RESUMO
The pancreatic islets of Langerhans regulate glucose homeostasis. The loss of insulin-producing ß cells within islets results in diabetes, and islet transplantation from cadaveric donors can cure the disease. In vitro production of whole islets, not just ß cells, will benefit from a better understanding of endocrine differentiation and islet morphogenesis. We used single-cell mRNA sequencing to obtain a detailed description of pancreatic islet development. Contrary to the prevailing dogma, we find islet morphology and endocrine differentiation to be directly related. As endocrine progenitors differentiate, they migrate in cohesion and form bud-like islet precursors, or "peninsulas" (literally "almost islands"). α cells, the first to develop, constitute the peninsular outer layer, and ß cells form later, beneath them. This spatiotemporal collinearity leads to the typical core-mantle architecture of the mature, spherical islet. Finally, we induce peninsula-like structures in differentiating human embryonic stem cells, laying the ground for the generation of entire islets in vitro.
Assuntos
Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/embriologia , Animais , Diferenciação Celular , Células Cultivadas , Células-Tronco Embrionárias Humanas/citologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Ilhotas Pancreáticas/metabolismo , Transplante das Ilhotas Pancreáticas/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Morfogênese , Pâncreas/citologiaRESUMO
The recent discovery that genetically modified α cells can regenerate and convert into ß-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-ß-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into ß-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated ß-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in ß-like cell counts, suggestive of α-to-ß-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated ß-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Células Secretoras de Glucagon/citologia , Células Secretoras de Insulina/citologia , Ácido gama-Aminobutírico/administração & dosagem , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Células Secretoras de Glucagon/efeitos dos fármacos , Humanos , Ilhotas Pancreáticas/citologia , Masculino , Camundongos , Proteínas do Tecido Nervoso , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/farmacologiaRESUMO
Type 1 diabetes is characterized by the destruction of pancreatic ß cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types, including glucagon-producing α cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of α cells to functional ß-like cells. Here, we identify artemisinins as small molecules that functionally repress Arx by causing its translocation to the cytoplasm. We show that the protein gephyrin is the mammalian target of these antimalarial drugs and that the mechanism of action of these molecules depends on the enhancement of GABAA receptor signaling. Our results in zebrafish, rodents, and primary human pancreatic islets identify gephyrin as a druggable target for the regeneration of pancreatic ß cell mass from α cells.
Assuntos
Artemisininas/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Modelos Animais de Doenças , Receptores de GABA-A/metabolismo , Transdução de Sinais , Animais , Artemeter , Artemisininas/administração & dosagem , Proteínas de Transporte/metabolismo , Transdiferenciação Celular/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Perfilação da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Estabilidade Proteica/efeitos dos fármacos , Ratos , Análise de Célula Única , Fatores de Transcrição/metabolismo , Peixe-Zebra , Ácido gama-Aminobutírico/metabolismoRESUMO
The cJun NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. The mechanism of organ crosstalk is mediated by a feed-forward regulatory loop caused by JNK-regulated FGF21 autocrine signaling in adipocytes that promotes increased expression of the adipokine adiponectin and subsequent hepatic expression of the hormone FGF21. The mechanism of organ cross-talk places circulating adiponectin downstream of autocrine FGF21 expressed by adipocytes and upstream of endocrine FGF21 expressed by hepatocytes. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues.
