3,170 research outputs found
Endothelial remodelling and intracellular calcium machinery
No full textRather being an inert barrier between vessel lumen and surrounding tissues, vascular endothelium plays a key role in the maintenance of cardiovascular homeostasis. The de-endothelialization of blood vessels is regarded as the early event that results in the onset of severe vascular disorders, including atherosclerosis, acute myocardial infarction, brain stroke, and aortic aneurysm. Restoration of the endothelial lining may be accomplished by the activation of neighbouring endothelial cells (ECs) freed by contact inhibition and by circulating endothelial progenitor cells (EPCs). Intracellular Ca(2+) signalling is essential to promote wound healing: however, the molecular underpinnings of the Ca(2+) response to injury are yet to be fully elucidated. Similarly, the components of the Ca(2+) toolkit that drive EPC incorporation into denuded vessels are far from being fully elucidated. The present review will survey the current knowledge on the role of Ca(2+) signalling in endothelial repair and in EPC activation. We propose that endothelial regeneration might be boosted by intraluminal release of specific Ca(2+) channel agonists or by gene transfer strategies aiming to enhance the expression of the most suitable Ca(2+) channels at the wound site. In this view, connexin (Cx) channels/hemichannels and store-operated Ca(2+) entry (SOCE) stand amid the most proper routes to therapeutically induce the regrowth of denuded vessels. Cx stimulation might trigger the proliferative and migratory behaviour of ECs facing the lesion site, whereas activation of SOCE is likely to favour EPC homing to the wounded vessel
An innovative assay for the analysis of in vitro endothelial remodeling: Experimental and computational evidence
No full textThe molecular and cellular mechanisms underlying vascular remodeling are currently investigated by experimental strategies which aim to mimic the complex environmental conditions found in vivo. Some of them focus on the tubulogenic activity of dispersed endothelial cell populations, while others evaluate vascular sprouting. Here we propose a new method to assess matrigel invasion starting from confluent or subconfluent monolayers of human microvascular ECs (HMVEC) seeded on different substrates. The experimental setting is also validated by an improved hybrid multiscale mathematical approach, which integrates a mesoscopic grid-based cellular Potts model, that describes HMVEC phenomenology, with a continuous one, accounting for the kinetics of diffusing growth factors. Both experimental and theoretical approaches show that the endothelial potential to invade, migrate, and organize in tubule structures is a function of selected environmental parameters. The present methodology is intended to be simple to use, standardized for rapid screening and suitable for mechanistic studies
Computational approaches for translational oncology: Concepts and patents
No full textBackground: Cancer is a heterogeneous disease, which is based on an intricate network of processes at different spatiotemporal scales, from the genome to the tissue level. Hence the necessity for the biomedical and pharmaceutical research to work in a multiscale fashion. In this respect, a significant help derives from the collaboration with theoretical sciences. Mathematical models can in fact provide insights into tumor-related processes and support clinical oncologists in the design of treatment regime, dosage, schedule and toxicity. Objective and Method: The main objective of this article is to review the recent computational-based patents which tackle some relevant aspects of tumor treatment. We first analyze a series of patents concerning the purposing the purposing or repurposing of anti-tumor compounds. These approaches rely on pharmacokinetics and pharmacodynamics modules, that incorporate data obtained in the different phases of clinical trials. Similar methods are also at the basis of other patents included in this paper, which deal with treatment optimization, in terms of maximizing therapy efficacy while minimizing side effects on the host. A group of patents predicting drug response and tumor evolution by the use of kinetics graphs are commented as well. We finally focus on patents that implement informatics tools to map and screen biological, medical, and pharmaceutical knowledge. Results and Conclusions: Despite promising aspects (and an increasing amount of the relative literature), we found few computational-based patents: There is still a significant effort to do for allowing modelling approaches to become an integral component of the pharmaceutical research
Hydrogen sulfide as regulator of calcium channels
