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Cardiovascular toxicity in cancer patients receiving chemotherapy remains one of the most undesirable side effects, limiting the choice of the most efficient therapeutic regimen, including combinations of different anticancer agents. Anthracyclines (doxorubicin) and antimetabolites (5-fluorouracil (5-FU), capecitabine) are among the most known agents used in breast cancer and other neoplasms and are associated with cardiotoxic effects. Extra-virgin olive oil (EVOO) is rich in polyphenols endowed with antioxidant cardioprotective activities. Olive mill wastewater (OMWW), a waste product generated by EVOO processing, has been reported to be enriched in polyphenols. In this study, we investigated the activities of polyphenol-rich extract from OMWW, A009, in cooperation with chemotherapy on two breast cancer cell lines, namely, BT459 and MDA-MB-231, in a cardio-oncology perspective. The effects of A009 on cardiac cells were also investigated with and without chemotherapeutic agents. Cell viability was determined on BT459 and MDA-MB-231 (i.e., breast cancer cells) and H9C2 (i.e., rat cardiomyocytes) cells, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A spheroids assay was used as a 3D in vitro model on BT459 and MDA-MB-231 cells. For in vivo studies, the murine sponge assay of angiogenesis was used as a model of breast cancer-associated vascularization. The embryo of Danio rerio (zebrafish) was used to detect the cardioprotective activities of the OMWW. We found that the A009 extract exhibited antiangiogenic activities induced by breast cancer cell supernatants and increased T-cell recruitment in vivo. The combination of the OMWW extracts with doxorubicin or 5-FU limited BT459 and MDA-MB-231 cell viability and the diameter of 3D spheroids, while mitigating their toxic effects on the rat H9C2 cardiomyocytes. Cardioprotective effects were observed by the combination of OMWW extracts with doxorubicin in zebrafish embryos. Finally, in human

Growing interest in hypertension—one of the main factors characterizing the cardiometabolic syndrome (CMS)—and anti-hypertensive drugs raised from the emergence of a new coronavirus, SARS-CoV-2, responsible for the COVID19 pandemic. The virus SARS-CoV-2 employs the Angiotensin-converting enzyme 2 (ACE2), a component of the RAAS (Renin- Angiotensin-Aldosterone System) system, as a receptor for entry into the cells. Several classes of synthetic drugs are available for hypertension, rarely associated with severe or mild adverse effects. New natural compounds, such as peptides, might be useful to treat some hypertensive patients. The main feature of ACE inhibitory peptides is the location of the hydrophobic residue, usually Proline, at the C-terminus. Some already known bioactive peptides derived from marine resources have potential ACE inhibitory activity and can be considered therapeutic agents to treat hypertension. Peptides isolated from marine vertebrates, invertebrates, seaweeds, or sea microorganisms displayed important biological activities to treat hypertensive patients. Here, we reviewed the antihypertensive activities of bioactive molecules isolated/extracted from marine organisms and discussed the associated molecular mechanisms involved. We also examined ACE2 modulation in sight of SARS2-Cov infection prevention.

SARS-CoV-2 is characterized by a spike protein allowing viral binding to the angiotensin-converting enzyme (ACE)-2, which acts as a viral receptor and is expressed on the surface of several pulmonary and extra-pulmonary cell types, including cardiac, renal, intestinal and endothelial cells. There is evidence that also endothelial cells are infected by SARS-COV-2, with subsequent occurrence of systemic vasculitis, thromboembolism and disseminated intravascular coagulation. Those effects, together with the “cytokine storm” are involved in a worse prognosis. In clinical practice, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are extensively used for the treatment of hypertension and other cardiovascular diseases. In in vivo studies, ACE-Is and ARBs seem to paradoxically increase ACE-2 expression, which could favour SARS-CoV-2 infection of host’s cells and tissues. By contrast, in patients treated with ACE-Is and ARBs, ACE-2 shows a downregulation at the mRNA and protein levels in kidney and cardiac tissues. Yet, it has been claimed that both ARBs and ACE-Is could result potentially useful in the clinical course of SARS-CoV-2-infected patients. As detected in China and as the Italian epidemiological situation confirms, the most prevalent comorbidities in deceased patients with COVID-19 are hypertension, diabetes and cardiovascular diseases. Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. Sex also plays a role, with chromosome X harbouring the gene coding for ACE-2, which is one of the possible explanations of why mortality in female patients is lower. Viral entry also depends on TMPRSS2 protease activity, an androgen dependent enzyme. Despite

