RESUMO
Autophagy, a conserved cellular degradation process, is crucial for various cellular processes such as immune responses, inflammation, metabolic and oxidative stress adaptation, cell proliferation, development, and tissue repair and remodeling. Dysregulation of autophagy is suspected in numerous diseases, including cancer, neurodegenerative diseases, digestive disorders, metabolic syndromes, and infectious and inflammatory diseases. If autophagy is disrupted, for example, this can have serious consequences and lead to chronic inflammation and tissue damage, as occurs in diseases such as Chron's disease and ulcerative colitis. On the other hand, the influence of autophagy on the development and progression of cancer is not clear. Autophagy can both suppress and promote the progression and metastasis of cancer at various stages. From inflammatory bowel diseases to gastrointestinal cancer, researchers are discovering the intricate role of autophagy in maintaining gut health and its potential as a therapeutic target. Researchers should carefully consider the nature and progression of diseases such as cancer when trying to determine whether inhibiting or stimulating autophagy is likely to be beneficial. Multidisciplinary approaches that combine cutting-edge research with clinical expertise are key to unlocking the full therapeutic potential of autophagy in digestive diseases.
Assuntos
Autofagia , Doenças do Sistema Digestório , Humanos , Autofagia/efeitos dos fármacos , Doenças do Sistema Digestório/metabolismo , Doenças do Sistema Digestório/patologia , Doenças do Sistema Digestório/terapia , Doenças do Sistema Digestório/fisiopatologia , Doenças do Sistema Digestório/imunologia , Animais , Progressão da DoençaRESUMO
Protein ubiquitination is an enzymatic cascade reaction and serves as an important protein post-translational modification (PTM) that is involved in the vast majority of cellular life activities. The key enzyme in the ubiquitination process is E3 ubiquitin ligase (E3), which catalyzes the binding of ubiquitin (Ub) to the protein substrate and influences substrate specificity. In recent years, the relationship between the subfamily of neuron-expressed developmental downregulation 4 (NEDD4), which belongs to the E3 ligase system, and digestive diseases has drawn widespread attention. Numerous studies have shown that NEDD4 and NEDD4L of the NEDD4 family can regulate the digestive function, as well as a series of related physiological and pathological processes, by controlling the subsequent degradation of proteins such as PTEN, c-Myc, and P21, along with substrate ubiquitination. In this article, we reviewed the appropriate functions of NEDD4 and NEDD4L in digestive diseases including cell proliferation, invasion, metastasis, chemotherapeutic drug resistance, and multiple signaling pathways, based on the currently available research evidence for the purpose of providing new ideas for the prevention and treatment of digestive diseases.
Assuntos
Ubiquitina-Proteína Ligases Nedd4 , Ubiquitinação , Humanos , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Ubiquitina-Proteína Ligases Nedd4/genética , Doenças do Sistema Digestório/metabolismo , Doenças do Sistema Digestório/patologia , Animais , Transdução de Sinais , Proliferação de Células , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
BMS-986020, BMS-986234 and BMS-986278, are three lysophosphatidic acid receptor 1 (LPA1) antagonists that were or are being investigated for treatment of idiopathic pulmonary fibrosis (IPF). Hepatobiliary toxicity (elevated serum AST, ALT, and ALP, plasma bile acids [BAs], and cholecystitis) was observed in a Phase 2 clinical trial with BMS-986020, and development was discontinued. In dogs and rats, the species used for the pivotal toxicology studies, there was no evidence of hepatobiliary toxicity in the dog while findings in the rat were limited to increased plasma BAs levels (6.1× control), ALT (2.9×) and bilirubin (3.4×) with no histopathologic correlates. Since neither rats nor dogs predicted clinical toxicity, follow-up studies in cynomolgus monkeys revealed hepatobiliary toxicity that included increased ALT (2.0× control) and GLDH (4.9×), bile duct hyperplasia, cholangitis, cholestasis, and cholecystitis at clinically relevant BMS-986020 exposures with no changes in plasma or liver BAs. This confirmed monkey as a relevant species for identifying hepatobiliary toxicity with BMS-986020. In order to assess whether the toxicity was compound-specific or related to LPA1 antagonism, two structurally distinct LPA1 antagonists (BMS-986234 and BMS-986278), were evaluated in rat and monkey. There were no clinical or anatomic pathology changes indicative of hepatobiliary toxicity. Mixed effects on plasma BAs in both rat and monkey has made this biomarker not a useful predictor of the hepatobiliary toxicity. In conclusion, the nonclinical data indicate the hepatobiliary toxicity observed clinically and in monkeys administered BMS-986020 is compound specific and not mediated via antagonism of LPA1.