2,529 research outputs found

    VALPROIC ACID PROTECTS KIDNEYS FROM CISPLATIN

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    Cisplatin treatment is effective against several types of carcinomas. However, it frequently leads to kidney injury, which warrants effective prevention methods. Sodium valproic acid is a prophylactic drug candidate with a high potential for clinical application against cisplatin-induced kidney injury. Therefore, in this study, we aimed to elucidate the mechanism underlying the prophylactic effect of valproic acid on cisplatin-induced kidney injury in a mouse model and HK2 and PODO cells with cisplatin-induced toxicity. In the mouse model of cisplatin-induced kidney injury, various renal function parameters and tubular damage scores were worsened by cisplatin, but they were significantly improved upon combination with valproic acid. No difference was observed in cisplatin accumulation between the cisplatin-treated and valproic acid-treated groups in whole blood and the kidneys. The mRNA expression levels of proximal tubular damage markers, apoptosis markers, and inflammatory cytokines significantly increased in the cisplatin group 72 h after cisplatin administration but significantly decreased upon combination with valproic acid. In HK2 cells, a human proximal tubular cell line, the cisplatin-induced decrease in cell viability was significantly suppressed by co-treatment with valproic acid. Valproic acid may inhibit cisplatin-induced kidney injury by suppressing apoptosis, inflammatory responses, and glomerular damage throughout the kidneys by suppressing proximal tubular cell damage. However, prospective controlled trials need to evaluate these findings before their practical application

    Galectins-1 and -3 Functions in M├╝ller Glia during Retinal Development and Degeneration

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    Within the retina, M├╝ller glial cells (MGCs) are central regulators of metabolic homeostasis during normal function and during pathogenic states. MGCs are major producers of Galectins (Gal) -1 and -3, carbohydrate-binding proteins which have been found to be key regulators of various cellular processes. This study aimed to investigate the potential roles of Gal-1 and -3 during inflammatory stimuli, as well as during models of retinal development and degeneration. Treatment of MIO-M1 cells with the pro-inflammatory cytokine IL-1 resulted in significant upregulation of Gal-1 (p.05). Inhibition of Gal-3 by siRNA increased the rate of MIO-M1 cell proliferation (p<.001). TGF-╬▓2 treatment increased the rate of migration of MIO-M1 cells (p<.01), but this effect was nullified following Gal-3 siRNA inhibition. During retinal organoid development, Gal-1 mRNA and protein expression peaked between days 10 and 30, whilst Gal-3 mRNA and protein expression increased steadily to peak at the end of the experimental period of 90 days. Using an experimental model of intraocular pressure elevation, Gal-3 protein expression was found to be upregulated in anterior chamber tissues including the iridocorneal angle and iris. Additional studies in a rodent model of optic neuropathy showed that MGC derived extracellular vesicles were effective in partially restoring retinal function at 2 weeks after treatment (p.05), for which further investigations are merited. Although the current study has provided a better understanding of the roles of Galectins during retinal development and degeneration, additional studies are warranted to elucidate the wider roles of Gal-1 and -3 during retinal degenerative diseases and explore any potential therapeutic applications of these molecules

    Choroidal-scleral cell interplay and the regulation of scleral biomechanics

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    Worldwide prevalence and severity of myopia have increased dramatically nowadays. High myopia and its irreversible associated eye elongation increase the risk of sight-threatening conditions. However, the exact mechanisms that drive myopia progression are still unknown. Myopia almost exclusively occurs in childhood, suggesting the adult sclera is functionally different from the young sclera. During myopia progression, the sclera becomes thinner and more elastic, and the composition of its scleral extracellular matrix changes. Similarly, the choroid is thinner and accommodation-induced choroidal secreted factors are linked to tissue biomechanics that may regulate scleral remodelling and eye elongation. Thus, we hypothesize that signals from the choroid are crucial to the regulation of scleral biomechanics. In addition, light exposure and subsequent dopamine release may regulate scleral remodelling and eye elongation, and myopia development and progression could be induced by near work. We used human primary fibroblasts isolated from the sclera and choroid of donor eyes from different ages and antero-posterior positions to test our hypothesis. We found that paediatric scleral fibroblastsembedded in the 3D collagen gels had greater contractility than adult ones, particularly those from the anterior part of the sclera. Scleral fibroblastsÔÇÖ ability to contract collagen gels was enhanced following stimulation with the choroid-conditioned medium, and this promotion was not due to an increase in proliferation or change in a-SMA expression. Furthermore, the ability of choroid conditioned medium to stimulate scleral fibroblasts was completely abolished when choroid cells were treated with dopamine. This suggests that normal scleral development is regulated by a balance between positive biochemical signals from the choroid, and negative signals resulting from a direct effect of retina-derived dopamine on the choroid cells. These findings may help improve clinical practice to control myopia development and progression in the future

