Ex vivo acidic preconditioning enhances bone marrow ckit+ cell therapeutic potential via increased CXCR4 expression

Triggering CXCR4 receptor signaling is known to enhance the efficacy of cell therapy for cardiovascular regeneration. Here it was examined the effect of ex vivo acidic reconditioning (AP) on CXCR4 expression, in vitro, and on the regenerative potential of mouse bone marrow (BM) ckit+ cells in a mouse model of hindlimb ischemia. AP was obtained by exposing BM ckit+ cells to hypercarbic acidosis (pH 7.0) for 24 hours and subsequently returning them to pH 7.4 throughout the experiments. Control (C) cells were always kept at pH 7.4. Interestingly, AP enhanced CXCR4 and SDF-1 mRNA levels of BM ckit+ cells. AP CXCR4 expression modulation appeared to depend on calcium mobilization and on nitric oxide, as assessed by cytosolic Ca2+ buffering with BAPTA and nitric oxide inhibitor L-NAME treatments. Further, AP increased Stromal Cell-Derived Factor 1 (SDF-1)-driven chemotaxis, transendothelial migration and differentiation toward the endothelial lineage in vitro. In a mouse model of hindlimb ischemia, BM ckit+ cells, subjected to AP, accelerated blood flow recovery, increased capillary and arteriole number as well as the number of regenerating muscle fibres. These effects were abolished by treating AP cells with L-NAME. In summary, AP may constitute a novel strategy to enhance BM ckit+ cell therapeutic potential via NO-dependent increase in CXCR4 expression

Ex vivo acidic preconditioning enhances bone marrow ckit+ cell therapeutic potential via increased CXCR4 expression

Triggering CXCR4 receptor signaling is known to enhance the efficacy of cell therapy for cardiovascular regeneration. Here it was examined the effect of ex vivo acidic reconditioning (AP) on CXCR4 expression, in vitro, and on the regenerative potential of mouse bone marrow (BM) ckit+ cells in a mouse model of hindlimb ischemia. AP was obtained by exposing BM ckit+ cells to hypercarbic acidosis (pH 7.0) for 24 hours and subsequently returning them to pH 7.4 throughout the experiments. Control (C) cells were always kept at pH 7.4. Interestingly, AP enhanced CXCR4 and SDF-1 mRNA levels of BM ckit+ cells. AP CXCR4 expression modulation appeared to depend on calcium mobilization and on nitric oxide, as assessed by cytosolic Ca2+ buffering with BAPTA and nitric oxide inhibitor L-NAME treatments. Further, AP increased Stromal Cell-Derived Factor 1 (SDF-1)-driven chemotaxis, transendothelial migration and differentiation toward the endothelial lineage in vitro. In a mouse model of hindlimb ischemia, BM ckit+ cells, subjected to AP, accelerated blood flow recovery, increased capillary and arteriole number as well as the number of regenerating muscle fibres. These effects were abolished by treating AP cells with L-NAME. In summary, AP may constitute a novel strategy to enhance BM ckit+ cell therapeutic potential via NO-dependent increase in CXCR4 expression

Oxidative stress and epigenetic regulation in ageing and age-related diseases

Recent statistics indicate that the human population is ageing rapidly. Healthy, but also diseased, elderly people are increasing. This trend is particularly evident in Western countries, where healthier living conditions and better cures are available. To understand the process leading to age-associated alterations is, therefore, of the highest relevance for the development of new treatments for age-associated diseases, such as cancer, diabetes, Alzheimer and cardiovascular accidents. Mechanistically, it is well accepted that the accumulation of intracellular damage determined by reactive oxygen species (ROS) might orchestrate the progressive loss of control over biological homeostasis and the functional impairment typical of aged tissues. Here, we review how epigenetics takes part in the control of stress stimuli and the mechanisms of ageing physiology and physiopathology. Alteration of epigenetic enzyme activity, histone modifications and DNA-methylation is, in fact, typically associated with the ageing process. Specifically, ageing presents peculiar epigenetic markers that, taken altogether, form the still ill-defined “ageing epigenome”. The comprehension of mechanisms and pathways leading to epigenetic modifications associated with ageing may help the development of anti-ageing therapies

