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Excessive weight (overweight and obesity) is a common disorder involving genetic and environmental factors, associated with cardiovascular diseases, type-2 diabetes, and others. NOTCH1 is critical for the maintenance of stem cells and adult tissues, being reported as a key player in metabolism and adipogenesis in animals. Thus, we test the hypothesis that NOTCH1 Single Nucleotide Polymorphisms (SNPs) are associated with excessive weight. Participants from the census-based cohort SABE (Saúde, Bem Estar e Envelhecimento-Health, Well-Being, and Aging), carried out in the city of São Paulo-Brazil, were stratified into cases and controls according to BMI. We filter the SNPs located at the start and end positions of NOTCH1 and 50 Kb on both sides. We selected SNPs with minor allelic frequency (MAF) greater than or equal to 0.01 and Hardy-Weinberg equilibrium (p > 0.05) and r2 ≥ 0.8. We performed an association study with genotypes and haplotypes, as well as in silico functional analysis of the identified SNPs. We observed an association of the SNP rs9411207 with the risk of excessive weight, under log-additive model, and the genotype distribution showed an increased frequency of homozygous TT (OR 1.50, CI 1.20-1.88; p = 0.0002). The haplotype GAT constructed from this and other SNPs in high Linkage Disequilibrium was more frequent in excessive-weight individuals (p = 0.003). In silico analyses suggested that these SNPs are likely to affect the transcription of NOTCH1 and other genes involved in adipogenesis and metabolism. This is the first study reporting association between NOTCH1 SNPs and the risk of excessive weight. Considering the possibility of NOTCH1 modulation, additional population studies are important to replicate these data and confirm the usefulness of risk genotypes for management strategies of excessive weight.

Assuntos

Obesidade , Sobrepeso , Polimorfismo de Nucleotídeo Único , Receptor Notch1 , Receptor Notch1/genética , Humanos , Brasil/epidemiologia , Masculino , Obesidade/genética , Feminino , Idoso , Sobrepeso/genética , Predisposição Genética para Doença , Pessoa de Meia-Idade , Haplótipos , Frequência do Gene , Estudos de Casos e Controles , Genótipo , Índice de Massa Corporal

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BACKGROUND: Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H2) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H2 provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H2 on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice. METHODS: In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H2) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H2 under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining. RESULTS: Our results indicate that 3-4% H2 does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H2 prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H2 inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H2 plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H2 promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreover, the retinal oxygen-sensing mechanisms (HIF-1α/VEGF) are also involved in hydrogen-mediated retinal revascularization and neovascularization suppression. CONCLUSIONS: Collectively, our results indicate that H2 could be a promising therapeutic agent for POR treatment and that its beneficial effect in human ROP might involve the activation of the Nrf2-Notch axis as well as HIF-1α/VEGF pathways.

Assuntos

Modelos Animais de Doenças , Hidrogênio , Neuroglia , Oxigênio , Neovascularização Retiniana , Retinopatia da Prematuridade , Animais , Hidrogênio/farmacologia , Neovascularização Retiniana/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Camundongos , Retinopatia da Prematuridade/tratamento farmacológico , Camundongos Endogâmicos C57BL , Retina/efeitos dos fármacos , Animais Recém-Nascidos , Regeneração/efeitos dos fármacos , Imuno-Histoquímica , Vasos Retinianos/efeitos dos fármacos

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The planar cell polarity (PCP) system is essential for positioning cells in 3D networks to establish the proper morphogenesis, structure, and function of organs during embryonic development. The PCP system uses inter- and intracellular feedback interactions between components of the core PCP, characterized by coordinated planar polarization and asymmetric distribution of cell populations inside the cells. PCP signaling connects the anterior-posterior to left-right embryonic plane polarity through the polarization of cilia in the Kupffer's vesicle/node in vertebrates. Experimental investigations on various genetic ablation-based models demonstrated the functions of PCP in planar polarization and associated genetic disorders. This review paper aims to provide a comprehensive overview of PCP signaling history, core components of the PCP signaling pathway, molecular mechanisms underlying PCP signaling, interactions with other signaling pathways, and the role of PCP in organ and embryonic development. Moreover, we will delve into the negative feedback regulation of PCP to maintain polarity, human genetic disorders associated with PCP defects, as well as challenges associated with PCP.

