553 research outputs found
Therapies to prevent post-infarction remodelling: From repair to regeneration
Get PDFMyocardial infarction is the first cause of worldwide mortality, with an increasing incidence also reported in developing countries. Over the past decades, preclinical research and clinical trials continually tested the efficacy of cellular and acellular-based treatments. However, none of them resulted in a drug or device currently used in combination with either percutaneous coronary intervention or coronary artery bypass graft. Inflammatory, proliferation and remodelling phases follow the ischaemic event in the myocardial tissue. Only recently, singlecell sequencing analyses provided insights into the specific cell populations which determine the final fibrotic deposition in the affected region. In this review, ischaemia, inflammation, fibrosis, angiogenesis, cellular stress and fundamental cellular and molecular components are evaluated as therapeutic targets. Given the emerging evidence of biomaterial-based systems, the increasing use of injectable hydrogels/scaffolds and epicardial patches is reported both as acellular and cellularised/functionalised treatments. Since several variables influence the outcome of any experimented treatment, we return to the pathological basis with an unbiased view towards any specific process or cellular component. Thus, by evaluating the benefits and limitations of the approaches based on these targets, the reader can weigh the rationale of each of the strategies that reached the clinical trials stage. As recent studies focused on the relevance of the extracellular matrix in modulating ischaemic remodelling and enhancing myocardial regeneration, we aim to portray current trends in the field with this review. Finally, approaches towards feasible translational studies that are as yet unexplored are also suggested
Synthetic/ECM-inspired hybrid platform for hollow microcarriers with ROS-triggered nanoporation hallmarks
Get PDFReactive oxygen species (ROS) are key pathological signals expressed in inflammatory diseases such as cancer, ischemic conditions and atherosclerosis. An ideal drug delivery system should not only be responsive to these signals but also should not elicit an unfavourable host response. This study presents an innovative platform for drug delivery where a natural/synthetic composite system composed of collagen type I and a synthesized polythioether, ensures a dual stimuli-responsive behaviour. Collagen type I is an extracellular matrix constituent protein, responsive to matrix metalloproteinases (MMP) cleavage per se. Polythioethers are stable synthetic polymers characterized by the presence of sulphur, which undergoes a ROS-responsive swelling switch. A polythioether was synthesised, functionalized and tested for cytotoxicity. Optimal conditions to fabricate a composite natural/synthetic hollow sphere construct were optimised by a template-based method. Collagen-polythioether hollow spheres were fabricated, revealing uniform size and ROS-triggered nanoporation features. Cellular metabolic activity of H9C2 cardiomyoblasts remained unaffected upon exposure to the spheres. Our natural/synthetic hollow microspheres exhibit the potential for use as a pathological stimuli-responsive reservoir system for applications in inflammatory diseases.This material is based upon works supported by the European Union funding under the AngioMatTrain 7th Framework Programme, Grant Agreement Number 317304. This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) and is co-funded under the European Regional Development Fund under Grant Number 13/RC/2073. The authors acknowledge the use of the facilities and the scientific and technical assistance of the Centre for Microscopy and Imaging at the National University of Ireland Galway (www.imagingnuigalway.ie), a facility that is co-funded by the Irish Government’s Programme for Research in Third Level Institutions, Cycles 4 and 5, National Development Plan 2007–2013
Targeted Approaches to Inhibit Sialylation of Multiple Myeloma in the Bone Marrow Microenvironment
No full textAberrant glycosylation modulates different aspects of tumor biology, and it has long been recognized as a hallmark of cancer. Among the different forms of glycosylation, sialylation, the addition of sialic acid to underlying oligosaccharides, is often dysregulated in cancer. Increased expression of sialylated glycans has been observed in many types of cancer, including multiple myeloma, and often correlates with aggressive metastatic behavior. Myeloma, a cancer of plasma cells, develops in the bone marrow, and colonizes multiple sites of the skeleton including the skull. In myeloma, the bone marrow represents an essential niche where the malignant cells are nurtured by the microenvironment and protected from chemotherapy. Here, we discuss the role of hypersialylation in the metastatic process focusing on multiple myeloma. In particular, we examine how increased sialylation modulates homing of malignant plasma cells into the bone marrow by regulating the activity of molecules important in bone marrow cellular trafficking including selectins and integrins. We also propose that inhibiting sialylation may represent a new therapeutic strategy to overcome bone marrow-mediated chemotherapy resistance and describe different targeted approaches to specifically deliver sialylation inhibitors to the bone marrow microenvironment