No full textAn increasing body of evidence suggests the involvement of hydrogen sulfide (H(2)S) in different physiological and pathological processes. Similarly to the other gasotransmitters nitric oxide (NO) and carbon monoxide (CO), this bioactive compound is rapidly diffusible through the biological membranes and acts in a paracrine fashion. Despite the large amount of biological actions observed in vitro and in vivo upon stimulation with H(2)S donors, as well as by interfering with its synthesis, the molecular targets and mechanisms through which it exerts its intracellular effects are only partially known. A number of proteins are covalently modified by H(2)S through sulfhydration of specific cysteine residues. However, only in few cases their identity has been discovered and the functional role of this post-translational modification needs to be investigated in more detail. Great attention has been devoted to potassium channels, particularly K(ATP), as they are considered key mediators of H(2)S-induced effects, and their sulfhydration has been clearly demonstrated. Recently, different authors reported the ability of H(2)S to interfere with calcium homeostasis in neurons, cardiomyocytes and endothelial cells. Since calcium signaling is involved in all cell processes, these observations attracted increasing attention from basic biology and medicine. Although some effects of H(2)S on calcium signals can be ascribed to K(ATP) modulation, there is growing consensus about the existence of other targets for the gasotransmitter. Some of them are Ca(2+)-permeable channels. In this review we discuss the state of the art in this specific field, providing an updated report of H(2)S interaction with Ca(2+) channels and its functional outcomes
Hydrogen sulfide and endothelial dysfunction: relationship with nitric oxide
No full textThe endothelium is a cellular monolayer that lines the inner surface of blood vessels and plays a central role in the maintenance of cardiovascular homeostasis by controlling platelet aggregation, vascular tone, blood fluidity and fibrinolysis, adhesion and transmigration of inflammatory cells, and angiogenesis. Endothelial dysfunctions are associated with various cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, and cardiovascular complications of diabetes. Numerous studies have established the anti-inflammatory, anti-apoptotic, and anti-oxidant effects of hydrogen sulfide (H2S), the latest member to join the gasotransmitter family along with nitric oxide and carbon monoxide, on vascular endothelium. In addition, H2S may prime endothelial cells (ECs) toward angiogenesis and contribute to wound healing, besides to its well-known ability to relax vascular smooth muscle cells (VSMCs), and thereby reducing blood pressure. Finally, H2S may inhibit VSMC proliferation and platelet aggregation. Consistently, a deficit in H2S homeostasis is involved in the pathogenesis of atherosclerosis and of hyperglycaemic endothelial injury. Therefore, the application of H2S-releasing drugs or using gene therapy to increase endogenous H2S level may help restore endothelial function and antagonize the progression of cardiovascular diseases. The present article reviews recent studies on the role of H2S in endothelial homeostasis, under both physiological and pathological conditions, and its putative therapeutic applications
An assessment of the impact of possible CAP reform scenarios on Romanian agriculture
No full textUsing a simplified model, with key-variable the prices of two different possible scenarios of CAP reform after 2013 (moderate and radical), this paper present a comparison between the price effects of implementation of each reform scenario at 2015 horizon on Romanian agriculture. This short analysis shows that, under the presented hypotheses, the net welfare effect, due to the price changes, for the selected products, is positive in both reform scenarios, yet greater in the case of the radical reform. Integrated in the large context of Romanian development, it seems that the influence of CAP reform upon agriculture and rural areas will be most likely a gradual one: an interpenetration between the two scenarios is foreseeable, starting with the moderate reform that will dominate the period around 2013, the reform measures acquiring a more radical character afterwards.CAP reform, Romania, welfare effects, Agricultural and Food Policy,
Rich, Sturmian, and trapezoidal words
No full textIn this paper we explore various interconnections between rich words, Sturmian words, and trapezoidal words. Rich words, first introduced by the second and third authors together with J. Justin and S. Widmer, constitute a new class of finite and infinite words characterized by having the maximal number of palindromic factors. Every finite Sturmian word is rich, but not conversely. Trapezoidal words were first introduced by the first author in studying the behavior of the subword complexity of finite Sturmian words. Unfortunately this property does not characterize finite Sturmian words. In this note we show that the only trapezoidal palindromes are Sturmian. More generally we show that Sturmian palindromes can be characterized either in terms of their subword complexity (the trapezoidal property) or in terms of their palindromic complexity. We also obtain a similar characterization of rich palindromes in terms of a relation between palindromic complexity and subword complexity