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The establishment of the embryonic dorsoventral axis in Xenopus occurs when the radial symmetry around the egg's animal-vegetal axis is broken to give rise to the typical symmetry of Bilaterians. We have previously shown that the Notch1 protein is ventrally enriched during early embryogenesis in Xenopus laevis and zebrafish and exerts ventralizing activity through ß-Catenin destabilization and the positive regulation of ventral center genes in X. laevis. These findings led us to further investigate when these asymmetries arise. In this work, we show that the asymmetrical distribution of Notch1 protein and mRNA precedes cortical rotation and even fertilization in X. laevis. Moreover, we found that in unfertilized eggs transcripts encoded by the ventralizing gene bmp4 are also asymmetrically distributed in the animal hemisphere and notch1 transcripts accumulate consistently on the same side of the eccentric maturation point. Strikingly, a Notch1 asymmetry orthogonal to the animal-vegetal axis appears during X. laevis oogenesis. Thus, we show for the first time a maternal bias in the distribution of molecules that are later involved in ventral patterning during embryonic axialization, strongly supporting the hypothesis of a dorsoventral prepattern or intrinsic bilaterality of Xenopus eggs before fertilization.

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Langerhans cell histiocytosis (LCH) is characterized by an expansion and accumulation of pathological histiocytes expressing langerin (CD207) and CD1a in different organs under an inflammatory milieu. The origin of pathognomonic precursors of LCH is widely debated, but monocytes and pre-dendritic cells (pre-DC) play a significant role. Remarkably, we found an expansion of AXLhigh cells in the CD11c+ subset of patients with active LCH, which also express the pathognomonic CD207 and CD1a. Moreover, we obtained a monocyte-derived LC-like (mo-LC-like) expressing high levels of AXL when treated with inflammatory cytokine, or plasma of patients with active disease. Intriguingly, inhibiting the mTOR pathway at the initial stages of monocyte differentiation to LC-like fosters the pathognomonic LCH program, highly increasing CD207 levels, together with NOTCH1 induction. We define here that AXLhigh could also be taken as a strong pathognomonic marker for LCH, and the release of Langerin and NOTCH1 expression depends on the inhibition of the mTOR pathway.

Assuntos

Antígenos CD , Receptor Tirosina Quinase Axl , Histiocitose de Células de Langerhans , Lectinas Tipo C , Lectinas de Ligação a Manose , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases , Serina-Treonina Quinases TOR , Feminino , Humanos , Masculino , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Biomarcadores , Diferenciação Celular , Histiocitose de Células de Langerhans/metabolismo , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Monócitos/metabolismo , Monócitos/imunologia , Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo

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A novel double-network conductive hydrogel based on lithium acetate/gelatin/polyacrylamide (PAAM) was synthesized by heating-cooling and subsequent γ-ray radiation-induced polymerization and cross-linking. Owing to the hydrogen bonding interaction between lithium acetate, physical cross-linked gelatin, and chemical cross-linked PAAM, the resultant hydrogel exhibited high tensile strength (1260 kPa), high ionic conductivity (35.2 mS cm-1), notch-insensitivity (tensile strength 415 kPa, elongation at break 872% with transverse notch), and extensive strain monitoring range (0.15-800%) under optimum conditions. The lithium acetate/gelatin/polyacrylamide hydrogel strain sensor attached to the skin can sensitively monitor the subtle movements of the human body. The strain sensor based on the resultant hydrogel with transverse notch can still work for 1200 cycles, due to that the covalent-cross-linked PAAm chain bridges the cracks and stabilizes the deformation, while the physical-cross-linked gelatin was unzipped to make the blunting of notch. The conductive hydrogel with high-sensitivity and high stability is expected to be used as materials for the preparation of flexible strain sensors in the future.

