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The enteric nervous system (ENS) in mammals forms from neural crest cells during embryogenesis and early postnatal life. Nevertheless, multipotent progenitors of the ENS can be identified in the adult intestine using clonal cultures and in vivo transplantation assays. The identity of these neurogenic precursors in the adult gut and their relationship to the embryonic progenitors of the ENS are currently unknown. Using genetic fate mapping, we here demonstrate that mouse neural crest cells marked by SRY box-containing gene 10 (Sox10) generate the neuronal and glial lineages of enteric ganglia. Most neurons originated from progenitors residing in the gut during mid-gestation. Afterward, enteric neurogenesis was reduced, and it ceased between 1 and 3 months of postnatal life. Sox10-expressing cells present in the myenteric plexus of adult mice expressed glial markers, and we found no evidence that these cells participated in neurogenesis under steady-state conditions. However, they retained neurogenic potential, as they were capable of generating neurons with characteristics of enteric neurons in culture. Furthermore, enteric glia gave rise to neurons in vivo in response to chemical injury to the enteric ganglia. Our results indicate that despite the absence of constitutive neurogenesis in the adult gut, enteric glia maintain limited neurogenic potential, which can be activated by tissue dissociation or injury.

Barrett's esophagus is lined by columnar and goblets cells with gastric and intestinal characteristics. Despite the association between goblet elements and malignancy, it was not demonstrated that other columnar cells lineages are not related to neoplasia. Chromosomal abnormalities were described in metaplasia adjacent to Barrett's neoplasia, but it is unknown which metaplastic lineages are involved. This work assessed the frequency and the type of chromosomal abnormalities in Barrett's esophagus without neoplasia and performed the identification of the metaplastic cells carrying chromosomal gains. Barrett's esophagus biopsies were collected and processed for short-term cell culture and cytogenetic analysis. Combined immunofluorescence/fluorescence in situ hybridization was performed in cases exhibiting chromosomal gains by using antisera against intestinal (MUC2) and gastric (MUC5AC and MUC6) apomucins and chromosome pericentromeric alpha satellite DNA probes for the chromosomes involved. Each case was scored for the number of spots (0, 1, 2, >2) in 200 nonoverlapping nuclei. Columnar and goblet cells were separately assessed. Short-term cell cultures were achieved in 40/60 cases (67%). There were clonal abnormalities in 27/40 cases (68%) and tetraploid (4n) clones in 10/40 (25%). Structural alterations were detected in 14/40 (35%) with recurrent breakpoints at 1q21, 15q15 and 15q22. Numerical changes (trisomies 7 and 18 and loss of Y) occurred in 16/40 (40%). Gains of chromosomes 7 and 18 were more frequent in columnar than in goblet cells (9.8% vs 0.7% ( P <0.05)) and (7.9 vs 1.9% ( P <0.05)) respectively. These alterations were detected in cells exhibiting gastric as well as intestinal features and were more frequent in cells without apomucin production. Conclusions: (1) chromosomal instability is a common finding in Barrett's esophagus without neoplasia. (2) The two metaplastic populations are committed, chromosomal gains being more frequent in columnar nongoblet than in goblet cells. (3) The two metaplastic phenotypes, gastric and intestinal, are equally involved.

Aim: The purpose of this study was to compare the immunohistochemical profile of cell cycle inhibitors of G1/S phase transition (p21, p53 and pRb), Ki-67 proliferation marker and DNA ploidy in male (MBC) and female breast cancer (FBC). Material and Methods: One hundred patients (50 non-consecutive cases of FBC and an equal number of MBC) were selected according to homogeneous features regarding age, histological type, tumour grading, nodal status and absence of neoadjuvant therapy. The expression of p21, p53, pRb and Ki-67 was assessed by immunohistochemistry, and DNA ploidy was analysed by flow cytometry. Correlations between variables were evaluated using the χ 2 test. Results: The incidence of DNA aneuploid, p21-positive and p53-negative tumours was significantly higher in MBC than in FBC; pRb and Ki-67 revealed no statistically significant differ- ences between the two entities. In MBC, high tumour grade correlated with aneuploidy, Ki-67 and pRb positivity; ploidy and p53 were also associated. In FBC, only ploidy and grade showed a strong correlation. Conclusion: The significant dissimilarities regarding DNA ploidy, p21 and p53 in these quite homogeneous groups of FBC and MBC point to different genomic instability and to differences in cell cycle proliferative control, reinforcing the view of somewhat distinct tumour oncogenesis.