The role of redox system in metastasis formation

The metastatic cancer disease represents the real and urgent clinical need in oncology. Therefore, an understanding of the complex molecular mechanisms sustaining the metastatic cascade is critical to advance cancer therapies. Recent studies highlight how redox signaling influences the behavior of metastatic cancer cells, contributes to their travel in bloodstream from the primary tumor to the distant organs and conditions the progression of the micrometastases or their dormant state. Radical oxygen species not only regulate intracellular processes but participate to paracrine circuits by diffusion to nearby cells, thus assuming unpredicted roles in the communication between metastatic cancer cells, blood circulating cells, and stroma cells at site of colonization. Here, we review recent insights in the role of radical oxygen species in the metastasis formation with a special focus on extravasation at metastatic sites. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10456-021-09779-5

Synthesis and biological evaluation of the first example of NO-donor histone deacetylase inhibitor

[Image: see text] The NO-donor histone deacetylase inhibitor 2, formally obtained by joining Entinostat 1, a moderately selective Class I histone deacetylases (HDACs) inhibitor, to a 4-(methylaminomethyl)furoxan-3-carbonitrile scaffold, is described and its preliminary biological profile discussed. This hybrid regulates Classes I and II HDACs. Nitric oxide (NO) released by the compound activates soluble guanylate cyclase (sGC), causing Class II nuclear shuttling and chromatin modifications, with consequences on gene expression. The hybrid affects a number of micro-RNAs not modulated by its individual components; it promotes myogenic differentiation, inducing the formation of larger myotubes with significantly more nuclei per fiber, in a more efficient manner than the 1:1 mixture of its two components. The hybrid is an example of a new class of NO-donor HDACs now being developed, which should be of interest for treating a number of diseases

The double life of cardiac mesenchymal cells: epimetabolic sensors and therapeutic assets for heart regeneration

Organ-specific mesenchymal cells naturally reside in the stroma, where they are exposed to some environmental variables affecting their biology and functions. Risk factors such as diabetes or aging influence their adaptive response. In these cases, permanent epigenetic modifications may be introduced in the cells with important consequences on their local homeostatic activity and therapeutic potential. Numerous results suggest that mesenchymal cells, virtually present in every organ, may contribute to tissue regeneration mostly by paracrine mechanisms. Intriguingly, the heart is emerging as a source of different cells, including pericytes, cardiac progenitors, and cardiac fibroblasts. According to phenotypic, functional, and molecular criteria, these should be classified as mesenchymal cells. Not surprisingly, in recent years, the attention on these cells as therapeutic tools has grown exponentially, although only very preliminary data have been obtained in clinical trials to date. In this review, we summarized the state of the art about the phenotypic features, functions, regenerative properties, and clinical applicability of mesenchymal cells, with a particular focus on those of cardiac origin

Structural and biological characterization of new hybrid drugs joining an HDAC inhibitor to different NO-donors

HDAC inhibitors and NO donors have already revealed independently their broad therapeutic potential in pathologic contexts. Here we further investigated the power of their combination in a single hybrid molecule. Nitrooxy groups or substituted furoxan derivatives were joined to the α-position of the pyridine ring of the selective class I HDAC inhibitor MS-275. Biochemical analysis showed that the association with the dinitrooxy compound 31 or the furoxan derivative 16 gives hybrid compounds the ability to preserve the single moiety activities. The two new hybrid molecules were then tested in a muscle differentiation assay. The hybrid compound bearing the moiety 31 promoted the formation of large myotubes characterized by highly multinucleated fibers, possibly due to a stimulation of myoblast fusion, as implicated by the strong induction of myomaker expression. Thanks to their unique biological features, these compounds may represent new therapeutic tools for cardiovascular, neuromuscular and inflammatory diseases