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Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks receptors for targeted therapy. Deeper insight into the molecular mechanisms regulating TNBC metastasis is urgently needed. The epithelial-mesenchymal transition process facilitates the metastasis of neighboring epithelial tumor cells. Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the Wee family of protein kinases, is upregulated in BC, and its high expression predicts poor prognosis in BC patients. Notch signaling activation is a pathognomonic feature of TNBC. PKMYT1 has been found to induce EMT in non-small cell lung cancer by activating Notch signaling. However, whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling remains unknown. Objectives: The objective of this study was to investigate whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling. Methods: Fifty cases of surgically resected BC samples (tumor and adjacent non-tumor tissue samples) were collected from patients diagnosed with BC. We measured the expression of PKMYT1 in clinical samples with real-time quantitative polymerase chain reaction (RT-qPCR). For in vitro analysis, RT-qPCR and Western blotting were conducted to evaluate PKMYT1 expression in TNBC cells. Then, the viability, migration, and invasion of TNBC cells were detected by cell counting kit-8 assays, wound healing assays, and Transwell assays. The EMT event was examined by evaluating the levels of EMT-associated proteins. For in vivo analysis, xenograft models in nude mice were established to explore PKMYT1 roles. E-cadherin and Ki67 expression in xenograft models were estimated by immunohistochemistry staining. Hematoxylin and eosin staining was performed to assess tumor metastasis. The underlying mechanisms by which PKMYT1 affected the malignant phenotypes of TNBC cells were explored by Western blotting measuring the pathway-associated proteins. Results: PKMYT1 was upregulated in BC tissues and cells, and its knockdown prevented cell proliferation, migration, invasion, and EMT event in TNBC. Mechanistically, Notch signaling was inactivated by PKMYT1 depletion, and Notch activation abolished the PKMYT1 silencing-induced inhibition in the malignant phenotypes of TNBC cells. For in vivo analysis, PKMYT1 knockdown inhibited tumorigenesis and metastasis of TNBC. Conclusion: PKMYT1 promotes EMT, proliferation, migration, and invasion of TNBC cells and facilitates tumor growth and metastasis by activating Notch signaling.

Assuntos

Transição Epitelial-Mesenquimal , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Proteínas de Membrana/metabolismo , Camundongos Nus , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia

RESUMO

Evidence for folate's protective effects on neural tube defects led the USA and Chile to start mandatory folic acid (FA) fortification programs, decreasing up to 50%. However, ∼30% of the population consuming fortified foods reach supraphysiologic serum levels. Although controversial, several epidemiological and clinical observations suggest that folate increases cancer risk, giving concern about the risks of FA supplementation. The Cancer stem cells (CSCs) model has been used to explain survival to anticancer therapies. The Notch-1 pathway plays a role in several cancers and is associated with the stemness process. Different studies show that modulation of metabolic pathways regulates stemness capacity in cancer. Supraphysiologic concentrations of FA increase the proliferation of HT-29 cells by Notch-1 activation. However, whether folate can induce a stemness-like phenotype in cancer is not known. We hypothesized that FA protects from glucose deprivation-induced cell death through Notch-1 activation. HT-29 cells were challenged with glucose deprivation at basal (20 nM) and supraphysiological (400 nM) FA and 5-MTHF concentrations. We analyzed changes in stemness-like gene expression, cell death and different energetic metabolic functions. Supraphysiological concentrations of FA increased stemness-like genes, and improved survival and oxygen consumption, inducing AMPK phosphorylation and HSP-70 protein expression. We evaluated the Notch-1 pathway using the DAPT and siRNA as inhibitors, decreasing the stemness-like gene expression and preventing the FA protection against glucose deprivation-induced cell death. Moreover, they decreased oxygen consumption and AMPK phosphorylation. These results suggest that FA protects against glucose deprivation. These effects were associated with AMPK activation, a critical metabolic mediator in nutrient consumption and availability that activates the Notch-1 pathway.