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doenças do Sistema Digestório/induzido quimicamente , Fígado/efeitos dos fármacos , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Animais , Ácidos e Sais Biliares/sangue , Bilirrubina/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doenças do Sistema Digestório/sangue , Doenças do Sistema Digestório/metabolismo , Cães , Feminino , Haplorrinos , Fígado/metabolismo , Hepatopatias/sangue , Hepatopatias/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Ferroptosis, a newly described type of iron-dependent programmed cell death that is distinct from apoptosis, necroptosis, and other types of cell death, is involved in lipid peroxidation (LP), reactive oxygen species (ROS) production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for ferroptosis in multiple diseases, including acute kidney injury, cancer, hepatic fibrosis, Parkinson's disease, and Alzheimer's disease. Therefore, ferroptosis has become one of the research hotspots for disease treatment and attracted extensive attention in recent years. This review mainly summarizes the relationship between ferroptosis and various diseases classified by the system, including the urinary system, digestive system, respiratory system, nervous system. In addition, the role and molecular mechanism of multiple inhibitors and inducers for ferroptosis are further elucidated. A deeper understanding of the relationship between ferroptosis and multiple diseases may provide new strategies for researching diseases and drug development based on ferroptosis.
Assuntos
Doenças do Sistema Digestório/metabolismo , Ferroptose , Doenças do Sistema Nervoso/metabolismo , Doenças Urológicas/metabolismo , Doenças do Sistema Digestório/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Terapia de Alvo Molecular , Doenças do Sistema Nervoso/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Doenças Urológicas/tratamento farmacológicoRESUMO
Several evidence suggests that, in addition to the respiratory tract, also the gastrointestinal tract is a main site of severe acute respiratory syndrome CoronaVirus 2 (SARS-CoV-2) infection, as an example of a multi-organ vascular damage, likely associated with poor prognosis. To assess mechanisms SARS-CoV-2 responsible of tissue infection and vascular injury, correlating with thrombotic damage, specimens of the digestive tract positive for SARS-CoV-2 nucleocapsid protein were analyzed deriving from three patients, negative to naso-oro-pharyngeal swab for SARS-CoV-2. These COVID-19-negative patients came to clinical observation due to urgent abdominal surgery that removed different sections of the digestive tract after thrombotic events. Immunohistochemical for the expression of SARS-CoV-2 combined with a panel of SARS-CoV-2 related proteins angiotensin-converting enzyme 2 receptor, cluster of differentiation 147 (CD147), human leukocyte antigen-G (HLA-G), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 was performed. Tissue samples were also evaluated by electron microscopy for ultrastructural virus localization and cell characterization. The damage of the tissue was assessed by ultrastructural analysis. It has been observed that CD147 expression levels correlate with SARS-CoV-2 infection extent, vascular damage and an increased expression of VEGF and thrombosis. The confirmation of CD147 co-localization with SARS-CoV-2 Spike protein binding on gastrointestinal tissues and the reduction of the infection level in intestinal epithelial cells after CD147 neutralization, suggest CD147 as a possible key factor for viral susceptibility of gastrointestinal tissue. The presence of SARS-CoV-2 infection of gastrointestinal tissue might be consequently implicated in abdominal thrombosis, where VEGF might mediate the vascular damage.