Nano-Pore Size of Alumina Affects Osteoblastic Response
No full textThe rapid development and application of nanotechnology to biological interfaces has impacted the bone implant field, allowing researchers to finely modulate the interface between biomaterials and recipient tissues. In the present study, oxidative anodization was exploited to generate two alumina surfaces with different pore diameters. The former displayed surface pores in the mean range of 16–30 nm, while in the latter pores varied from to 65 to 89 nm. The samples were characterized by Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersive X-ray spectroscopy (EDX) analysis prior to being tested with pre-osteoblastic MC3T3-E1 cells. In vitro cell response was studied in terms of early cell adhesion, viability, and morphology, including focal adhesion quantification. Both the alumina samples promoted higher cell adhesion and viability than the control condition represented by the standard culture dish plastic. Osteogenic differentiation was assessed through alkaline phosphatase activity and extracellular calcium deposition, and it was found that of the two nano-surfaces, one was more efficient than the other. By comparing for the first time two nano-porous alumina surfaces with different pore diameters, our data supported the role of nano-topography in inducing cell response. Modulating a simple aspect of surface texture may become an attractive route for guiding bone healing and regeneration around implantable metals
A cellular Potts model analyzing differentiated cell behavior during in vivo vascularization of a hypoxic tissue
No full textAngiogenesis, the formation of new blood vessel networks from existing capillary or post-capillary venules, is an intrinsically multiscale process occurring in several physio-pathological conditions. In particular, hypoxic tissue cells activate downstream cascades culminating in the secretion of a wide range of angiogenic factors, including VEGF isoforms. Such diffusive chemicals activate the endothelial cells (ECs) forming the external walls of the nearby vessels that chemotactically migrate toward the hypoxic areas of the tissue as multicellular sprouts. A functional network eventually emerges by further branching and anastomosis processes. We here propose a CPM-based approach reproducing selected features of the angiogenic progression necessary for the reoxygenation of a hypoxic tissue. Our model is able to span the different scale involved in the angiogenic progression as it incorporates reaction-diffusion equations for the description of the evolution of microenvironmental variables in a discrete mesoscopic cellular Potts model (CPM) that reproduces the dynamics of the vascular cells. A key feature of this work is the explicit phenotypic differentiation of the ECs themselves, distinguished in quiescent, stalk and tip. The simulation results allow identifying a set of key mechanisms underlying tissue vascularization. Further, we provide evidence that the nascent pattern is characterized by precise topological properties. Finally, we link abnormal sprouting angiogenesis with alteration in selected cell behavior
A multiscale hybrid approach for vasculogenesis and related potential blocking therapies
No full textSolid tumors must recruit and form new blood vessels for maintenance, growth and detachments of metastases. Discovering drugs that block malignant angiogenesis is thus an important approach in cancer treatment and has given rise to multiple in vitro and in silico models. The present hybrid individual cell-based model incorporates some underlying biochemical events relating more closely the classical Cellular Potts Model (CPM) parameters to subcellular mechanisms and to the activation of specific signaling pathways. The model spans the three fundamental biological levels: at the extracellular level a continuous model describes secretion, diffusion, uptake and decay of the autocrine VEGF; at the cellular level, an extended lattice CPM, based on a system energy reduction, reproduces cell dynamics such as migration, adhesion and chemotaxis; at the subcellular level, a set of reaction-diffusion equations describes a simplified VEGF-induced calcium-dependent intracellular pathway. The results agree with the known interplay between calcium signals and VEGF dynamics and with their role in malignant vasculogenesis. Moreover, the analysis of the link between the microscopic subcellular dynamics and the macroscopic cell behaviors confirms the efficiency of some pharmacological interventions that are currently in use and, more interestingly, proposes some new therapeutic approaches, that are counter-intuitive but potentially effective
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