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ABSTRACT Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks receptors for targeted therapy. Deeper insight into the molecular mechanisms regulating TNBC metastasis is urgently needed. The epithelial-mesenchymal transition process facilitates the metastasis of neighboring epithelial tumor cells. Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the Wee family of protein kinases, is upregulated in BC, and its high expression predicts poor prognosis in BC patients. Notch signaling activation is a pathognomonic feature of TNBC. PKMYT1 has been found to induce EMT in non-small cell lung cancer by activating Notch signaling. However, whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling remains unknown. Objectives: The objective of this study was to investigate whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling. Methods: Fifty cases of surgically resected BC samples (tumor and adjacent non-tumor tissue samples) were collected from patients diagnosed with BC. We measured the expression of PKMYT1 in clinical samples with real-time quantitative polymerase chain reaction (RT-qPCR). For in vitro analysis, RT-qPCR and Western blotting were conducted to evaluate PKMYT1 expression in TNBC cells. Then, the viability, migration, and invasion of TNBC cells were detected by cell counting kit-8 assays, wound healing assays, and Transwell assays. The EMT event was examined by evaluating the levels of EMT-associated proteins. For in vivo analysis, xenograft models in nude mice were established to explore PKMYT1 roles. E-cadherin and Ki67 expression in xenograft models were estimated by immunohistochemistry staining. Hematoxylin and eosin staining was performed to assess tumor metastasis. The underlying mechanisms by which PKMYT1 affected the malignant phenotypes of TNBC cells were explored by Western blotting measuring the pathway-associated proteins. Results: PKMYT1 was upregulated in BC tissues and cells, and its knockdown prevented cell proliferation, migration, invasion, and EMT event in TNBC. Mechanistically, Notch signaling was inactivated by PKMYT1 depletion, and Notch activation abolished the PKMYT1 silencing-induced inhibition in the malignant phenotypes of TNBC cells. For in vivo analysis, PKMYT1 knockdown inhibited tumorigenesis and metastasis of TNBC. Conclusion: PKMYT1 promotes EMT, proliferation, migration, and invasion of TNBC cells and facilitates tumor growth and metastasis by activating Notch signaling.

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ABSTRACT Introduction Triple-negative breast cancer is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This phenotype renders triple-negative breast cancer cells refractory to conventional therapies, resulting in poor clinical outcomes and an urgent need for novel therapeutic approaches. Recent studies have implicated dysregulation of the Notch receptor signaling pathway in the development and progression of triple-negative breast cancer. Objective This study aimed to conduct a comprehensive literature review to identify potential therapeutic targets of the Notch pathway. Our analysis focused on the upstream and downstream components of this pathway to identify potential therapeutic targets. Results Modulating the Notch signaling pathway may represent a promising therapeutic strategy to treat triple-negative breast cancer. Several potential therapeutic targets within this pathway are in the early stages of development, including upstream (such as Notch ligands) and downstream (including specific molecules involved in triple-negative breast cancer growth). These targets represent potential avenues for therapeutic intervention in triple-negative breast cancer. Comments Additional research specifically addressing issues related to toxicity and improving drug delivery methods is critical for the successful translation of these potential therapeutic targets into effective treatments for patients with triple-negative breast cancer.

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The aim of this study was twofold: (1) evaluate the effect of benzo[a]pyrene (BaP) on expression levels of AQP3 and Notch1 genes in HaCaT cells exposed "in vitro" and (2) investigate the possible biological role of assessed genes by bioinformatics methods. Cells were exposed to increasing concentrations of BaP (0.0-4.0 µM) for 1-4 days. After treatments, cell viability and expression levels of AhR, CYP1A1, AQP3, and Notch1 genes were evaluated. The possible biological role of assessed genes was evaluated using bioinformatics tools. Low cytotoxicity in HaCaT cells dosed with BaP was detected. A significant overexpression (p < .05) of CYP1A1, AQP3, and Notch1 was found in exposed HaCaT cells. The gene expression upregulation was dependent on AhR activation. The bioinformatics analysis showed that these genes were enriched in related cancer signaling pathways. The findings suggest that AQP3 and Notch1 are upregulated by AhR activation in HaCaT cells exposed to BaP.