    ├Üloha transkrip─Źn├şch faktor┼» p┼Öi v├Żvoji oka my┼íi

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    Vid─Ťn├ş /zrak je slo┼żit├Ż proces, kter├Ż za─Ź├şn├í p┼Öenosem a lomem sv─Ťtla p┼Öes vysoce specializovanou pr┼»hlednou tk├í┼ł naz├Żvanou rohovka. Rohovka slou┼ż├ş jako ochrann├í bari├ęra a p┼Öisp├şv├í k zaost┼Öovac├ş schopnosti oka. V├Żvoj sav─Ź├ş rohovky sest├ív├í z n─Ťkolika f├íz├ş, zahrnuj├şc├ş tvorbu rohovkov├ęho epitelu (CE), rohovkov├ęho stromatu a endotelu (CEn) b─Ťhem embryogeneze, n├ísledovan├ę postnat├íln├ş stratifikac├ş epitelu a pravidelnou obnovou odlupovan├Żch povrchov├Żch bun─Ťk epitelu. Transkrip─Źn├ş faktor Paired box protein (Pax) 6 je evolu─Źn─Ť konzervovan├Ż transkrip─Źn├ş factor, d┼»le┼żit├Ż pro spr├ívn├Ż v├Żvoj oka. Pro dal┼í├ş porozum─Ťn├ş ├║loze Pax6 p┼Öi v├Żvoji rohovky jsme vyu┼żili syst├ęm Cre-loxP k selektivn├ş inaktivaci Pax6 ve dvou tk├ín├şch oka, konkr├ętn─Ť postnat├íln├şm CE a tk├ín├ş "epitelu o─Źn├şho povrchu" (OSE) (rohovka, limbus a spojivka). Vytvo┼Öili jsme novou transgenn├ş my┼í├ş linii s postnat├íln─Ť specifickou expres├ş Cre-rekombin├ízy v CE, Aldh3-Cre. Inaktivace Pax6 v postnat├íln├şm CE pomoc├ş Aldh3-Cre vedla k abnorm├íln─Ť tenk├ę rohovce s defekty v bun─Ť─Źn├ę adhezi. T├şm jsme p┼Ö├şmo prok├ízali, ┼że Pax6 hraje kl├ş─Źovou roli v postnat├íln├şm v├Żvoji rohovky. Pot├ę jsme selektivn─Ť inaktivovali Pax6 v OSE pomoc├ş dal┼í├ş specifick├ę my┼í├ş linie K14- Cre. U t─Ťchto my┼í├ş doch├ízelo ke "konjunktivalizaci" CE a epitelu limbu (p┼Öem─Ťn─Ť tk├ín─Ť CE a limbu v tk├í┼ł...Vision is a complex process that begins with the transmission and refraction of light through a highly specialised transparent tissue called the cornea. The cornea acts as a protective barrier and contributes to the focusing power of the eye. The development of mammalian cornea is a multiphase process involving the formation of the corneal epithelium (CE), stroma and endothelium (CEn) during embryogenesis, followed by the postnatal stratification of epithelium and constant renewal of desquamated outermost cells. Paired box protein (Pax) 6 is an evolutionarily conserved transcription factor important for the proper development of the eye. To provide further insights into the role of Pax6 in corneal development, we took the advantage of Cre-loxP system for selectively inactivating Pax6 in two ocular domains, specifically, the postnatal CE and the ocular surface epithelium (OSE) (cornea, limbus, and conjunctiva). We generated a novel postnatal CE-specific Cre-expressing transgenic mouse line, Aldh3-Cre. Inactivation of Pax6 in the postnatal CE using Aldh3-Cre resulted in the abnormal thin cornea with defective cell-cell adhesion, thus providing direct evidence for the function of Pax6 in postnatal corneal development. Subsequently, the OSE-specific depletion of Pax6 using K14-Cre, resulted in the...Katedra bun─Ť─Źn├ę biologieDepartment of Cell BiologyP┼Ö├şrodov─Ťdeck├í fakultaFaculty of Scienc

