Anticancer activity of biogenerated silver nanoparticles: an integrated proteomic investigation Anticancer activity of biogenerated silver nanoparticles: an integrated proteomic investigation

Colorectal cancer (CRC) develops by genetic and epigenetic alterations. However, the molecular mechanisms underlying metastatic dissemination remain unclear and could benefit from multi-omics investigations of specific protein families. Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in ECM remodeling and the processing of bioactive molecules. Increased MMP expression promotes the hallmarks of tumor progression, including angiogenesis, invasion, and metastasis, and is correlated with a shortened survival. Nevertheless, the collective role and the possible coordination of MMP members in CRC are poorly investigated. Here, we performed a multi-omics analysis of MMP expression in CRC using data mining and experimental investigations. Several databases were used to deeply mine different expressions between tumor and normal tissues, the genetic and epigenetic alterations, the prognostic value as well as the interrelationships with tumor immune-infiltrating cells (TIICs). A special focus was placed on to MMP2 and MMP9: their expression was correlated with immune markers and the interaction network of co-expressed genes disclosed their implication in epithelial to mesenchymal transition (EMT) and immune response. Finally, the activity levels of MMP2 and MMP9 in a cohort of colon cancer samples, including tissues and the corresponding sera, was also investigated by zymography. Our findings suggested that MMPs could have a high potency, as they are targeted in colon cancer, and might serve as novel biomarkers, especially for their involvement in the immune response. However, further studies are needed to explore the detailed biological functions and molecular mechanisms of MMPs in CRC, also in consideration of their expression and different regulation in several tissues.

Regenerative medicine aims to repair damaged, tissues or organs for the treatment of various diseases, which have been poorly managed with conventional drugs and medical procedures. To date, multimodal regenerative methods include transplant of healthy organs, tissues, or cells, body stimulation to activate a self-healing response in damaged tissues, as well as the combined use of cells and bio-degradable scaffold to obtain functional tissues. Certainly, stem cells are promising tools in regenerative medicine due to their ability to induce de novo tissue formation and/or promote organ repair and regeneration. Currently, several studies have shown that the beneficial stem cell effects, especially for mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) in damaged tissue restore are not dependent on their engraftment and differentiation on the injury site, but rather to their paracrine activity. It is now well known that paracrine action of stem cells is due to their ability to release extracellular vesicles (EVs). EVs play a fundamental role in cell-to-cell communication and are directly involved in tissue regeneration. In the present review, we tried to summarize the molecular mechanisms through which MSCs and iPSCs-derived EVs carry out their therapeutic action and their possible application for the treatment of several diseases.

Breast cancer is a complex and heterogeneous disease: Several molecular alterations cause cell proliferation and the acquisition of an invasive phenotype. Extracellular matrix (ECM) is considered essential for sustaining tumor growth and matrix metalloproteinases (MMPs) have been identified as drivers of many aspects of the tumor phenotype. Mounting evidence indicates that both α-enolase (ENO1) and Myc promoter-binding protein-1 (MBP-1) also played pivotal roles in tumorigenesis, although as antagonists. ENO1 is involved in cell growth, hypoxia tolerance and autoimmune activities besides its major role in the glycolysis pathway. On the contrary, MBP-1, an alternative product of ENO1, suppresses cell proliferation and the invasive ability of cancer cells. Since an important task in personalized medicine is to discriminate a different subtype of patients with different clinical outcomes including chances of recurrence and metastasis, we investigated the functional relationship between ENO1/MBP-1 expression and MMP-2 and MMP-9 activity levels in both tissues and sera of breast cancer patients. We focused on the clinical relevance of ENO1 and MMPs (MMP-2 and MMP-9) overexpression in breast cancer tissues: The association between the higher ENO1, MMP-2 and MMP-9 expression with a worse prognosis suggest that the elevated ENO1 and MMPs expression are promising biomarkers for breast cancer. A relationship seems to exist between MBP-1 expression and the decrease in the activity levels of MMP-9 in cancer tissues and MMP-2 in sera. Moreover, the sera of breast cancer patients grouped for MBP-1 expression differentially induced, in vitro, cell proliferation and migration. Our findings support the hypothesis of patient’s stratification based on ENO1, MBP-1 and MMPs expression. Elucidating the molecular pathways through which MBP-1 influences MMPs expression and breast cancer regression can lead to the discovery of new management strategies.

Extracellular matrix metalloproteinases (MMPs) are a group of proteins that activate substrates by enzymatic cleavage and, on the basis of their activities, have been demonstrated to play a role in ageing. Thus, in order to gain insight into the pathophysiology of ageing and to identify new markers of longevity, we analysed the activity levels of MMP-2 and MMP-9 in association with some relevant haematochemical parameters in a Sicilian population, including long-living individuals (LLIs, ≥95 years old). A cohort of 154 healthy subjects (72 men and 82 women) of different ages (age range 20-112) was recruited. The cohort was divided into five subgroups: the first group with subjects less than 40 years old, the second group ranging from 40 to 64 years old, the third group ranging from 65 to 89 years old, the fourth group ranging from 90 to 94 years old, and the fifth group with subjects more than 95 years old. A relationship was observed between LLIs and MMP-2, but not between LLIs and MMP-9. However, in the LLI group, MMP-2 and MMP-9 values were significantly correlated. Furthermore, in LLIs, we found a positive correlation of MMP-2 with the antioxidant catabolite uric acid and a negative correlation with the inflammatory marker C-reactive protein. Finally, in LLIs MMP-9 values correlated directly both with cholesterol and with low-density lipoproteins. On the whole, our data suggest that the observed increase of MMP-2 in LLIs might play a positive role in the attainment of longevity. This is the first study that shows that serum activity of MMP-2 is increased in LLIs as compared to younger subjects. As far as we are concerned, it is difficult to make wide-ranging conclusions/assumptions based on these observations in view of the relatively small sample size of LLIs. However, this is an important starting point. Larger-scale future studies will be required to clarify these findings including the link with other systemic inflammatory and antioxidant markers.

Pyrrolomycins (PMs) are polyhalogenated antibiotics known as powerful biologically active compounds, yet featuring high cytotoxicity. The present study reports the antibacterial and antitumoral properties of new chemically synthesized PMs, where the three positions of the pyrrolic nucleus were replaced by nitro groups, aiming to reduce their cytotoxicity while maintaining or even enhancing the biological activity. Indeed, the presence of the nitro substituent in diverse positions of the pyrrole determined an improvement of the minimal bactericidal concentration (MBC) against Gram-positive (i.e., Staphylococcus aureus) or -negative (i.e., Pseudomonas aeruginosa) pathogen strains as compared to the natural PM-C. Moreover, some new nitro-PMs were as active as or more than PM-C in inhibiting the proliferation of colon (HCT116) and breast (MCF 7) cancer cell lines and were less toxic towards normal epithelial (hTERT RPE-1) cells. Altogether, our findings contribute to increase the knowledge of the mode of action of these promising molecules and provide a basis for their rationale chemical or biological manipulation.