Assuntos
Tecido Adiposo/fisiologia , Comunicação Autócrina/genética , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica/genética , Transdução de Sinais/genética , Adipócitos/metabolismo , Adiponectina/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Sistema Endócrino/metabolismo , Metabolismo Energético/genética , Retroalimentação Fisiológica/fisiologia , Fatores de Crescimento de Fibroblastos/sangue , Hepatócitos/metabolismo , Resistência à Insulina/genética , Fígado/metabolismo , MAP Quinase Quinase 4/deficiência , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , CamundongosRESUMO
Multiple transcription factors have been shown to promote pancreatic ß-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced ß-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Peixe-Zebra , Animais , Diferenciação Celular/genética , Camundongos , Organogênese/genética , Pâncreas , Peixe-Zebra/genéticaRESUMO
In animals, the brain regulates feeding behavior in response to local energy demands of peripheral tissues, which secrete orexigenic and anorexigenic hormones. Although skeletal muscle is a key peripheral tissue, it remains unknown whether muscle-secreted hormones regulate feeding. In Drosophila, we found that decapentaplegic (dpp), the homolog of human bone morphogenetic proteins BMP2 and BMP4, is a muscle-secreted factor (a myokine) that is induced by nutrient sensing and that circulates and signals to the brain. Muscle-restricted dpp RNAi promotes foraging and feeding initiation, whereas dpp overexpression reduces it. This regulation of feeding by muscle-derived Dpp stems from modulation of brain tyrosine hydroxylase (TH) expression and dopamine biosynthesis. Consistently, Dpp receptor signaling in dopaminergic neurons regulates TH expression and feeding initiation via the downstream transcriptional repressor Schnurri. Moreover, pharmacologic modulation of TH activity rescues the changes in feeding initiation due to modulation of dpp expression in muscle. These findings indicate that muscle-to-brain endocrine signaling mediated by the myokine Dpp regulates feeding behavior.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/genética , Drosophila/metabolismo , Comportamento Alimentar/fisiologia , Animais , Encéfalo/fisiologia , Proteínas de Ligação a DNA/metabolismo , Dopaminérgicos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Drosophila/enzimologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Levodopa/farmacologia , Monoiodotirosina/farmacologia , Transdução de Sinais , Fatores de Transcrição/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Regulação para CimaRESUMO
The autonomic nervous system innervates the pancreas by sympathetic, parasympathetic and sensory branches during early organogenesis, starting with neural crest cell invasion and formation of an intrinsic neuronal network. Several studies have demonstrated that signals from pancreatic neural crest cells direct pancreatic endocrinogenesis. Likewise, autonomic neurons have been shown to regulate pancreatic islet formation, and have also been implicated in type I diabetes. Here, we provide an overview of recent progress in mapping pancreatic innervation and understanding the interactions between pancreatic neurons, epithelial morphogenesis and cell differentiation. Finally, we discuss pancreas innervation as a factor in the development of diabetes.
Assuntos
Diabetes Mellitus , Ilhotas Pancreáticas , Humanos , Diferenciação Celular , Organogênese , PâncreasRESUMO
The actions of estrogens and related estrogenic molecules are complex and multifaceted in both sexes. A wide array of natural, synthetic, and therapeutic molecules target pathways that produce and respond to estrogens. Multiple receptors promulgate these responses, including the classical estrogen receptors of the nuclear hormone receptor family (estrogen receptors α and ß), which function largely as ligand-activated transcription factors, and the 7-transmembrane G protein-coupled estrogen receptor, GPER, which activates a diverse array of signaling pathways. The pharmacology and functional roles of GPER in physiology and disease reveal important roles in responses to both natural and synthetic estrogenic compounds in numerous physiological systems. These functions have implications in the treatment of myriad disease states, including cancer, cardiovascular diseases, and metabolic disorders. This review focuses on the complex pharmacology of GPER and summarizes major physiological functions of GPER and the therapeutic implications and ongoing applications of GPER-targeted compounds.