    VEXAS syndrome: a new paradigm for adult-onset monogenic autoinflammatory diseases

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    VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described pathological entity. It is an acquired monogenic autoinflammatory disease caused by somatic mutations of the UBA1 gene in blood cells precursors; the gene encodes one of the two E1 enzyme isoforms that initiates ubiquitylation in cell's cytoplasm. VEXAS syndrome leads to systemic inflammation, with all organs and tissues potentially involved. The clinical picture may be extremely heterogenous, mimicking different other systemic rheumatologic entities coexisting with haematological disorders, especially myelodysplastic syndrome. This new disease represents a very intriguing clinical condition in several respects: it accounts for the paradigm of adult-onset monogenic autoinflammatory diseases determined by a genetic mosaicism resulting in the development of a challenging multiorgan inflammatory condition. Moreover, VEXAS syndrome is perhaps not an exceptionally rare condition and represents an example of a systemic genetic autoinflammatory disease drawing its origin in bone marrow disorders. VEXAS syndrome should be strongly considered in each adult patient with an unexplained systemic inflammatory condition, especially when recurrent fevers, neutrophilic dermatosis, relapsing polychondritis, ocular inflammation and other systemic inflammatory symptoms accompanying myelodysplastic syndrome or other haematological disorders. The syndrome deserves a multidisciplinary approach to reach the diagnosis and ensure the best management of a potentially very challenging condition. To quickly describe the clinical course, long-term outcomes, and the optimal management of this new syndrome it is essential to join forces internationally. To this end, the international AutoInflammatory Disease Alliance (AIDA) registry dedicated to VEXAS syndrome has been developed and is already active. ┬ę 2023, The Author(s)

    Cerebrovascular dysfunction in cerebral small vessel disease

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    INTRODUCTION: Cerebral small vessel disease (SVD) is the cause of a quarter of all ischaemic strokes and is postulated to have a role in up to half of all dementias. SVD pathophysiology remains unclear but cerebrovascular dysfunction may be important. If confirmed many licensed medications have mechanisms of action targeting vascular function, potentially enabling new treatments via drug repurposing. Knowledge is limited however, as most studies assessing cerebrovascular dysfunction are small, single centre, single imaging modality studies due to the complexities in measuring cerebrovascular dysfunctions in humans. This thesis describes the development and application of imaging techniques measuring several cerebrovascular dysfunctions to investigate SVD pathophysiology and trial medications that may improve small blood vessel function in SVD. METHODS: Participants with minor ischaemic strokes were recruited to a series of studies utilising advanced MRI techniques to measure cerebrovascular dysfunction. Specifically MRI scans measured the ability of different tissues in the brain to change blood flow in response to breathing carbon dioxide (cerebrovascular reactivity; CVR) and the flow and pulsatility through the cerebral arteries, venous sinuses and CSF spaces. A single centre observational study optimised and established feasibility of the techniques and tested associations of cerebrovascular dysfunctions with clinical and imaging phenotypes. Then a randomised pilot clinical trial tested two medicationsÔÇÖ (cilostazol and isosorbide mononitrate) ability to improve CVR and pulsatility over a period of eight weeks. The techniques were then expanded to include imaging of blood brain barrier permeability and utilised in multi-centre studies investigating cerebrovascular dysfunction in both sporadic and monogenetic SVDs. RESULTS: Imaging protocols were feasible, consistently being completed with usable data in over 85% of participants. After correcting for the effects of age, sex and systolic blood pressure, lower CVR was associated with higher white matter hyperintensity volume, Fazekas score and perivascular space counts. Lower CVR was associated with higher pulsatility of blood flow in the superior sagittal sinus and lower CSF flow stroke volume at the foramen magnum. Cilostazol and isosorbide mononitrate increased CVR in white matter. The CVR, intra-cranial flow and pulsatility techniques, alongside blood brain barrier permeability and microstructural integrity imaging were successfully employed in a multi-centre observational study. A clinical trial assessing the effects of drugs targeting blood pressure variability is nearing completion. DISCUSSION: Cerebrovascular dysfunction in SVD has been confirmed and may play a more direct role in disease pathogenesis than previously established risk factors. Advanced imaging measures assessing cerebrovascular dysfunction are feasible in multi-centre studies and trials. Identifying drugs that improve cerebrovascular dysfunction using these techniques may be useful in selecting candidates for definitive clinical trials which require large sample sizes and long follow up periods to show improvement against outcomes of stroke and dementia incidence and cognitive function