Assuntos

Benzo(a)pireno , Citocromo P-450 CYP1A1 , Humanos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Benzo(a)pireno/metabolismo , Células HaCaT , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Regulação para Cima

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ABSTRACT Introduction: Chronic graft-versus-host disease (cGvHD) not only remains the main cause of late mortality after allogeneic hematopoietic cell transplant, but also has the capacity of causing severe organ impairment in those who survive. The Notch, a highly conserved ligand-receptor pathway, is involved in many immunological processes, including inflammatory and regulatory responses. Recently, mouse models have shown that the blockage of canonical Notch signaling prevents GvHD. Objective and Method: Due to the lack of data on the Notch pathway in human chronic GvHD, we sought to study the expression of NOTCH components in primary samples of patients who received allo-HCT and presented active cGvHD or a long-term clinical tolerance to cGvHD. Results: Our results showed a significantly lower expression of NOTCH components in both groups that received allo-HCT, independently of their cGvHD status, when compared to healthy controls. Conclusion: Moreover, there were no differences in gene expression levels between the active cGvHD and clinically tolerant groups. To our knowledge, this is one of the first studies performed in human primary samples and our data indicate that much remains to be learned regarding NOTCH signaling as a new regulator of GvHD.

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OBJECTIVE: Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is insufficient. The purpose of this study was to explore the toxic effects and potential mechanism of action of trastuzumab on cardiomyocytes. METHOD: Human Cardiomyocyte (HCM) viability was assessed using the MTT method. HCM apoptosis was detected using the Hoechst33342/PI Fluorescent staining. The LDH and CK activities of the cell were measured using commercially available LDH and CK assay kits. The expression levels of Notch2, JAK2, STAT3, cleaved caspase 3, bax, and bcl 2 in HCMs were detected using western blotting. RESULTS: The results showed that 250 mg/L trastuzumab induced cardiomyocyte injury and apoptosis, inhibited viability, activated the Notch2 receptor, and inhibited JAK2/STAT3 expression in HCM. Inhibition of Notch2 expression in HCM by targeted siNotch2 transfection reversed the trastuzumab-induced injury and apoptosis, and the expression of JAK2/STAT3 returned to normal levels. CONCLUSIONS: Trastuzumab induces Notch2 expression by inhibiting the JAK2/STAT3 pathway of HCMs, promotes cell apoptosis, and causes cardiomyocyteinjury. Notch2 may be a potential target of trastuzumab-inducedmyocardial injury. This experiment reveals the mechanism of trastuzumab-induced cardiotoxicity, providing a theoretical basis for the application of trastuzumab.

Assuntos

Cardiotoxicidade , Miócitos Cardíacos , Humanos , Miócitos Cardíacos/metabolismo , Trastuzumab/efeitos adversos , Trastuzumab/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Receptor Notch2/metabolismo , Apoptose , Janus Quinase 2/metabolismo , Janus Quinase 2/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/farmacologia

RESUMO

Gastrointestinal epithelial cells respond to milk-born molecules throughout breastfeeding, influencing growth, and development. The rapid renewal of the small intestine depends on the proliferation in the crypt that drives cell fates. We used early weaning model to investigate immediate and late effects of breastfeeding on proliferation, differentiation of jejunal epithelial cells. Wistar rats were either allowed to suckle (S) until 21 postnatal days or submitted to early weaning (EW) at 15 days. By comparing ages (18, 60, and 120 days), we found that EW decreased Ki67 indices and villi height at 18 and 60 days (p < 0.05), and at 120 days they were similar between diets. Proliferative reduction and augmented expression of Cdkn1b (p27 gene) were parallel. In the stem cell niche, EW increased the number and activity (Defa24) of Paneth cells at 18 and 60 days (p < 0.05), and Lgr5 and Ascl2 genes showed inverted responses between ages. Among target cells, EW decreased goblet cell number at 18 and 60 days (p < 0.05) and increased it at 120 days (p < 0.05), whereas enteroendocrine marker genes were differentially altered. EW reduced enterocytes density at 18 days (p < 0.05), and at 120 days this population was decreased (vs. 60 days). Among cell fate crypt-controlling genes, Notch and Atoh1 were the main targets of EW. Metabolically, intraperitoneal glucose tolerance was immediately reduced (18 days), being reverted until 120 days (p < 0.05). Currently, we showed that breastfeeding has a lifespan influence on intestinal mucosa and on its stem cell compartment. We suggest that, although jejunum absorptive function is granted after early weaning, the long lasting changes in gene expression might prime the mucosa with a different sensitivity to gut disorders that still have to be further explored.