The immune escape mechanisms at the base of tumor progression in endometrial cancer mimic immune tolerance mechanisms occurring at the maternal–fetal interface. The biological and immunological processes behind the maternal–fetal interface are finely tuned in time and space during embryo implantation and subsequent pregnancy stages; conversely, those behind cancer progression are often aberrant. The environment composition at the maternal–fetal interface parallels the pro-tumor microenvironment identified in many cancers, pointing to the possibility for the use of the maternal–fetal interface as a model to depict immune therapeutic targets in cancer. The framework of cancer environment signatures involved in immune adaptations, precisely timed in cancer progression, could reveal a specific “immune clock” in endometrial cancer, which might guide clinicians in patient risk class assessment, diagnostic workup, management, surgical and therapeutic approach, and surveillance strategies. Here, we review studies approaching this hypothesis, focusing on what is known so far about oncofetal similarities in immunity with the idea to individualize personalized immunotherapy targets, through the downregulation of the immune escape stage or the reactivation of the pro-inflammatory processes suppressed by the tumor.

As the COVID-19 epidemic expands in the world, and with the previous SARS epidemic, avian flu, Ebola and AIDS serving as a warning, biomedical and biotechnological research has the task to find solutions to counteract viral entry and pathogenesis. A novel approach can come from marine chemodiversity, recognized as a relevant source for developing a future natural “antiviral pharmacy”. Activities of antioxidants against viruses can be exploited to cope with human viral infection, from single individual infections to protection of populations. There is a potentially rich and fruitful reservoir of such compounds thanks to the plethora of bioactive molecules and families present in marine microorganisms. The aim of this communication is to present the state-of-play of what is known on the antiviral activities recognized in (micro)algae, highlighting the different molecules from various algae and their mechanisms of actions, when known. Given the ability of various algal molecules—mainly sulfated polysaccharides—to inhibit viral infection at Stage I (adsorption and invasion of cells), we envisage a need to further investigate the antiviral ability of algae, and their mechanisms of action. Given the advantages of microalgal production compared to other organisms, the opportunity might become reality in a short period of time.

Several diet-derived compounds have been reported to exert antioxidant, anti-proliferative and anti-angiogenic effects in numerous cancers and could be beneficial in cancer prevention. Olive oil production involves the generation of an aqueous phase defined as olive mill wastewater (OMWW), a polluting effluent rich in soluble polyphenols. Here, we assessed the cancer preventive properties exerted by a purified extract of OMWW (A009) for its activity on lung cancer cell lines. Hydroxytyrosol, the most abundant polyphenol present in our A009 extracts, was used as reference molecule in the assays performed. Extracts from OMWW from two different olive oil cultivars were used. We found that the A009 extracts limit lung cancer cell proliferation in a dose and time dependent manner. These effects were associated with the induction of apoptosis. A009 extracts were effective in inhibiting adhesion capabilities on a fibronectin layer accompanied with a reduction in their ability to generate invasive sprouts in a Matrigel layer. The production of chemokine CXCL12 and CXCR4 receptor were reduced by treatment with the extracts. Also, A009 interfered with the production of proangiogenic and pro-inflammatory VEGF, CXCL8, and CCL2 (as detected by FACS analysis) in the lung cell lines. A009 extracts were able to decrease STAT3 phosphorylation in lung cancer cells. Our results show that A009 extracts reduced activities related to tumor cell behavior in lung cancer cell lines, suggesting that they could have a potential cancer preventive role.