Assuntos
Basigina/metabolismo , COVID-19/complicações , Doenças do Sistema Digestório/patologia , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/metabolismo , Trombose/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Basigina/genética , COVID-19/virologia , Doenças do Sistema Digestório/genética , Doenças do Sistema Digestório/metabolismo , Doenças do Sistema Digestório/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Glicoproteína da Espícula de Coronavírus/genética , Trombose/genética , Trombose/metabolismo , Trombose/virologia , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid screening of drug candidates. This review attempts to summarize recent strategies for specification of iPSCs towards hepatobiliary lineages -hepatocytes and cholangiocytes-and their use as platforms for disease modeling and drug testing. The application of different tissue-engineering methods to promote accurate and reliable readouts is discussed. Space is given to open questions, including to what extent these novel systems can be informative. Potential pathways for improvement are finally suggested.
Assuntos
Técnicas de Reprogramação Celular/métodos , Doenças do Sistema Digestório/terapia , Descoberta de Drogas/métodos , Hepatócitos/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Medicina de Precisão/métodos , Animais , Linhagem da Célula , Doenças do Sistema Digestório/metabolismo , Doenças do Sistema Digestório/patologia , Hepatócitos/metabolismo , Humanos , Engenharia Tecidual/métodosRESUMO
Autophagy is a process of degradation and catabolism in cells. By removing damaged or dysfunctional organelles, autophagy interacts with the ubiquitinproteasome degradation system to jointly regulate cell function and energy homeostasis. Since autophagy plays a key role in physiology, disorders of the autophagy mechanism are associated with various diseases. Therefore, thorough understanding of the autophagy regulatory mechanism are crucially important in the diagnosis and treatment of diseases. To date, ion channels may affect the development and treatment of diseases by regulating autophagy, especially calciumpermeable ion channels, in the process of digestive system diseases. However, the mechanism by which calcium ions and their channels regulate autophagy is still poorly understood, thus emphasizing the need for further research in this field. The present review intends to discuss the association, mechanism and application of calcium ions, their channels and autophagy in the occurrence and development of digestive system diseases.
Assuntos
Autofagia/fisiologia , Canais de Cálcio/metabolismo , Cálcio/metabolismo , Doenças do Sistema Digestório/metabolismo , Íons/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Homeostase , Humanos , Canais Iônicos/fisiologia , Ubiquitina/metabolismoRESUMO
The food industry is constantly shifting focus based on prebiotics as health-promoting substrates rather than just food supplements. A prebiotic is "a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well-being and health." Prebiotics exert a plethora of health-promoting effects, which has lead to the establishment of multimillion food and pharma industries. The following are the health benefits attributed to prebiotics: mineral absorption, better immune response, increased resistance to bacterial infection, improved lipid metabolism, possible protection against cancer, relief from poor digestion of lactose, and reduction in the risk of diseases such as intestinal disease, non-insulin-dependent diabetes, obesity and allergy. Numerous studies in both animals and humans have demonstrated the health benefits of prebiotics.