Assuntos
Estrogênios , Receptores de Estrogênio , Masculino , Feminino , Humanos , Receptores de Estrogênio/metabolismo , Estrogênios/farmacologia , Estrogênios/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Proteínas de Ligação ao GTP/metabolismoRESUMO
Estrogen receptor α (ERα) drives the transcription of genes involved in breast cancer (BC) progression, relying on coregulatory protein recruitment for its transcriptional and biological activities. Mutation of ERα as well as aberrant recruitment of its regulatory proteins contribute to tumor adaptation and drug resistance. Therefore, understanding the dynamic changes in ERα protein interaction networks is crucial for elucidating drug resistance mechanisms in BC. Despite progress in studying ERα-associated proteins, capturing subcellular transient interactions remains challenging and, as a result, significant number of important interactions remain undiscovered. In this study, we employed biotinylation by antibody recognition (BAR), an innovative antibody-based proximity labeling (PL) approach, coupled with mass spectrometry to investigate the ERα proximal proteome and its changes associated with resistance to aromatase inhibition, a key therapy used in the treatment of ERα-positive BC. We show that BAR successfully detected most of the known ERα interactors and mainly identified nuclear proteins, using either an epitope tag or endogenous antibody to target ERα. We further describe the ERα proximal proteome rewiring associated with resistance applying BAR to a panel of isogenic cell lines modeling tumor adaptation in the clinic. Interestingly, we find that ERα associates with some of the canonical cofactors in resistant cells and several proximal proteome changes are due to increased expression of ERα. Resistant models also show decreased levels of estrogen-regulated genes. Sensitive and resistant cells harboring a mutation in the ERα (Y537C) revealed a similar proximal proteome. We provide an ERα proximal protein network covering several novel ERα-proximal partners. These include proteins involved in highly dynamic processes such as sumoylation and ubiquitination difficult to detect with traditional protein interaction approaches. Overall, we present BAR as an effective approach to investigate the ERα proximal proteome in a spatial context and demonstrate its application in different experimental conditions.
Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio , Feminino , Humanos , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteoma/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/uso terapêuticoRESUMO
While important insights were gained about how FGF21 and other endocrine fibroblast growth factors (FGFs) bind to Klotho proteins, the exact mechanism of Klotho/FGF receptor assembly that drives receptor dimerization and activation has not been elucidated. The prevailing dogma is that Klotho proteins substitute for the loss of heparan sulfate proteoglycan (HSPG) binding to endocrine FGFs by high-affinity binding of endocrine FGF molecules to Klotho receptors. To explore a potential role of HSPG in FGF21 signaling, we have analyzed the dynamic properties of FGF21-induced FGF21-ßKlotho-FGFR1c complexes on the surface of living wild-type (WT) or HSPG-deficient Chinese hamster ovary (CHO) cells by employing quantitative single-molecule fluorescence imaging analyses. Moreover, detailed analyses of FGF21 and FGF1 stimulation of cellular signaling pathways activated in WT or in HSPG-deficient CHO cells are also analyzed and compared. These experiments demonstrate that heparin is required for the formation of FGF21-ßKlotho-FGFR1c complexes on the cell membrane and that binding of heparin or HSPG to FGFR1c is essential for optimal FGF21 stimulation of FGFR1c activation, mitogen-activated protein kinase responses, and intracellular Ca2+ release. It is also shown that FGF1 binding stimulates assembly of ßKlotho and FGFR1c on cell membranes, resulting in endocytosis and degradation of ßKlotho. We conclude that heparin or HSPG is essential for FGF21 signaling and for regulation of ßKlotho cellular stability by acting as a coligand of FGFR1c.
Assuntos
Proteoglicanas de Heparan Sulfato , Proteínas Klotho , Cricetinae , Animais , Células CHO , Cricetulus , Heparina , Fator 1 de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Environmental toxicants and pollutants are causes of adverse health consequences, including well-established associations between environmental exposures and cardiovascular diseases. Environmental degradation is widely prevalent and has a long latency period between exposure and health outcome, potentially placing a large number of individuals at risk of these health consequences. Emerging evidence suggests that environmental exposures in early life may be key risk factors for cardiovascular conditions across the life span. Children are a particularly sensitive population for the detrimental effects of environmental toxicants and pollutants given the long-term cumulative effects of early-life exposures on health outcomes, including congenital heart disease, acquired cardiac diseases, and accumulation of cardiovascular disease risk factors. This scientific statement highlights representative examples for each of these cardiovascular disease subtypes and their determinants, focusing specifically on the associations between climate change and congenital heart disease, airborne particulate matter and Kawasaki disease, blood lead levels and blood pressure, and endocrine-disrupting chemicals with cardiometabolic risk factors. Because children are particularly dependent on their caregivers to address their health concerns, this scientific statement highlights the need for clinicians, research scientists, and policymakers to focus more on the linkages of environmental exposures with cardiovascular conditions in children and adolescents.
