Search

Background: Chronic, degenerative diseases are often characterized by inflammation and aberrant angiogenesis. For these pathologies, including rheumatoid arthritis, cardiovascular and autoimmune diseases, cancer, diabetes, and obesity, current therapies have limited efficacy. Objectives: The validation of novel (chemo)preventive and interceptive approaches, and the use of new or repurposed agents, alone or in combination with registered drugs, are urgently required. Results: Phytochemicals (triterpenoids, flavonoids, retinoids) and their derivatives, nonsteroidal anti-inflammatory drugs (aspirin) as well as biguanides (metformin and phenformin) originally developed from phytochemical backbones, are multi-target agents showing antiangiogenic and anti-anti-inflammatory proprieties. Many of them target AMPK and metabolic pathways such as the mTOR axis. We summarize the beneficial effects of several compounds in conferring protection and supporting therapy, and as a paradigm, we present data on terpenoids & biquanides on beer hop xanthohumol and hydroxytryrosol from olive mill waste waters. Conclusions: These molecules could be employed for combinatorial chemoprevention and interception approaches or chemoprevention/therapy regimens for cancer and other chronic complex diseases.

Angiogenesis induction is a hallmark of cancer. Antiangiogenic properties of Xanthohumol (XN), a naturally occurring prenylated chalcone from hops, have been widely reported. Here we describe the synthesis and study the antiangiogenic activity in vitro of a series of XN derivatives, where different substituents on the B-ring of the chalcone scaffold were inserted. The new XN derivatives inhibited human umbilical-vein endothelial cell (HUVEC) proliferation, adhesion, migration, invasion and their ability to form capillary-like structures in vitro at 10 mu M concentration. The preliminary results indicate that the phenolic OH group in R, present in natural XN, is not necessary for having antiangiogenic activity. In fact, the most effective compound from this series, 13, was characterized by a para-methoxy group in R and a fluorine atom in R-2 on B-ring. This study paves the way for future development of synthetic analogues of XN to be used as cancer angiopreventive and chemopreventive agents

Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9, and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to the previously discovered compound 1. A new series of hydroxamates was designed, synthesized, and tested for their antiangiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9, and MMP-14 inhibitor was identified, compound 3, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound 3 in order to investigate its binding mode to MMP-9 and MMP-14.

Carbon nanotubes (CNTs) have been extensively investigated and employed for industrial use because of their peculiar physical properties, which make them ideal for many industrial applications. However, rapid growth of CNT employment raises concerns about the potential risks and toxicities for public health, environment, and workers associated with the manufacture and use of these new materials. Here we investigate the main routes of entry following environmental exposure to multi-wall CNTs (MWCNTs; currently the most widely used in industry). We developed a novel murine model that could represent a surrogate of a workplace exposure to MWCNTs. We traced the localization of MWCNTs and their possible role in inducing an innate immune response, inflammation, macrophage recruitment, and inflammatory conditions. Following environmental exposure of CD1 mice, we observed that MWCNTs rapidly enter and disseminate in the organism, initially accumulating in lungs and brain and later reaching the liver and kidney via the bloodstream. Since recent experimental studies show that CNTs are associated with the aggregation process of proteins associated with neurodegenerative diseases, we investigated whether MWCNTs are able to induce amyloid fibril production and accumulation. Amyloid deposits in spatial association with macrophages and MWCNT aggregates were found in the brain, liver, lungs, and kidneys of exposed animals. Our data suggest that accumulation of MWCNTs in different organs is associated with inflammation and amyloid accumulation. In the brain, where we observed rapid accumulation and amyloid fibril deposition, exposure to MWCNTs might enhance progression of neurodegenerative and other amyloid-related diseases. Our data highlight the conclusion that, in a novel rodent model of exposure, MWCNTs may induce macrophage recruitment, activation, and amyloid deposition, causing potential damage to several organs.