The Baci
Get PDFTwo articles concerning the ceremony of the baci in Lao culture. Includes a copy of a book chapter written by Thao Nhouy Abhay, the former Minister of Education.The baci is an expression of welcome. The scanned book pages are from "Kingdom of Laos: The Land of the Million Elephants and of the White Parasol" edited by Rene de Berval; Saigon: France-Asie, 195
An optimized protocol for combined fluorescent lectin/immunohistochemistry to characterize tissue-specific glycan distribution in human or rodent tissues
Get PDF: Lectin histochemical analysis of tissues combined with immunohistochemistry is a valuable tool to characterize and correlate the spatial distribution of glycans with the presence of specific cell types or antigens of interest. The current protocol describes the application of monosaccharide motif specificity of lectin binding to glycan residues to different tissue types. In addition, we describe stereological methods to provide further quantification of the analyzed tissues. For complete details on the use and execution of this protocol, please refer to Mohd Isa et al. (2018), Contessotto et al. (2020), and Samal et al. (2020)
Distinct glycosylation in membrane proteins within neonatal versus adult myocardial tissue
No full textMammalian hearts have regenerative potential restricted to early neonatal stage and lost within seven days after birth. Carbohydrates exclusive to cardiac neonatal tissue may be key regulators of regenerative potential. Although cell surface and extracellular matrix glycosylation are known modulators of tissue and cellular function and development, variation in cardiac glycosylation from neonatal tissue to maturation has not been fully examined.In this study, glycosylation of the adult rat cardiac ventricle showed no variability between the two strains analysed, nor were there any differences between the glycosylation of the right or left ventricle using lectin histochemistry and microarray profiling. However, in the Sprague-Dawley strain, neonatal cardiac glycosylation in the left ventricle differed from adult tissues using mass spectrometric analysis, showing a higher expression of high mannose structures and lower expression of complex N-linked glycans in the three-day-old neonatal tissue. Man(6)GlcNAc(2) was identified as the main high mannose N-linked structure that was decreased in adult while higher expression of sialylated N-linked glycans and lower core fucosylation for complex structures were associated with ageing. The occurrence of mucin core type 2 O-linked glycans was reduced in adult and one sulfated core type 2 O-linked structure was identified in neonatal tissue. Interestingly, O-linked glycans from mature tissue contained both N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), while all sialylated N-linked glycans detected contained only Neu5Ac.As glycans are associated with intracellular communication, the specific neonatal structures found may indicate a role for glycosylation in the neonatal associated regenerative capacity of the mammalian heart. New strategies targeting tissue glycosylation could be a key contributor to achieve an effective regeneration of the mammalian heart in pathological scenarios such as myocardial infarction. (C) 2019 The Author(s). Published by Elsevier B.V
Synthesis of model compounds acting as Nitric Oxide (NO)-scavengers and the fabrication of NO-scavenging hydrogels targeting the treatment of triple-negative breast cancer
No full textTriple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with an early recurrence within two to three years of first diagnosis. Moreover, the heterogeneity of the TNBC tissue creates difficulty in developing specific treatments for different TNBC subtypes. At certain stages of its development, a correlation exists between the tumour progression of TNBC and the overexpression of inducible nitric oxide synthase (iNOS). Hence, the modulation of the intracellular levels of ●NO can be employed to treat this type of tumour by inhibiting the metastatic behaviour of cancer cells and decreasing angiogenesis. Various NOS inhibitors can slow down the migration of TNBC cells. However, these inhibitors have certain drawbacks, such as a lack of specificity and reduced commercial interest in developing related therapeutics. To overcome these limitations, ●NO-scavenging is proposed as an alternative approach to reduce the intracellular levels of ●NO and inhibit cancer cell migration. The goal of this thesis is to target TNBC cell migration and angiogenesis within the tumour tissue through ●NO-scavenging. The goal was to synthesize several hemin-based ●NO-scavenging compounds and develop functional hyaluronic acid (HA)- based ●NO-scavenging hydrogels. The biological effects of these compounds were evaluated in vitro and in vivo. The initial stage of the project involved examining the effectiveness of hemin as a model compound for ●NO-scavenging and its impact on TNBC cell migration, the production of reactive