Assuntos
American Heart Association , Doenças Cardiovasculares , Exposição Ambiental , Humanos , Exposição Ambiental/efeitos adversos , Estados Unidos/epidemiologia , Criança , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/epidemiologia , Cardiologia/normas , Fatores de Risco , Adolescente , Poluentes Ambientais/efeitos adversosRESUMO
In recent years, environmental epidemiology and toxicology have seen a growing interest in the environmental factors that contribute to the increased prevalence of neurodevelopmental disorders, with the purpose of establishing appropriate prevention strategies. A literature review was performed, and 192 articles covering the topic of endocrine disruptors and neurodevelopmental disorders were found, focusing on polychlorinated biphenyls, polybrominated diphenyl ethers, bisphenol A, and pesticides. This study contributes to analyzing their effect on the molecular mechanism in maternal and infant thyroid function, essential for infant neurodevelopment, and whose alteration has been associated with various neurodevelopmental disorders. The results provide scientific evidence of the association that exists between the environmental neurotoxins and various neurodevelopmental disorders. In addition, other possible molecular mechanisms by which pesticides and endocrine disruptors may be associated with neurodevelopmental disorders are being discussed.
Assuntos
Disruptores Endócrinos , Transtornos do Neurodesenvolvimento , Praguicidas , Disruptores Endócrinos/efeitos adversos , Disruptores Endócrinos/toxicidade , Humanos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/epidemiologia , Praguicidas/toxicidade , Praguicidas/efeitos adversos , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/toxicidade , Poluentes Ambientais/efeitos adversos , Fenóis/efeitos adversos , Fenóis/toxicidade , Feminino , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/toxicidade , Animais , Éteres Difenil Halogenados/toxicidade , Bifenilos Policlorados/toxicidade , Bifenilos Policlorados/efeitos adversos , GravidezRESUMO
Age-associated alterations of the hormone-secreting endocrine system cause organ dysfunction and disease states. However, the cell biology of endocrine tissue ageing remains poorly understood. Here, we perform comparative 3D imaging to understand age-related perturbations of the endothelial cell (EC) compartment in endocrine glands. Datasets of a wide range of markers highlight a decline in capillary and artery numbers, but not of perivascular cells in pancreas, testis and thyroid gland, with age in mice and humans. Further, angiogenesis and ß-cell expansion in the pancreas are coupled by a distinct age-dependent subset of ECs. While this EC subpopulation supports pancreatic ß cells, it declines during ageing concomitant with increased expression of the gap junction protein Gja1. EC-specific ablation of Gja1 restores ß-cell expansion in the aged pancreas. These results provide a proof of concept for understanding age-related vascular changes and imply that therapeutic targeting of blood vessels may restore aged endocrine tissue function. This comprehensive data atlas offers over > 1,000 multicolour volumes for exploration and research in endocrinology, ageing, matrix and vascular biology.
Assuntos
Envelhecimento/fisiologia , Sistema Endócrino/fisiologia , Células Endoteliais/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Vasos Sanguíneos , Glândulas Endócrinas/fisiologia , Feminino , Humanos , Imageamento Tridimensional/métodos , Células Secretoras de Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neovascularização Patológica/patologia , Pâncreas/fisiologia , Testículo/fisiologia , Glândula Tireoide/fisiologia , Adulto JovemRESUMO
The multifaceted interaction between coronavirus disease 2019 (COVID-19) and the endocrine system has been a major area of scientific research over the past two years. While common endocrine/metabolic disorders such as obesity and diabetes have been recognized among significant risk factors for COVID-19 severity, several endocrine organs were identified to be targeted by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). New-onset endocrine disorders related to COVID-19 were reported while long-term effects, if any, are yet to be determined. Meanwhile, the "stay home" measures during the pandemic caused interruption in the care of patients with pre-existing endocrine disorders and may have impeded the diagnosis and treatment of new ones. This review aims to outline this complex interaction between COVID-19 and endocrine disorders by synthesizing the current scientific knowledge obtained from clinical and pathophysiological studies, and to emphasize considerations for future research.