O uso de recursos naturais, de origem vegetal, desempenha um papel importante na descoberta e desenvolvimento de potenciais compostos com ação terapêutica. As plantas têm sido amplamente utilizadas por pessoas de todas as culturas para o tratamento de diferentes doenças. O termo nutracêutico é aplicado a produtos que são isolados de plantas, suplementos alimentares, dietas específicas e alimentos processados, que são utilizados não apenas com funções nutritivas, mas também com funções terapêuticas. Trata-se de uma categoria de produtos pouca regulamentada, com definições não consensuais, mas que tem sido alvo de grande pesquisa nos últimos anos, representando um segmento de mercado com crescimento rápido. São muitas as plantas atualmente estudadas com propriedades nutracêuticas e, como tal, esta tese apresenta o seu principal foco na avaliação do potencial nutracêutico do Taraxacum hispanicum, uma espécie conhecida como dente-de-leão, e ainda pouco estudada dentro do género. Para tal, foi determinado o perfil fitoquímico dos extratos aquosos e hidroalcoólicos das folhas da planta, assim como o seu teor de compostos fenólicos. Seguidamente, e sabendo que as plantas do género Taraxacum apresentam uma potente atividade antioxidante, estudou-se a influencia de diferentes variáveis no processo extrativo, como o efeito dos solventes, o tamanho das partículas, a temperatura e tempos de extração na sua atividade antioxidante.A espécie T. officinale é a mais estudada do género e a mais consumida, tanto como alimento como na medicina tradicional. Esta planta encontra-se aprovada para tratamento de alterações no fluxo biliar, estimulação da diurese, perda de apetite e dispepsia no caso das raízes, e perda de apetite, dispepsia (enfartamento e flatulência), no caso das folhas, sendo que novos estudos evidenciam a sua ação no tratamento e prevenção de vários tipos de cancro. Apesar de existirem vários estudos relativos à caracterização da espécie T. officinale, são praticamente inexistentes os estudos com a identificação do perfil fitoquímico e da atividade antioxidante da espécie T. hispanicum. O perfil fitoquímico do T. hispanicum foi semelhante ao encontrado em outras espécies do géneroTaraxacum, demonstrando resultados positivos para os polifenóis, flavonóides, taninos e diterpenos, em ambos os extratos estudados. Também a ausência de triterpenos nas amostras estudadas encontra-se de acordo com o previsto. No caso dos compostos fenólicos, saponinas e alcalóides os resultados foram diferentes em ambos os extratos (aquoso e hidroalcoólico), apresentando um resultado positivo apenas no extrato hidroalcoólico.Quanto à análise das diferentes variáveis na atividade antioxidante do extrato de folhas de dente-de-leão (T. hispanicum), recorrendo a diferentes ensaios antioxidantes, como o DPPH, a quelação de Fe2+ e o ensaio do radical superóxido, observou-se, pelos valores de IC50, que a utilização de água destilada, tamanhos reduzidos das partículas (em pó), temperaturas baixas (60 °) e tempos mais prolongados de extração (20 minutos) parecem influenciar a atividade antioxidante da planta em estudo.De modo geral, os resultados observados nesta tese providenciam uma importante base para estudos futuros, no sentido de permitir uma melhor compreensão do perfil fitoquímico da espécie T. hispanicum e do efeito de diferentes variáveis nos procedimentos extrativos da planta. Estes resultados são importantes para que possamos optar no futuro por procedimentos que nos permitam uma maior eficiência na extração de compostos ativos e, consequentemente, uma maior atividade antioxidante.

Pterospartum tridendatum is an important source of active compounds with anti-inflammatory properties. The ability of P. tridentatum leaves methanolic extract in preventing/reversing inflammation was studied in adult rats using a model of experimental osteoarthritis (OA) and ear edema. Control animals (SHAM) were administered phosphate buffer solution (PBS), while OA animals received either P. tridentatum 100 mg/kg, 300 mg/kg, or a commercial anti-inflammatory (15 mg/Kg, Ibuprofen) via gavage, daily, for three weeks. Ear edema was induced, and the animals were divided into five groups treated with: (i) ethanol, (ii) P. tridentatum, (iii) croton oil, (iv) croton oil + P. tridentatum, and (v) croton oil + medrol. The inflammatory effect was evaluated by the measurement of the knee and ear edema. The chromatographic profile, evaluated by HPLC-DAD, showed numerous phenolic compounds are present. In the docking analysis of these compounds, isoquercetin demonstrated strong molecular interactions for peroxisome proliferator-activated receptor alpha and gamma (PPARα and PPARƴ, respectively), protein kinase 2 subunit α (CK2 α), and 5-lipoxygenase-activating proteins. Genistein had strong docking binding energies for CK2α and prostaglandin H (2) synthase-1. Our analysis showed the treatment with P. tridentatum extract reversed OA-induced edema in the rat knee, as well as ear edema, highlights this plant as a potential source of compounds that can be used as adjuvants in the management of inflammation.

