1,721,012 research outputs found
Evaluation of the Anti-Cancer Potential of Extracellular Vesicles Derived from Human Amniotic Fluid Stem Cells: Focus on Effective miRNAs in the Treatment of Melanoma Progression
Full text linkMesenchymal stromal cells (MSCs) and their secretome show intrinsic antitumor properties, however, the anti-cancer effects of MSCs remain debated and depend on the cancer type or model. MSCs derived from discarded samples, such as human amniotic fluid (hAFSC), have been introduced as an attractive and potent stem cell source for clinical applications due to their collection procedures, which minimize ethical issues. Until now, various studies have obtained controversial results and poor understanding of the mechanisms behind the effects of perinatal cells on cancer cells. To better clarify this aspect, protein and miRNA expression profiling isolated from Extracellular vesicles (EVs) secreted by hAFSCs, obtained in the II or III trimester, were evaluated. Bioinformatic analysis was performed aiming at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted that most of the highest expressed proteins and miRNAs are mainly involved in antioxidant and anti-cancer effects. Indeed, in the presence of hAFSC-EVs, a reduction of the G2/M phase was observed on melanoma cell lines, an activation of the apoptotic pathway occurred and the migration and invasion ability reduced. Our data demonstrated that II or III trimester hAFSCs can release bioactive factors into EVs, causing an efficient anti-cancer effect inhibiting melanoma progression
Phosphoinositide-specific phospholipase C in health and disease
Full text linkPhospholipases are widely occurring and can be found in several different organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase C (PLC) is a class of phospholipases that cleaves phospholipids on the diacylglycerol (DAG) side of the phosphodiester bond producing DAGs and phosphomonoesters. Among PLCs, phosphoinositide-specific PLC (PI-PLC) constitutes an important step in the inositide signaling pathways. The structures of PI-PLC isozymes show conserved domains as well as regulatory specific domains. This is important, as most PI-PLCs share a common mechanism, but each of them has a peculiar role and can have a specific cell distribution that is linked to a specific function. More importantly, the regulation of PLC isozymes is fundamental in health and disease, as there are several PLC-dependent molecular mechanisms that are associated with the activation or inhibition of important physiopathological processes. Moreover, PI-PLC alternative splicing variants can play important roles in complex signaling networks, not only in cancer but also in other diseases. That is why PI-PLC isozymes are now considered as important molecules that are essential for better understanding the molecular mechanisms underlying both physiology and pathogenesis, and are also potential molecular targets useful for the development of innovative therapeutic strategies.open
TP53 gene status can promote sensitivity and resistance to chemotherapeutic drugs and small molecule signal transduction inhibitors
No full textTP53 is normally a tumor suppressor. However, it is mutated in at least 50% of human cancers. Usually, we assume that mutation of the TP53 is associated with loss of sensitivity to various drugs as in most cases wild type (WT) TP53 activity is lost. This type of mutations is often dominant-negative (DN) mutations as they can interfere with the normal functions of WT-TP53 which acts as a tetramer. These mutations can result in altered gene expression patterns. There are some TP53 mutations which may lack some of the normal functions of TP53 but have additional functions; these types of mutations are called gain of function (GOF) mutations. There is another class of TP53 mutations, they are TP53 null mutations as the cells have deleted the TP53 gene (TP53-null). Although TP53 mutations were initially considered undruggable, other approaches have been developed to increase TP53 activity. One approach was to develop mouse double minute 2 homolog (MDM2) inhibitors as MDM2 suppresses TP53 activity. In addition, there have been mutant TP53 reactivators created, which will at least partially restore some of the critical growth suppressing effects of TP53. Some of these mutant TP53 reactivators have shown promise in clinical trial in certain types of cancer patients, especially myelodysplastic syndrome (MDS). In this review, we summarize the development of novel TP53 reactivators and MDM2 inhibitors. Both approaches are aimed at increasing or restoring TP53 activity. Attempts to increase TP53 activity in various TP53 mutant tumors could increase therapy of multiple deadly diseases
Nuclear Nox4 interaction with prelamin A is associated with nuclear redox control of stem cell aging