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Aim: The aim of the study was to calculate the most important parameters of ulna and to determine its gender. Classifying trochlear notch joint surface types and to establish their representation in Serbian population. To determine the ideal position for olecranon osteotomy. Material and methods: The study included 69 bones. Gender determination was performed using digital scale and photographs of the ulna. The bones weight, maximum and physiological length were measured. The place for the ideal position of olecranon osteotomy (projection of the bare area on its posterior wall) was determined on profile images. Results: Gender related, 45 (65.21%) bones belonged to males, 24 (34.79%) ulnas belonged to females. Type I of the bare area was present in 38 (55%) ulnas, type II in 20 (29%), whereas type III was present in 11 (16%) bones. The average value for the ideal position of olecranon osteotomy was 23.02 mm. In males' ulnas, it was 23.22 mm, in females, it was 22.59 mm. Conclusion: Type I of the bare area is the most common type of trochlear notch joint surface in Serbian population. The average value for the ideal position of olecranon osteotomy was 23.02 mm. We believe that a uniform name for the bare area should be established.

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Objetivos: Calcular los parámetros más importantes del cúbito y determinar su género. Clasificar los tipos de superficie de la articulación de la escotadura troclear y establecer su representación en la población serbia. Determinación de la posición ideal para la osteotomía del olécranon. Material y métodos: El estudio incluyó 69 huesos. La determinación del sexo se realizó mediante escala digital y fotografías del cúbito. Se midió el peso de los huesos, la longitud máxima y fisiológica. El lugar para la posición ideal de la osteotomía del olécranon se determinó en imágenes de perfil. Resultados: Relacionado con el género, 45 (65.21%) huesos pertenecían a hombres, 24 (34.79%) cúbitos pertenecían a mujeres. El tipo I del área descubierta estuvo presente en 38 (55%) ulna, el tipo II en 20 (29%), mientras que el tipo III estuvo presente en 11 (16%) huesos. El valor medio para la posición ideal de la osteotomía del olécranon fue de 23,02 mm. Conclusión: El área desnuda tipo I es el tipo más frecuente de superficie articular de muesca troclear en la población serbia. El valor promedio para la posición ideal de la osteotomía del olécranon fue de 23,02 mm. Creemos que se debe establecer un nombre uniforme para el área descubierta.

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Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke. Despite being the most prevalent vascular hereditary disease, clinical data regarding the Brazilian population are scarce. Considering that the Brazilian population has one of the most heterogeneous genetic constitutions in the world, knowledge about genetic and epidemiological profiles is mandatory. The present study aimed to elucidate the epidemiological and clinical features of CADASIL in Brazil. Methods We performed a case series study comprising 6 rehabilitation hospitals in Brazil and reported the clinical and epidemiological data from the medical records of patients admitted from 2002 to 2019 with genetic confirmation. Results We enrolled 26 (16 female) patients in whom mutations in exons 4 and 19 were the most common. The mean age at the onset of the disease was of 45 years. Ischemic stroke was the first cardinal symptom in 19 patients. Cognitive impairment, dementia, and psychiatric manifestations were detected in 17, 6, and 16 patients respectively. In total, 8 patients had recurrent migraines, with aura in 6 (75%) of them. White matter hyperintensities in the temporal lobe and the external capsule were found in 20 (91%) and 15 patients (68%) respectively. The median Fazekas score was of 2. Lacunar infarcts, microbleeds, and larger hemorrhages were observed in 18 (82%), 9, and 2 patients respectively. Conclusion The present is the most extensive series of Brazilian CADASIL patients published to date, and we have reported the first case of microbleeds in the spinal cord of a CADASIL patient. Most of our clinical and epidemiological data are in accordance with European cohorts, except for microbleeds and hemorrhagic strokes, for which rates fall in between those of European and Asian cohorts.