Assuntos
COVID-19 , Diabetes Mellitus , Humanos , SARS-CoV-2 , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/terapia , Fatores de RiscoRESUMO
Transgender people often face barriers in health care due to lack of access to care, lack of knowledgeable healthcare professionals, discrimination, and gaps in medical and mental health research. Existing research on transgender health has focused heavily on mental health, HIV/AIDS, sexually transmitted diseases/infections, and substance abuse. Gender-affirming hormone therapy and/or surgery allows for some alignment of biology and gender identity. Gender-affirming care may offer quality-of-life benefits, which may outweigh modest concerns related to exogenous hormone therapy. The Endocrine Society treatment guidelines were revised in 2017, and this article reviews recent data that might inform a future guideline revision. Future longitudinal research is needed to close the gap in knowledge in the field of transgender medicine.
Assuntos
Pessoas Transgênero , Humanos , Adulto , Masculino , Feminino , Pessoas Transgênero/psicologia , Identidade de Gênero , HormôniosRESUMO
Alveolar macrophages (AMs) are extremely versatile cells with complex functions involved in health or diseases such as pneumonia, asthma, and pulmonary alveolar proteinosis. In recent years, it has been widely identified that the different functions and states of macrophages are the results from the complex interplay between microenvironmental signals and macrophage lineage. Diverse and complicated signals to which AMs respond are mentioned when they are described individually or in a particular state of AMs. In this review, the microenvironmental signals are divided into autocrine, paracrine, and endocrine signals based on their secreting characteristics. This new perspective on classification provides a more comprehensive and systematic introduction to the complex signals around AMs and is helpful for understanding the roles of AMs affected by physiological environment. The existing possible treatments of AMs are also mentioned in it. The thorough understanding of AMs signals modulation may be contributed to the development of more effective therapies for AMs-related lung diseases.
Assuntos
Asma , Pneumopatias , Proteinose Alveolar Pulmonar , Humanos , Macrófagos Alveolares , MacrófagosRESUMO
BACKGROUND & AIMS: The pancreas is composed of endocrine and exocrine parts, and its interlacing structure indicates potential interaction between endocrine and exocrine cells. Although the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) has been well characterized, the role of pancreatic endocrine cells during carcinogenesis is relatively understudied. METHODS: The changes of endocrine cells in PDAC by single-cell transcriptome sequencing, spatial transcriptome sequencing, and multiplex immunohistochemistry were depicted. After that, the interaction between pancreatic carcinogenesis and endocrine changes was explored in orthotopic transplantation mice, KrasLSL-G12DPdx1-Cre mice, and KrasLSL-G12Dp53LoxPPdx1-CreER mice. Finally, we proved the mechanism of the interaction between endocrine and exocrine parts of the pancreas through islet isolation, co-culture in vitro and co-injection in vivo. RESULTS: Pancreatic endocrine cells displayed significantly different transcriptomic characteristics and increased interaction with exocrine part in PDAC. Specifically, among all of the changes, pancreatic polypeptide-positive cells showed a sharp increment accompanied by the progression of the cancer lesion, which might be derived from the transdifferentiation of α and ß cells. Interestingly, it was proved that PDAC cells were able to induce the transdifferentiation of pancreatic α cells and ß cells into glucagon-pancreatic polypeptide and insulin-pancreatic polypeptide double-positive cells, which further promoted carcinogenesis and development of PDAC in a paracrine-dependent manner and formed a reciprocal interaction. CONCLUSIONS: This study systematically maps the alteration of pancreatic endocrine cells in PDAC and elucidates the potential endocrine-exocrine interaction mechanisms during PDAC carcinogenesis. In addition, cancer-associated endocrine cells are defined and characterized, thereby further broadening the composition of PDAC microenvironment.