Full text linkMesenchymal stem cells have emerged as an important tool that can be used for tissue regeneration thanks to their easy preparation, differentiation potential and immunomodulatory activity. However, an extensive culture of stem cells in vitro prior to clinical use can lead to oxidative stress that can modulate different stem cells properties, such as self-renewal, proliferation, differentiation and senescence. The aim of this study was to investigate the aging process occurring during in vitro expansion of stem cells, obtained from amniotic fluids (AFSC) at similar gestational age. The analysis of 21 AFSC samples allowed to classify them in groups with different levels of stemness properties. In summary, the expression of pluripotency genes and the proliferation rate were inversely correlated with the content of reactive oxygen species (ROS), DNA damage signs and the onset premature aging markers, including accumulation of prelamin A, the lamin A immature form. Interestingly, a specific source of ROS, the NADPH oxidase isoform 4 (Nox4), can localize into PML nuclear bodies (PML-NB), where it associates to prelamin A. Besides, Nox4 post translational modification, involved in PML-NB localization, is linked to its degradation pathway, as it is also for prelamin A, thus possibly modulating the premature aging phenotype occurrence
Myoblast-Derived Galectin 3 Impairs the Early Phases of Osteogenesis Affecting Notch and Akt Activity
Full text linkGalectin-3 (Gal-3) is a pleiotropic lectin produced by most cell types, which regulates multiple cellular processes in various tissues. In bone, depending on its cellular localization, Gal-3 has a dual and opposite role. If, on the one hand, intracellular Gal-3 promotes bone formation, on the other, its circulating form affects bone remodeling, antagonizing osteoblast differentiation and increasing osteoclast activity. From an analysis of the secretome of cultured differentiating myoblasts, we interestingly found the presence of Gal-3. After that, we confirmed that Gal-3 was expressed and released in the extracellular environment from myoblast cells during their differentiation into myotubes, as well as after mechanical strain. An in vivo analysis revealed that Gal-3 was triggered by trained exercise and was specifically produced by fast muscle fibers. Speculating a role for this peptide in the muscle-to-bone cross talk, a direct co-culture in vitro system, simultaneously combining media that were obtained from differentiated myoblasts and osteoblast cells, confirmed that Gal-3 is a mediator of osteoblast differentiation. Molecular and proteomic analyses revealed that the secreted Gal-3 modulated the biochemical processes occurring in the early phases of bone formation, in particular impairing the activity of the STAT3 and PDK1/Akt signaling pathways and, at the same time, triggering that one of Notch. Circulating Gal-3 also affected the expression of the most common factors involved in osteogenetic processes, including BMP-2, -6, and -7. Intriguingly, Gal-3 was able to interfere with the ability of differentiating osteoblasts to interact with the components of the extracellular bone matrix, a crucial condition required for a proper osteoblast differentiation. All in all, our evidence lays the foundation for further studies to present this lectin as a novel myokine involved in muscle-to-bone crosstalk
Nuclear phospholipase C isoenzyme imbalance leads to pathologies in brain, hematologic, neuromuscular, and fertility disorders
Full text linkPhosphoinositide-specific phospholipases C (PI-PLCs) are involved in signaling pathways related to critical cellular functions, such as cell cycle regulation, cell differentiation, and gene expression. Nuclear PI-PLCs have been studied as key enzymes, molecular targets, and clinical prognostic/diagnostic factors in many physiopathologic processes. Here, we summarize the main studies about nuclear PI-PLCs, specifically, the imbalance of isozymes such as PI-PLC1 and PI-PLC, in cerebral, hematologic, neuromuscular, and fertility disorders. PI-PLC1 and PI-PLC1 affect epilepsy, depression, and bipolar disorder. In the brain, PI-PLC1 is involved in endocannabinoid neuronal excitability and is a potentially novel signature gene for subtypes of high-grade glioma. An altered quality or quantity of PI-PLC contributes to sperm defects that result in infertility, and PI-PLC1 aberrant inositide signaling contributes to both hematologic and degenerative muscle diseases. Understanding the mechanisms behind PI-PLC involvement in human pathologies may help identify new strategies for personalized therapies of these conditions.—Ratti, S., M. Y. Follo, G. Ramazzotti, I. Faenza, R. Fiume, P-G. Suh, J. A. McCubrey, L. Manzoli, and L. Cocco. Nuclear phospholipase C isoenzyme imbalance leads to pathologies in brain, hematologic, neuromuscular, and fertility disorders
Nuclear Nox4-derived reactive oxygen species in myelodysplastic syndromes
