TLR3-/4-Priming Differentially Promotes Ca2+ Signaling and Cytokine Expression and Ca2+-Dependently Augments Cytokine Release in hMSCs

In human mesenchymal stem cells (hMSCs), toll-like receptor 3 (TLR3) and TLR4 act as key players in the tissue repair process by recognizing their ligands and stimulating downstream processes including cytokine release. The mechanisms of TLR3- and TLR4-mediated cytokine releases from hMSCs remain uncertain. Here, we show that exposure to the TLR3 agonist polyinosinic-polycytidylic acid (poly(I:C)) or incubation with the TLR4 agonist lipopolysaccharide (LPS) increased the mRNA expression levels of TLR3, TLR4 and cytokines in hMSCs. Poly(I:C) exposure rather than LPS incubation not only elevated inositol 1,4,5-triphosphate receptor (IP(3)R) expression and IP(3)R-mediated Ca(2+) release, but also promoted Orai and STIM expression as well as store-operated Ca(2+) entry into hMSCs. In addition, we also observed that 21 Ca(2+) signaling genes were significantly up-regulated in response to TLR3 priming of hMSCs by RNA sequencing analysis. Both poly(I:C) and LPS exposure enhanced cytokine release from hMSCs. The enhanced cytokine release vanished upon siRNA knockdown and chelation of intracellular Ca(2+). These data demonstrate that TLR3- and TLR4-priming differentially enhance Ca(2+) signaling and cytokine expression, and Ca(2+) -dependently potentiates cytokine release in hMSCs

Cardiovascular and Central Nervous System Toxicity by Anticancer Drugs in Breast Cancer Patients

Breast cancer is one of the most malignant diseases, associated with high rate mortality. In this chapter a particular attention is paid on cardiovascular and central nervous system toxicity induced by chemotherapeutic agents used for both primary and metastatic treatment of this life-threatening pathology. With respect to traditional drugs, including anthracyclines, taxanes, and fluoropyrimidines, the more recent targeted therapies, such as human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF), aimed to ameliorate anticancer activity and to reduce toxic effects by affecting more specific molecular sites. However, despite the improvement in breast cancer treatment, these novel drugs were also found to be associated, even if at a lesser extent, with important side effects, such as cardiotoxicity, with consequent heart failure. For this reason, the cardiovascular and brain safety profile of all anticancer drugs and protocols remains important items to be carefully evaluated in breast cancer patients