Non-small cell lung cancer (NSCLC), the most frequent lung cancer (80%), can be phenotypically classified into two main subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC). While SCC has relatively rapid doubling times from the onset, ADC has longer doubling times initially that become reduced during tumor progression, suggesting a key role for the microenvironment. During lung tumor progression, a complex and dynamic interplay occurs between proliferating tumor cells and stromal, endothelial and immune tumor-conditioned host cells within the tumor microenvironment (TUMIC). Several factors within the TUMIC, such as hypoxia, cytokines and soluble factors, appear to blunt the anti-tumor immune response and polarize immune cells towards a pro-tumor phenotype. Phenotypically and functionally altered immune cells found in cancer patients include macrophages, neutrophils, myeloid, dendritic, and even NK cells. We studied tumor infiltrating (TINK) and tumor associated (TANK) NK cells in NSCLC. NSCLC TINKs and TANKs show similarities to decidual NK cells, being polarized toward tissue builders, rather than killers, and producing pro-angiogenic cytokines. The functionally polarized immune cells in NSCLC provide the stromal support and neovascularization required for NSCLC tumor expansion and progression in a feed-forward mechanism, leading to tumor progression. Further, systemic alterations of immune cells are also present in NSCLC patients. The precise knowledge of these immune cell alterations within the TUMIC has become crucial for diagnosis, targeted therapeutic intervention, as well as prevention, of NSCLC cancer

Background: Serum steroids are crucial molecules altered in prostate cancer (PCa). Mass spectrometry (MS) is currently the elected technology for the analysis of steroids in diverse biological samples. Steroids have complex biological pathways and stoichiometry and it is important to evaluate their quantitative ratio. MS applications to patient hormone profiling could lead to a diagnostic approach. Methods: Here, we employed the Surface Activated Chemical Ionization-Electrospray-NIST (SANIST) developed in our laboratories, to obtain quantitative serum steroid ratio relationship profiles with a machine learning Bayesian model to discriminate patients with PCa. The approach is focused on steroid relationship profiles and disease association. Results: A pilot study on patients affected by PCa, benign prostate hypertrophy (BPH), and control subjects [prostate-specific antigen (PSA) lower than 2.5 ng/mL] was done in order to investigate the classification performance of the SANIST platform. The steroid profiles of 71 serum samples (31 controls, 20 patients with PCa and 20 subjects with benign prostate hyperplasia) were evaluated. The levels of 10 steroids were quantitated on the SANIST platform: Aldosterone, Corticosterone, Cortisol, 11-deoxycortisol, Androstenedione, Testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), 17-OH-Progesterone and Progesterone. We performed both traditional and a machine learning analysis. Conclusion: We show that the machine learning approach based on the steroid relationships developed here was much more accurate than the PSA, DHEAS, and direct absolute value match method in separating the PCa, BPH and control subjects, increasing the sensitivity to 90% and specificity to 84%. This technology, if applied in the future to a larger number of samples will be able to detect the individual enzymatic disequilibrium associated with the steroid ratio and correlate it with the disease. This learning machine approach could be

NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solidmalignancies,NKcells have compromised functions.Wehave previously reported that lung tumor-associated NKcells (TANKs; peripheralblood) andtumor-infiltratingNKcells (TINK s ) showproangiogenic,decidualNK-like (dNK) phenotype. In this study, we functionally andmolecularly investigated TINK s and TANK s fromblood and tissue samples of patients with colorectal cancer (CRC), a neoplasmin which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINK s /TANK s showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-likeNKpolarization toward the CD5 6bright CD16 dim/- 2CD9 + CD49 + subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; amongwhich, angiogenin and invasion-associated enzymes related to theMMP9-TIMP1/2 axis.Here,we describe, for the first time, to our knowledge, the expression of angiogenin,MMP2/9, and TIMP by TANK s in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANK s , and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 orMMP inhibitors with immunotherapy could help repolarizeCRCTINK s and TANK s to anti-tumor antimetastatic ones.