Assuntos
Carboidratos da Dieta/administração & dosagem , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/fisiologia , Metabolismo dos Lipídeos/fisiologia , Prebióticos/administração & dosagem , Animais , Carboidratos/administração & dosagem , Doenças do Sistema Digestório/metabolismo , Doenças do Sistema Digestório/terapia , Humanos , Neoplasias/metabolismo , Neoplasias/terapia , Oligossacarídeos/administração & dosagemRESUMO
BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) had become a big threat worldwide. Liver injury is not uncommon in patients with COVID-19, and clarifying its characteristics is needed. This study aimed to identify factors associated with liver injury and to develop a new classification of predictive severity in patients with COVID-19. METHODS: Confirmed patients with COVID-19 (n = 60) were recruited retrospectively from Musashino Red Cross Hospital. The factors of liver injury especially on the elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed. Grading was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: During a median hospitalization follow-up of 15 (4-41) days, 51 (85.0%) patients had COVID-19 pneumonia. In clinical courses, oxygenation was needed for 25 (41.6%) patients and intubation was needed for 9 (15.0%) patients. A total of 27 (45.0%) patients had gastrointestinal symptoms (GS), such as appetite loss, diarrhea, and nausea. A logistic regression analysis revealed that C-reactive protein (CRP) at baseline, oxygenation, intubation, and GS were significant factors of liver injury. Based on these results, patients were classified into three groups: group 1, no oxygenation pneumonia; group 2, pneumonia with oxygenation or GS; and group 3, intubation. We classified 25 (41.7%), 26 (43.3%), and 9 (15.0%) patients into mild, moderate, and severe groups, respectively. The peak of AST and ALT levels was significantly stratified with this criteria (mild [median AST, 28 IU/L; median ALT, 33 IU/L], moderate [median AST, 48 IU/L; median ALT, 47.5 IU/L], and severe [median AST, 109 IU/L; median ALT, 106 IU/L]; P<0.001 and P = 0.0114, respectively). CONCLUSION: COVID-19-related liver injury was significantly stratified based on GS and severity of pneumonia.
Assuntos
Infecções por Coronavirus/patologia , Doenças do Sistema Digestório/patologia , Doenças do Sistema Digestório/virologia , Hepatopatias/patologia , Hepatopatias/virologia , Pneumonia Viral/patologia , Pneumonia/patologia , Pneumonia/virologia , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Proteína C-Reativa/metabolismo , COVID-19 , Doenças do Sistema Digestório/metabolismo , Feminino , Seguimentos , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia/metabolismo , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.
Assuntos
Adipocinas/metabolismo , Adipocinas/fisiologia , Doenças do Sistema Digestório/metabolismo , Adipócitos/metabolismo , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Biomarcadores/metabolismo , Sistema Digestório/metabolismo , Sistema Digestório/patologia , Doenças do Sistema Digestório/fisiopatologia , Homeostase , Humanos , Inflamação/metabolismo , Leptina/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismoAssuntos
Infecções por Coronavirus/fisiopatologia , Doenças do Sistema Digestório/fisiopatologia , Pneumonia Viral/fisiopatologia , Dor Abdominal/etiologia , Dor Abdominal/metabolismo , Dor Abdominal/fisiopatologia , Dor Abdominal/terapia , Assistência Ambulatorial , Anorexia/etiologia , Anorexia/metabolismo , Anorexia/fisiopatologia , Anorexia/terapia , Antibacterianos/efeitos adversos , Antipiréticos/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus , COVID-19 , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , China , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/tratamento farmacológico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/terapia , Diarreia/etiologia , Diarreia/metabolismo , Diarreia/fisiopatologia , Diarreia/terapia , Doenças do Sistema Digestório/etiologia , Doenças do Sistema Digestório/metabolismo , Doenças do Sistema Digestório/terapia , Endoscopia do Sistema Digestório , Gastroenterologia , Humanos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Náusea/etiologia , Náusea/metabolismo , Náusea/fisiopatologia , Náusea/terapia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/terapia , Probióticos/uso terapêutico , SARS-CoV-2 , Sociedades Médicas , Vômito/etiologiaRESUMO
Metaproteomics, as a subfield of proteomics, has quickly emerged as a pivotal tool for global characterization of a microbiome system at a functional level. It has been increasingly applied in studying human digestive and metabolic diseases, and provides information-rich data to identify the dysbiosis of human gut microbiome related to healthy or disease states to elucidate the molecular events underlying host-microbiota interplays. While significant technical challenges still exist, this emerging technology has been demonstrated to provide essential information in interrogating functional changes in the human gut microbiome, complementary to metagenomics and metatranscriptomics. This chapter overviews the overall metaproteomic work flow and its recent applications in studying human gut microbiome relevant to digestive and metabolic diseases.