oxygen species, and the expression of glycoproteins associated with metastasis. Additionally, the study examined the expression of epithelial-mesenchymal transition markers and mitochondrial functions in TNBC cells. Next, considering the catalytic processes of hemin for nitrite/H2O2-induced protein nitration, its influence in combination with ●NO on the nitration of cellular proteins was also evaluated. Furthermore, the mechanism of hemin/●NO-catalyzed nitration of BSA as a model protein was studied. This was a mechanistic study for the initial evaluation of the cellular effects of hemin and ●NO, and the influence of ●NO-scavenging in a group of molecular events in the TNBC cells. Modification of the properties of hemin through conjugation to specific aromatic moieties was the next step. The objective of this step was to reduce the aggregation behaviour of hemin molecules, protect them against oxidative degradation, and preserve their ●NO-scavenging efficiency. The properties of hemin and its derivatives were evaluated experimentally and theoretically. Next, their cytocompatibility was evaluated by measuring their effects on the intracellular levels of ●NO in TNBC cells, migration, and the accompanying downstream effects. Furthermore, the effects of different compounds on the ●NOinduced vasodilation in zebrafish embryos were investigated. The study introduced a novel class of iron based ●NO-scavenging compounds, which were synthesized using straightforward procedures and possessed unique chemical properties. Furthermore, the synthesized compounds exhibited diverse abilities to regulate TNBC cell migration and blood vessel dilation, each with distinct molecular effects at the cellular level. Next, the study investigated the interactions between HA, one of the primary components of the hydrogels, and ●NO, as well as how these interactions can lead to HA fragmentation. These interactions inhibited TNBC cell migration and dilation of blood vessels in zebrafish embryos. While ●NO induced the depolymerization of HA chains, with similar effects to other active radicals, hemin and its different derivatives prevented that with different levels. These interactions were examined via several techniques to understand how HA can scavenge ●NO, the involved mechanism, and the further effects on modulation of TNBC cell migration and ●NO-induced vasodilation. Multiple formulations were synthesised, and their properties were adjusted to create biodegradable hydrogels with customized compositions and ●NO-scavenging strength, utilizing surface functional ●NO-scavenging molecules. The hydrogel formulations continuously released active ●NOscavenging molecules, particularly of hemin and its derivative, hemin-tyrosine, which were evaluated in vitro. The ●NO-scavenging properties of certain hydrogels and their products following degradation were accompanied by an ability to decrease the levels of intracellular ●NO and inhibit TNBC cell migration. After collecting these observations, the final step was to develop chemically crosslinked HA-hydrogels with tuneable properties and ●NO-scavenging efficiency. This thesis aims to explore a fresh approach to treating TNBC by targeting one of the main gasotransmitters that play a critical molecular role in cancer metastasis. This study synthesised a new class of functional compounds and hydrogels that can scavenge ●NO and regulate cancer cell migration and angiogenesis. The chemical properties of the synthesized compounds and their ●NO-scavenging efficiencies were evaluated, and the further cellular effects were also assessed in vitro and in vivo. Candidate hydrogel formulations, loaded with candidate ●NO-scavenging compounds, were developed, and their reactivity against ●NO was verified by various assays, including in vitro studies.2027-07-1
Enabling Biomaterials for New Biomedical Technologies and Clinical Therapies
No full textThis eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contac
Advanced Functional Materials and Cell‐Based Therapies for the Treatment of Ischemic Stroke and Postischemic Stroke Effects
Get PDFIschemic stroke is considered one of the most threatening neurological disorders with high percentages of mortality and morbidity worldwide. Although in recent years, several nanotechnological advances have improved the survival rates, severe untreated poststroke side-effects continue to significantly influence the way of life of many. Tissue plasminogen activator and mechanical thrombectomy are considered the gold standards for the treatment of acute cerebral ischemia. These, however, fail to improve postischemic disorders. Herein, after a brief description of the pathophysiology of ischemic stroke and the following biochemical cascade, the most recent biomaterial and cell-based strategies are reviewed for its treatment. Other therapeutics that have been proposed not only for the treatment of cerebral ischemia but also for the regeneration of the infarcted brain that is responsible for a variety of disorders, including cognitive, motor, and speech problems are also presented. Finally, a few reported studies on diagnostic and theranostic nanostructures are also provided
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