The COVID-19 pandemic imposed changes upon the capacity of healthcare systems, with significant repercussions on healthcare provision, particularly at end-of-life. This study aims to analyze the concept map of death unpreparedness due to the COVID-19 pandemic, capturing the relationships among the attributes, antecedents, consequences, and empirical indicators. Walker and Avant’s method was used to guide an analysis of this concept. A literature search was performed systematically, between May 2022 and August 2023, using the following electronic databases on the Elton Bryson Stephens Company (EBSCO) host platform: Medical Literature Analysis and Retrieval System Online (Medline), Psychological Information Database (PsycINFO), Cumulative Index to Nursing and Allied Health Literature (CINAHL) Complete, Cochrane Library, and Nursing and Allied Health Collection. Thirty-four articles were retrieved. The unexpected and unpredictable impositions associated with inexperience and unskillfulness in dealing with COVID-19 configured challenges for healthcare professionals, family/caregivers, and even the dying person. Nine key attributes emerged in three main domains: (1) Individual: (a) disease-related conditions, (b) separation distress, and (c) scarcity of death and grief literacy; (2) Relational: (a) Dying alone, (b) poor communication, and (c) existential issues; and (3) Contextual: (a) disrupted collective mourning and grieving, (b) disrupted compassionate care and, (c) pandemic social stigma. This study contributed a full definition of death unpreparedness in a global pandemic scenario such as COVID-19. In this sense, feeling unprepared or unready for death brought new challenges to the bioecological resources of those affected. It is essential to embrace strategies capable of providing emotional and spiritual support in the dying process and to respect patient wishes. The lessons learned from COVID-19 should be applied to events with a comparable impact to minimize their consequences.

Rheumatoid arthritis (RA) is a disabling autoimmune disease whose treatment is ineffective for one-third of patients. Thus, the immunomodulatory potential of mesenchymal stromal/stem cells (MSCs) makes MSC-based therapy a promising approach to RA. This study aimed to explore the immunomodulatory action of human bone marrow (BM)-MSCs on myeloid dendritic cells (mDCs) and monocytes, especially on cytokines/chemokines involved in RA physiopathology. For that, LPS plus IFNγ-stimulated peripheral blood mononuclear cells from RA patients (n = 12) and healthy individuals (n = 6) were co-cultured with allogeneic BM-MSCs. TNF-α, CD83, CCR7 and MIP-1β protein levels were assessed in mDCs, classical, intermediate, and non-classical monocytes. mRNA expression of other cytokines/chemokines was also evaluated. BM-MSCs effectively reduced TNF-α, CD83, CCR7 and MIP-1β protein levels in mDCs and all monocyte subsets, in RA patients. The inhibition of TNF-α production was mainly achieved by the reduction of the percentage of cellsproducing this cytokine. BM-MSCs exhibited a remarkable suppressive action over antigen-presenting cells from RA patients, potentially affecting their ability to stimulate the immune adaptive response at different levels, by hampering their migration to the lymph node and the production of proinflammatory cytokines and chemokines. Accordingly, MSC-based therapies can be a valuable approach for RA treatment, especially for non-responder patients.

Pterospartum tridendatum (PtL) is used in popular medicine for its anti-inflammatory properties. Herein, we show PtL extract reversed experimental osteoarthritis induced knee edema, as well as acute ear edema, highlighting its potential as an adjuvant in the management of inflammation.

With the discovery of Th17 cells, it became unclear whether rheumatoid arthritis (RA) is a Th1-mediated and/or a Th17-mediated disease. Objective: The aim of this study was to identify and characterize the pro-inflammatory function of IL-17-producing T cell subsets (Th(c)17) in RA. Flow cytometry analysis was performed on peripheral blood from RA patients with inactive or low disease activity (LDA, n  = 19) and moderate to high disease activity (HDA, n  = 13) to analyze the number and functional activity of Th(c)17 and Th(c)1 cell subsets according to the frequency of IL-2-, TNF-α- and IFN-γ-producers cells, as well as, their cytokine amount. Additionally, 13 age-matched healthy volunteers were added to the study. Our data point to a slight increase in Tc17 frequency in RA patients, more evident in HDA, and a higher ability of Th17 to produce IL-17, whereas a lower production of TNF-α was noted either in Th17 or Tc17 cells, particularly from HDA. A similar decrease was observed in Th(c)1 for almost all studied pro-inflammatory cytokines, with the exception of IL-2, which was increased in Tc1 from LDA patients. Analysing the proportion of pro-inflammatory cytokines-producing cells, a polarization to a Tc1 phenotype seemed to occur in CD8 T cells, while CD4 T cells appear to be decreased in their frequency of IFN-γ-producing cells. Taken together, the functional plasticity features of Th17 and Tc17 cells suggest a particular contribution to the local cytokine production, pointing an underestimated role, namely of Tc1 and Tc17 cells, in the RA pathophysiology.