Assuntos
Doenças do Sistema Digestório/metabolismo , Microbioma Gastrointestinal , Doenças Metabólicas/metabolismo , Proteínas/metabolismo , Proteômica , HumanosRESUMO
The novel coronavirus disease is currently causing a major pandemic. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the Betacoronavirus genus that also includes the SARS-CoV and Middle East respiratory syndrome coronavirus. While patients typically present with fever and a respiratory illness, some patients also report gastrointestinal symptoms such as diarrhea, vomiting, and abdominal pain. Studies have identified the SARS-CoV-2 RNA in stool specimens of infected patients, and its viral receptor angiotensin converting enzyme 2 was found to be highly expressed in gastrointestinal epithelial cells. These suggest that SARS-CoV-2 can actively infect and replicate in the gastrointestinal tract. This has important implications to the disease management, transmission, and infection control. In this article, we review the important gastrointestinal aspects of the disease.
Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus , Doenças do Sistema Digestório/virologia , Sistema Digestório/virologia , Pandemias , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral , Aerossóis/efeitos adversos , Enzima de Conversão de Angiotensina 2 , Betacoronavirus/metabolismo , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/transmissão , Sistema Digestório/citologia , Sistema Digestório/metabolismo , Doenças do Sistema Digestório/metabolismo , Transmissão de Doença Infecciosa/prevenção & controle , Humanos , Controle de Infecções/métodos , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/metabolismo , Pneumonia Viral/transmissão , RNA Viral/isolamento & purificação , SARS-CoV-2RESUMO
Tight junctions (TJ) are intercellular adhesion complexes on epithelial cells and composed of integral membrane proteins as well as cytosolic adaptor proteins. Tight junction proteins have been recognized to play a key role in health and disease. In the liver, TJ proteins have several functions: they contribute as gatekeepers for paracellular diffusion between adherent hepatocytes or cholangiocytes to shape the blood-biliary barrier (BBIB) and maintain tissue homeostasis. At non-junctional localizations, TJ proteins are involved in key regulatory cell functions such as differentiation, proliferation, and migration by recruiting signaling proteins in response to extracellular stimuli. Moreover, TJ proteins are hepatocyte entry factors for the hepatitis C virus (HCV)-a major cause of liver disease and cancer worldwide. Perturbation of TJ protein expression has been reported in chronic HCV infection, cholestatic liver diseases as well as hepatobiliary carcinoma. Here we review the physiological function of TJ proteins in the liver and their implications in hepatobiliary diseases.
Assuntos
Doenças do Sistema Digestório/metabolismo , Hepacivirus/fisiologia , Proteínas de Junções Íntimas/metabolismo , Diferenciação Celular , Proliferação de Células , Doenças do Sistema Digestório/genética , Doenças do Sistema Digestório/virologia , Regulação da Expressão Gênica , Humanos , Fígado/metabolismo , Proteínas de Junções Íntimas/genética , Internalização do VírusRESUMO
Defects in the Fanconi anemia (FA) DNA damage-response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. Fancd2-/- and wildtype (WT) mice were fed a standard diet (SD), a diet enriched in fat, cholesterol, and cholic acid (Paigen diet), or a diet enriched in lipid alone (high-fat diet (HFD)). Fancd2-/- mice developed hepatobiliary disease and exhibited decreased survival when fed a Paigen diet but not a HFD. Male Paigen diet-fed mice lacking Fancd2 had significant biliary hyperplasia, increased serum bile acid concentration, and increased hepatic pathology. In contrast, female mice were similarly impacted by Paigen diet feeding regardless of Fancd2 status. Upon Paigen diet challenge, male Fancd2-/- mice had altered expression of genes encoding hepatic bile acid transporters and cholesterol and fatty acid metabolism proteins, including Scp2/x, Abcg5/8, Abca1, Ldlr, Srebf1, and Scd-1 Untargeted lipidomic profiling in liver tissue revealed 132 lipid species, including sphingolipids, glycerophospholipids, and glycerolipids, that differed significantly in abundance depending on Fancd2 status in male mice. We conclude that the FA pathway has sex-specific impacts on hepatic lipid and bile acid metabolism, findings that expand the known functions of the FA pathway and may provide mechanistic insight into the metabolic disease predisposition in individuals with FA.