Full text linkA role for intracellular ROS production has been recently implicated in the pathogenesis and progression of a wide variety of neoplasias. ROS sources, such as NAD(P)H oxidase (Nox) complexes, are frequently activated in AML (acute myeloid leukemia) blasts and strongly contribute to their proliferation, survival, and drug resistance. Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop AML. The molecular basis for MDS progression is unknown, but a key element in MDS disease progression is the genomic instability. NADPH oxidases are now recognized to have specific subcellular localizations, this targeting to specific compartments for localized ROS production. Local Nox-dependent ROS production in the nucleus may contribute to the regulation of redox-dependent cell growth, differentiation, senescence, DNA damage, and apoptosis. We observed that Nox1, 2, and 4 isoforms and p22phox and Rac1 subunits are expressed in MDS/AML cell lines and MDS samples, also in the nuclear fractions. Interestingly, Nox4 interacts with ERK and Akt1 within nuclear speckle domain, suggesting that Nox4 could be involved in regulating gene expression and splicing factor activity. These data contribute to the elucidation of the molecular mechanisms used by nuclear ROS to drive MDS evolution to AML
Effects of chloroquine and hydroxychloroquine on the sensitivity of pancreatic cancer cells to targeted therapies
Full text linkApproaches to improve pancreatic cancer therapy are essential as this disease has a very bleak outcome. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is a cancer which is difficult to effectively treat as it is often detected late in the disease process. Almost all PDACs (over 90%) have activating mutations in the GTPase gene KRAS. These mutations result in constitutive KRas activation and the mobilization of downstream pathways such as the Raf/MEK/ERK pathway. Small molecule inhibitors of key components of the KRas/Raf/MEK/ERK pathways as well as monoclonal antibodies (MoAbs) specific for upstream growth factor receptors such insulin like growth factor-1 receptor (IGF1-R) and epidermal growth factor receptors (EGFRs) have been developed and have been evaluated in clinical trials. An additional key regulatory gene frequently mutated (∼75%) in PDAC is the TP53 tumor suppressor gene which controls the transcription of multiple genes involved in cell cycle progression, apoptosis, metabolism, cancer progression and other growth regulatory processes. Small molecule mutant TP53 reactivators have been developed which alter the structure of mutant TP53 protein and restore some of its antiproliferative activities. Some mutant TP53 reactivators have been examined in clinical trials with patients with mutant TP53 genes. Inhibitors to the TP53 negative regulator Mouse Double Minute 2 (MDM2) have been developed and analyzed in clinical trials. Chloroquine and hydroxychloroquine are established anti-malarial and anti-inflammatory drugs that also prevent the induction of autophagy which can have effects on cancer survival. Chloroquine and hydroxychloroquine have also been examined in various clinical trials. Recent studies are suggesting effective treatment of PDAC patients may require chemotherapy as well as targeting multiple pathways and biochemical processes
Nuclear phospholipase C β1 signaling, epigenetics and treatments in MDS.
No full textMyelodysplastic syndromes (MDS), clonal hematopoietic stem-cell disorders mainly affecting older adult patients, show ineffective hematopoiesis in one or more of the lineages of the bone marrow. Most MDS are characterized by anemia, and a number of cases progresses to acute myeloid leukemia (AML). Indeed, the molecular mechanisms underlying the MDS evolution to AML are still unclear, even though the nuclear signaling elicited by PI-PLCβ1 has been demonstrated to play an important role in the control of the balance between cell cycle progression and apoptosis in MDS cells. Here we review both the role of epigenetic therapy on PI-PLCβ1 promoter and the changes in PI-PLCβ1 expression in MDS patients treated for anemia.Myelodysplastic syndromes (MDS), clonal hematopoietic stem-cell disorders mainly affecting older adult patients, show ineffective hematopoiesis in one or more of the lineages of the bone marrow. Most MDS are characterized by anemia, and a number of cases progresses to acute myeloid leukemia (AML). Indeed, the molecular mechanisms underlying the MDS evolution to AML are still unclear, even though the nuclear signaling elicited by PI-PLCÎ21 has been demonstrated to play an important role in the control of the balance between cell cycle progression and apoptosis in MDS cells. Here we review both the role of epigenetic therapy on PI-PLCÎ21 promoter and the changes in PI-PLCÎ21 expression in MDS patients treated for anemia. © 2012 Elsevier Ltd
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