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Resumo Antecedentes Arteriopatia cerebral autossômica dominante com enfartes subcorticais e leucoencefalopatia (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, CADASIL, em inglês) é uma causa genética de acidente vascular cerebral (AVC) isquêmico e a forma mais comum de acidente vascular cerebral não aterosclerótico. Apesar de ser a doença vascular hereditária mais prevalente que há, os dados clínicos para a população brasileira são escassos. Considerando que o Brasil tem uma das constituições genéticas mais heterogêneas do mundo, o conhecimento sobre perfis genéticos e epidemiológicos é obrigatório. Este estudo teve como objetivo elucidar as características clínicas e epidemiológicas de pacientes com CADASIL no Brasil. Métodos Apresentamos uma série de casos envolvendo 6 hospitais de reabilitação no Brasil, e relatamos dados clínicos e epidemiológicos de prontuários de pacientes admitidos entre 2002 e 2019 com confirmação genética. Resultados incluímos 26 pacientes (16 mulheres) em que as mutações nos éxons 4 e 19 eram as mais comuns. A idade média de início da doença foi de 45 anos. O AVC isquêmico foi o primeiro sintoma cardinal em 19 pacientes. Comprometimento cognitivo, demência e manifestações psiquiátricas foram detectados em 17, seis e 16 pacientes, respectivamente. Ao todo, 8 pacientes apresentavam enxaqueca, sendo com aura em 6 (75%) pacientes. Hiperintensidades de substância branca no polo temporal e na cápsula externa foram encontradas em 20 (91%) e 15 pacientes (68%), respectivamente. A pontuação mediana na escala de Fazekas foi de 2. Infartos lacunares, microssangramentos e macro-hemorragias foram observadas em 18 (82%), 9 (41%) e 2 (9%) pacientes, respectivamente. Conclusão O presente estudo representa a mais extensa série de pacientes brasileiros com CADASIL publicada até o momento, e relatamos o primeiro caso de micro-hemorragia na medula espinhal de um paciente com CADASIL. A maior parte dos nossos dados clínicos e epidemiológicos está de acordo com as coortes europeias, exceto para micro-hemorragias e macro-hemorragias, para as quais as taxas se enquadram entre as das coortes europeias e asiáticas.

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BACKGROUND: The events of bone formation and osteoblast/titanium (Ti) interactions may be affected by Hedgehog and Notch signalling pathways. Herein, we investigated the effects of modulation of these signalling pathways on osteoblast differentiation caused by the nanostructured Ti (Ti-Nano) generated by H2SO4/H2O2. METHODS: Osteoblasts from newborn rat calvariae were cultured on Ti-Control and Ti-Nano in the presence of the Hedgehog agonist purmorphamine or antagonist cyclopamine and of the Notch antagonist N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) or agonist bexarotene. Osteoblast differentiation was evaluated by alkaline phosphatase activity and mineralization, and the expression of Hedgehog and Notch receptors was also evaluated. RESULTS: In general, purmorphamine and DAPT increased while cyclopamine and bexarotene decreased osteoblast differentiation and regulated the receptor expression on both Ti surfaces, with more prominent effects on Ti-Nano. The purmorphamine and DAPT combination exhibited synergistic effects on osteoblast differentiation that was more intense on Ti-Nano. CONCLUSION: Our results indicated that the Hedgehog and Notch signalling pathways drive osteoblast/Ti interactions more intensely on nanotopography. We also demonstrated that combining Hedgehog activation with Notch inhibition exhibits synergistic effects on osteoblast differentiation, especially on Ti-Nano. The uncovering of these cellular mechanisms contributes to create strategies to control the process of osseointegration based on the development of nanostructured surfaces.