Olive oil, a major feature of the Mediterranean diet, is an abundant source of phenolic compounds. Olive oil production is associated with the generation of waste material, termed ‘olive mill wastewater’ (OMWW), that has been reported to be enriched in soluble polyphenols. Given the known beneficial activity of polyphenols, we investigated whether the use of purified extracts from OMWW, termed A009, rich in hydroxytyrosol, might have anticancer activities on colon cancer (CC) cell lines in vitro and in vivo and could represent a chemopreventive preparation for CC. A009 from different batches inhibited proliferation, migration, invasion, adhesion, sprouting of CC cells and release of angiogenic, pro-inflammatory cytokines (VEGF, IL-8). Our data demonstrate that a novel purified, polyphenol enriched extract, obtained from food industry waste material, with similar activity than purified hydroxytyrosol but easier to produce in large quantities and with an environment-sensitive approach, has potential cancer chemopreventive properties for colon cancer cells.

With the great advances made in the treatment and prevention of infectious diseases over the last century, chronic degenerative Diseases-cardiovascular, cerebrovascular, and cancer-represent the major causes of death in the developed world. Although massive efforts and investments have been made in cancer therapy, the progress made towards reducing mortality has been more successful for cardiovascular disease than for tumours. This can be attributable largely to an active prevention approach implemented for cardiovascular disease. Cardiologists treat their patients before the overt disease becomes life threatening, performing early interventions in phenotypically healthy patients, by using several markers that predict risk. If the concept of prevention could be applied to cancer in a more extensive way, a significant number of tumours could be avoided through preventive measures. Prevention approaches range from avoiding tobacco exposure to dietary strategies to active pharmacological approaches in higher risk groups. Host targets rather than the tumour cells themselves are attractive for chemoprevention, in particular endothelial and immune cells. Angioprevention i.e. preventing cancer angiogenesis is a key concept that we introduced; yet one of the major current challenges for anti-angiogenesis in therapy and prevention is finding the right biomarkers. Here we discuss the importance of angioprevention and the potential use of VEGF, PlGF, CD31, Ang and Tie, circulating vascular cell precursors, and microRNA as potential biomarkers.

Olive oil, a major feature of the Mediterranean diet, is an important source of phenolic compounds. Poliphenols are associated with inhibition of several pathological processes, including cancer. Soluble phenols are contained in the aqueous part of olive and are discarded during oil production in the ‘olive mill wastewaters’. Here we investigated the properties of a purified extract of olive mill wastewaters, named A009, as potential anti-angiogenic compound. While the strong anti-oxidant activity of olive derived phenolic compounds has been well characterized, little is known about their anti-angiogenic properties. We investigated effects of A009 on endothelial cell morphogenesis, proliferation, migration and apoptosis, comparing the results obtained with the activity of a well-characterized olive oil phenol, Hydroxytyrosol (HT). Further, we tested the effects of A009 and HT in an in vivo angiogenesis assay. We found that A009 exerted strong anti-angiogenic effects both in vitro and in vivo, and that the complex natural purified extract has stronger anti-angiogenic potential when compared to the same concentrations of HT in most of the assays performed. These data demonstrate that a novel purified, phenols enriched, extract with anti-angiogenic, and angiopreventive potential can be obtained from olive oil mill waste material, recovering useful products from an agricultural waste

Specific alimentary habits, including oriental and Mediterranean diets characterized by high consumption of vegetables, fruits, cereals and, for the Mediterranean diet, olive oil, are associated with a reduction of risk of cardiovascular diseases, type 2 diabetes, neurodegenerative diseases, and some cancers. Numerous beverages contain diverse natural compounds, termed phytochemicals, that have been reported to exert antitumor, antiangiogenic, and antioxidant properties. Here we review the chemopreventive and angiopreventive properties of selected phytochemicals found in common beverages: epigallocatechin(green tea), triterpenoids (citrus juices), resveratrol (red wine), xanthohumol (beer), procyanidin (chocolate), and caffeine (coffee), focusing on their molecular mechanisms, providing "ready to drink" prevention approaches