Myeloid-derived suppressor cells (MDSCs) contribute to the induction of an immune suppressive/anergic, tumor permissive environment. MDSCs act as immunosuppression orchestrators also by interacting with several components of both innate and adaptive immunity. Natural killer (NK) cells are innate lymphoid cells functioning as primary effector of immunity, against tumors and virus-infected cells. Apart from the previously described anergy and hypo-functionality of NK cells in different tumors, NK cells in cancer patients show pro-angiogenic phenotype and functions, similar to decidual NK cells. We termed the pro-angiogenic NK cells in the tumor microenvironment "tumor infiltrating NK" (TINKs), and peripheral blood NK cells in cancer patients "tumor associated NK" (TANKs). The contribution of MDSCs in regulating NK cell functions in tumor-bearing host, still represent a poorly explored topic, and even less is known on NK cell regulation of MDSCs. Here, we review whether the crosstalk between MDSCs and NK cells can impact on tumor onset, angiogenesis and progression, focusing on key cellular and molecular interactions. We also propose that the similarity of the properties of tumor associated/tumor infiltrating NK and MDSC with those of decidual NK and decidual MDSCs during pregnancy could hint to a possible onco-fetal origin of these pro-angiogenic leukocytes.

Epidemiological studies are providing strong evidence on beneficial health effects from dietary measures, leading scientists to actively investigate which foods and which specific agents in the diet can prevent diseases. Public health officers and medical experts should collaborate toward the design of disease prevention diets for nutritional intervention. Functional foods are emerging as an instrument for dietary intervention in disease prevention. Functional food products are technologically developed ingredients with specific health benefits. Among promising sources of functional foods and chemopreventive diets of interest, microalgae are gaining worldwide attention, based on their richness in high-value products, including carotenoids, proteins, vitamins, essential amino acids, omega-rich oils and, in general, anti-inflammatory and antioxidant compounds. Beneficial effects of microalgae on human health and/or wellness could in the future be useful in preventing or delaying the onset of cancer and cardiovascular diseases. During the past decades, microalgal biomass was predominately used in the health food market, with more than 75% of the annual microalgal biomass production being employed for the manufacture of powders, tablets, capsules or pastilles. In this review, we report and discuss the present and future role of microalgae as marine sources of functional foods/beverages for human wellbeing, focusing on perspectives in chemoprevention. We dissected this topic by analyzing the different classes of microalgal compounds with health outputs (based on their potential chemoprevention activities), the biodiversity of microalgal species and how to improve their cultivation, exploring the perspective of sustainable food from the sea.

The link between cancer development or progression and immune system dysregulation has long been established. Virtually every cell type belonging to both the innate and adaptive immune system has been reported to be involved in a complex interplay that might culminate into either a pro- or anti-tumorigenic response. Among the cellular components of the innate immune system, cells belonging to the monocyte/macrophage lineage have been consistently shown to play a key role in the tumorigenic process. The most advanced human tumors are reported to be strongly infiltrated with Tumor-Associated Macrophages (TAMs) endowed with the ability to contribute to tumor growth and dissemination. However, given their widely acknowledged functional plasticity, macrophages can display anti-tumor properties as well. Based on these premises, experimental approaches to promote the in vivo macrophage shift from pro-tumor to anti-tumor phenotype represent one of the most promising research field aimed at developing immune system-mediated tumor suppressive therapies. In this context, the human RNASET2 oncosuppressor gene has emerged as a potential tool for macrophage-mediated tumor suppression. A growing body of experimental evidence has been reported to suggest a role for this gene in the regulation of macrophage activity in both in vitro and in vivo experimental models. Moreover, several recent reports suggest a role for this gene in a broad range of cell types involved in immune response, pointing at RNASET2 as a putative regulator of several functional features within the immune system.

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.