RESUMO

PURPOSE: The hypoxic tumor microenvironment and the maintenance of stem cells are relevant to the malignancy of prostate cancer (PCa). However, whether HIF-1α in the hypoxic microenvironment mediates the transformation of prostate cancer to a stem cell phenotype and the mechanism have not been elucidated. MATERIALS AND METHODS: Prostate cancer stem cells (PCSCs) from PC-3 cell lines were examined for the expression of CD44, CD133, ALDH1, HIF-1α, Notch1, and HES1. We observed the effect of knockdown HIF-1α in vitro and mice models and evaluated the impact of HIF-1α on the Notch1 pathway as well as stem cell dedifferentiation. The effects on sphere formation, cell proliferation, apoptosis, cell cycle, and invasive metastasis were evaluated. RESULTS: In our study, hypoxia upregulated HIF-1α expression and induced a stem cell phenotype through activation of the Notch1 pathway, leading to enhanced proliferation, invasion, and migration of PCa PC-3 cells. The knockdown of HIF-1α significantly inhibited cell dedifferentiation and the ability to proliferate, invade and metastasize. However, the inhibitory effect of knocking down HIF-1α was reversed by Jagged1, an activator of the Notch1 pathway. These findings were further confirmed in vivo, where hypoxia could enhance the tumorigenicity of xenograft tumors by upregulating the expression of HIF-1α to activate the Notch1 pathway. In addition, the expression of HIF-1α and Notch1 was significantly increased in human PCa tissues, and high expression of HIF-1α correlated with the malignancy of PCa. CONCLUSION: In a hypoxic environment, HIF-1α promotes PCa cell dedifferentiation to stem-like cell phenotypes by activating the Notch1 pathway and enhancing the proliferation and invasive capacity of PC-3 cells.

Assuntos

Subunidade alfa do Fator 1 Induzível por Hipóxia , Próstata , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias da Próstata/patologia , Transdução de Sinais , Microambiente Tumoral

RESUMO

BACKGROUND: The study of the tentorial notch can improve the understanding of brain injury mechanisms. Tentorial morphology has been analysed primarily in cadaveric studies. However, the postmortem effect can cause variability in the measurements. The objective was to evaluate the morphometry of the tentorial notch and the third cranial nerve on living subjects using magnetic resonance imaging (MRI). MATERIALS AND METHODS: A retrospective cross-sectional study was performed. Using consecutive cases, 60 MRI scans were analysed for tentorial notch morphology. Maximum notch width (MNW), notch length (NL), interpedunculoclival (IC) distance, apicotectal (AT) distance, third cranial nerve (CN-III) distance, and inter- CN-III angle, were obtained. For the classification of the tentorial notch quartile distribution technique for MNW, NL, AT distance, and IC distance were used. RESULTS: According to the quartile of the MNW, patients were stratified into narrow, midrange, and wide groups. Using the NL quartile groups, they were also classified as short, midrange, and long. With these, the tentorial notch could be classified into eight types. Statistical differences between genders in the MNW and inter-CN-III angle were found, as well as a strong positive correlation between NL and AT distance, and between right and left CN-III distances. CONCLUSIONS: There were differences between the cadaveric samples and living subjects in the CN-III distances. This difference could be explained by the dehydration of brain volume in the postmortem process which may cause nerve elongation. Morphometry of the tentorial notch and its neurovascular relations allows a better understanding of the mechanisms of brain herniation.

Assuntos

Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Estudos Retrospectivos , Estudos Transversais , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Cadáver

RESUMO

INTRODUCTION: Chronic graft-versus-host disease (cGvHD) not only remains the main cause of late mortality after allogeneic hematopoietic cell transplant, but also has the capacity of causing severe organ impairment in those who survive. The Notch, a highly conserved ligand-receptor pathway, is involved in many immunological processes, including inflammatory and regulatory responses. Recently, mouse models have shown that the blockage of canonical Notch signaling prevents GvHD. OBJECTIVE AND METHOD: Due to the lack of data on the Notch pathway in human chronic GvHD, we sought to study the expression of NOTCH components in primary samples of patients who received allo-HCT and presented active cGvHD or a long-term clinical tolerance to cGvHD. RESULTS: Our results showed a significantly lower expression of NOTCH components in both groups that received allo-HCT, independently of their cGvHD status, when compared to healthy controls. CONCLUSION: Moreover, there were no differences in gene expression levels between the active cGvHD and clinically tolerant groups. To our knowledge, this is one of the first studies performed in human primary samples and our data indicate that much remains to be learned regarding NOTCH signaling as a new regulator of GvHD.