RESUMO
As pancreatic cyst incidence rises, likely due to the ubiquitous increase in cross-sectional imaging, their management presents multiple challenges for both the practitioner and patient. It is critical that all pancreatic cysts are appropriately characterized, as treatment decisions depend on an accurate diagnosis. Diagnostic modalities such as cytology, biopsy, and cyst fluid biomarkers allow for definitive diagnosis of virtually all lesions. Some cysts, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and cystic pancreatic endocrine neoplasms, have malignant potential and must be surveyed. Other cysts, such as serous cystadenomas and pancreatic fluid collections, do not have malignant potential. Surveillance strategies vary widely depending on cyst type and size and while multiple medical societies advocate surveillance, their published surveillance guidelines are heterogenous. Cysts with high-risk stigmata or worrisome features are usually resected, depending on the patient's surgical fitness. In patients unfit for resection, newer endoscopic ablative techniques are advocated. Controversial aspects regarding cyst management include whether surveillance can be stopped, how surveillance should be performed, and the extensive financial burden cyst management places on the health care system. Further study into the natural history of cystic lesions, including definitive determination of the rate of malignant transformation for each cyst type, is essential.
Assuntos
Cisto Pancreático , Humanos , Cisto Pancreático/terapia , Cisto Pancreático/diagnóstico , Cisto Pancreático/patologia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Conduta Expectante , Endossonografia , Valor Preditivo dos Testes , BiópsiaRESUMO
Imprinting control region (ICR1) controls the expression of the Igf2 and H19 genes in a parent-of-origin specific manner. Appropriate expression of the Igf2-H19 locus is fundamental for normal fetal development, yet the importance of ICR1 in the placental production of hormones that promote maternal nutrient allocation to the fetus is unknown. To address this, we used a novel mouse model to selectively delete ICR1 in the endocrine junctional zone (Jz) of the mouse placenta (Jz-ΔICR1). The Jz-ΔICR1 mice exhibit increased Igf2 and decreased H19 expression specifically in the Jz. This was accompanied by an expansion of Jz endocrine cell types due to enhanced rates of proliferation and increased expression of pregnancy-specific glycoprotein 23 in the placenta of both fetal sexes. However, changes in the endocrine phenotype of the placenta were related to sexually-dimorphic alterations to the abundance of Igf2 receptors and downstream signalling pathways (Pi3k-Akt and Mapk). There was no effect of Jz-ΔICR1 on the expression of targets of the H19-embedded miR-675 or on fetal weight. Our results demonstrate that ICR1 controls placental endocrine capacity via sex-dependent changes in signalling.
Assuntos
Glândulas Endócrinas/metabolismo , Fator de Crescimento Insulin-Like II/genética , Região de Controle de Locus Gênico , Placenta/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Animais , Feminino , Loci Gênicos , Impressão Genômica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Gravidez , Proteínas da Gravidez/genética , Proteínas da Gravidez/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismoRESUMO
Estrogens are well-known to regulate development of sexual dimorphism of the brain; however, their role in embryonic brain development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs from early neurogenesis specifically in a type of glia in the olfactory bulb (OB), which we name estrogen-responsive olfactory bulb (EROB) cells. In response to estrogen, EROB cells overlay the outermost layer of the OB and interact tightly with olfactory sensory neurons at the olfactory glomeruli. Inhibiting estrogen activity using an estrogen receptor antagonist, ICI182,780 (ICI), and/or EROB cell ablation impedes olfactory glomerular development, including the topological organisation of olfactory glomeruli and inhibitory synaptogenesis in the OB. Furthermore, activation of estrogen signalling inhibits both intrinsic and olfaction-dependent neuronal activity in the OB, whereas ICI or EROB cell ablation results in the opposite effect on neuronal excitability. Altering the estrogen signalling disrupts olfaction-mediated behaviour in later larval stage. We propose that estrogens act on glia to regulate development of OB circuits, thereby modulating the local excitability in the OB and olfaction-mediated behaviour.