    Assessment and reporting of adverse drug reactions to iopromide: a study of risk perception and pharmacovigilance

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    Tesis por compendio de publicaciones[EN]To achieve the thesis goals, two original articles were performed, the first to evaluate patientsÔÇÖ awareness of ADR risks and the Portuguese Pharmacovigilance System and the second to provide a retrospective analysis of ADR to iopromide in a Portuguese private unit of radiology. In addition, to reinforce the background of the thesis, two review articles were incorporated: a narrative review of the safety assessment of iopromide focusing on adverse events and a scoping review of all-round approaches to increase adverse drug reaction reporting. [ES]Para lograr los objetivos de la tesis, organizada en compendio de art├şculos, se realizaron dos art├şculos originales, uno para evaluar el conocimiento de los pacientes sobre los riesgos de RAM y el Sistema de Farmacovigilancia de Portugal y otro para proporcionar un an├ílisis retrospectivo de RAM a iopromida en una unidad privada de radiolog├şa portuguesa. Adem├ís, para reforzar los antecedentes de la tesis, se agregaron dos art├şculos de revisi├│n, uno que utiliza una revisi├│n narrativa de la evaluaci├│n de la seguridad de la iopromida que se centra en los eventos adversos y una revisi├│n de alcance de enfoques integrales para aumentar la notificaci├│n de reacciones adversas a medicamentos

    Assesment of Structure, Function, and Microevolutionary Dynamics of Extrachromosomal Circular DNA in Chinese Hamster Ovary Cells

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    Chinese hamster ovary (CHO) cell lines are among the most popular expression hosts used in biopharmaceutical manufacturing due to relative ease of culture, capacity to perform human-like post-translational modifications, and non-susceptibility to viruses. However, the intrinsic plasticity of the CHO genome can lead to undesired genetic rearrangements, phenotypic shifts, reduced product quality, and early culture termination that prevents continuous biomanufacturing. A characteristic of plastic and unstable genomes that is poorly understood in CHO cells is extrachromosomal circular DNA (eccDNA). EccDNAs are focal amplifications of the genome that reside in the extranuclear space. These plasmid-like entities are structurally complex and are capable of contributing to a wide variety of biological functions including gene overexpression, regulation of nuclear-encoded genes, immunostimulation, and adaptive stress responses. The objective of this work is to establish the foundational knowledge of eccDNA structure, function, and microevolutionary dynamics in CHO cells under various conditions. This work characterizes eccDNA content in CHO cells grown in bioreactors for two weeks under control and lactate-stressed conditions, two CHO K-1-derived cell lines of different ages, and CHO cells gradually adapted to high extracellular lactate levels. More than 2,000 genes were observed to be encoded on eccDNAs and summaries of gene function are presented using Gene Ontology and KEGG pathway analyses. RNA-seq data is utilized to identify potential changes in gene expression mediated by eccDNAs. Furthermore, the study presents a broad characterization of eccDNA sequence structures and biogenesis sites that may be used as targets in future work
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