that glutamate, alanine, aspartate, glycine, and serine can be produced by tumors. These findings support that changes in amino acid patterns occurring in the host system are related to tumor development.

Hyperforin, a bio‐active compound of St. John's Wort, is a new inhibitor of angiogenesis targeting several key steps of the process

Hyperforin, a phloroglucinol derivative found in St. Johns wort related mainly to its antidepressant effects, has been reported recently to induce apoptosis in tumour cells and to inhibit cancer invasion and metastasis. We show that hyperforin inhibits angiogenesis in vitro in bovine aortic endothelial cells and in vivo in the chorioallantoic membrane assay. In a variety of experimental systems representing the sequential events of the angiogenic process, hyperforin treatment of endothelial cells resulted in strong inhibitory effects. Hyperforin inhibited the growth of endothelial cells in culture. Capillary tube formation on Matrigel was abrogated completely by addition of hypeforin at the low micromolar range. Hyperforin also exhibited a clear inhibitory effect on the invasive capabilities of endothelial cells. Zymographic assays showed that hyperforin treatment produced a complete inhibition of urokinase and a remarkable inhibition of matrix metalloproteinase 2. Our data indicates that hyperforin is a compound that interferes with key events in angiogenesis, confirming the recent and growing evidence about a potential role of this compound in cancer and metastasis inhibition and making it a promising drug for further evaluation in the treatment of angiogenesis‐related pathologies.

Topology, tinkering and evolution of the human transcription factor network

Patterns of protein interactions are organized around complex heterogeneous networks. Their architecture has been suggested to be of relevance in understanding the interactome and its functional organization, which pervades cellular robustness. Transcription factors are particularly relevant in this context, given their central role in gene regulation. Here we present the first topological study of the human protein–protein interacting transcription factor network built using the TRANSFAC database. We show that the network exhibits scale‐free and small‐world properties with a hierarchical and modular structure, which is built around a small number of key proteins. Most of these proteins are associated with proliferative diseases and are typically not linked to each other, thus reducing the propagation of failures through compartmentalization. Network modularity is consistent with common structural and functional features and the features are generated by two distinct evolutionary strategies: amplification and shuffling of interacting domains through tinkering and acquisition of specific interacting regions. The function of the regulatory complexes may have played an active role in choosing one of them.

Anti-angiogenic and anti-inflammatory properties of kahweol, a coffee diterpene.

Background Epidemiological studies have shown that unfiltered coffee consumption is associated with a low incidence of cancer. This study aims to identify the effects of kahweol, an antioxidant diterpene contained in unfiltered coffee, on angiogenesis and key inflammatory molecules. Methodology/Principal Findings The experimental procedures included in vivo angiogenesis assays (both the chicken and quail choriallantoic membrane assay and the angiogenesis assay with fluorescent zebrafish), the ex vivo mouse aortic ring assay and the in vitro analysis of the effects of treatment of human endothelial cells with kahweol in cell growth, cell viability, cell migration and zymographic assays, as well as the tube formation assay on Matrigel. Additionally, two inflammation markers were determined, namely, the expression levels of cyclooxygenase 2 and the levels of secreted monocyte chemoattractant protein-1. We show for the first time that kahweol is an anti-angiogenic compound with inhibitory effects in two in vivo and one ex vivo angiogenesis models, with effects on specific steps of the angiogenic process: endothelial cell proliferation, migration, invasion and tube formation on Matrigel. We also demonstrate the inhibitory effect of kahweol on the endothelial cell potential to remodel extracellular matrix by targeting two key molecules involved in the process, MMP-2 and uPA. Finally, the anti-inflammatory potential of this compound is demonstrated by its inhibition of both COX-2 expression and MCP-1 secretion in endothelial cells. Conclusion/Significance Taken together, our data indicate that, indeed, kahweol behaves as an anti-inflammatory and anti-angiogenic compound with potential use in antitumoral therapies. These data may contribute to the explanation of the reported antitumoral effects of kahweol, including the recent epidemiological meta-analysis showing that drinking coffee could decrease the risk of certain cancers.