Assuntos
Bile/metabolismo , Dieta , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/deficiência , Metabolismo dos Lipídeos , Fígado/metabolismo , Caracteres Sexuais , Animais , Colesterol/metabolismo , Dano ao DNA , Doenças do Sistema Digestório/metabolismo , Suscetibilidade a Doenças , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Comportamento Alimentar , Feminino , Regulação da Expressão Gênica , Cinética , Metabolismo dos Lipídeos/genética , Masculino , CamundongosRESUMO
Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytic proliferation that occurs in nodal and extranodal sites. Rare examples of the disease involving the digestive system have been described. To characterize the digestive tract manifestations of this disease, 12 specimens from 11 patients with extranodal RDD affecting the digestive organs were analyzed. Hematoxylin and eosin sections and available immunohistochemical stains were reviewed, and the clinical information was obtained from patients' electronic or submitted records. Eight patients were female and 3 male (median age, 65 y; range, 17 to 76 y). Abdominal pain was the most frequent symptom. Six patients had an associated immunologic or malignant disease. Nine lesions arose in the gastrointestinal tract (1 involving the appendix, 2 right colon, 6 left colon), 2 in the pancreas, and 1 in the liver. Two patients had the coexistent nodal disease, and 1 had bone and soft-tissue involvement. The lesions were generally composed of polygonal to spindle-shaped histiocytes with eosinophilic to clear cytoplasm admixed with lymphoplasmacytic cells. The inflammatory cells formed lymphoid aggregates in 7 cases and included focally scattered or small collections of neutrophils in 6 cases. Fibrosis was variable, and 4 cases had a storiform pattern. Vasculopathy in the form of a thickened capillary wall, medium-sized arterial wall infiltration by lesional and inflammatory cells and phlebitis was seen in 10, 5, and 2 cases, respectively. All cases were reactive for S100-protein. Of the 5 patients with follow-up, 1 developed immunoglobulin A nephropathy and died of renal failure.
Assuntos
Proliferação de Células , Doenças do Sistema Digestório/patologia , Sistema Digestório/irrigação sanguínea , Sistema Digestório/patologia , Histiócitos/patologia , Histiocitose Sinusal/patologia , Doenças Vasculares/patologia , Adolescente , Idoso , Bases de Dados Factuais , Diagnóstico Diferencial , Sistema Digestório/química , Doenças do Sistema Digestório/metabolismo , Feminino , Fibrose , Histiócitos/química , Histiocitose Sinusal/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas S100/análise , Doenças Vasculares/metabolismoRESUMO
Aquaporins (AQPs) are a family of membrane water channel proteins that osmotically modulate water fluid homeostasis in several tissues; some of them also transport small solutes such as glycerol. At the cellular level, the AQPs regulate not only cell migration and transepithelial fluid transport across membranes, but also common events that are crucial for the inflammatory response. Emerging data reveal a new function of AQPs in the inflammatory process, as demonstrated by their dysregulation in a wide range of inflammatory diseases including edematous states, cancer, obesity, wound healing and several autoimmune diseases. This chapter summarizes the discoveries made so far about the structure and functions of the AQPs and provides updated information on the underlying mechanisms of AQPs in several human inflammatory diseases. The discovery of new functions for AQPs opens new vistas offering promise for the discovery of mechanisms and therapeutic opportunities in inflammatory disorders.
Assuntos
Aquaporinas/metabolismo , Inflamação/metabolismo , Água/metabolismo , Animais , Aquaporinas/análise , Aquaporinas/imunologia , Autoimunidade , Doenças do Sistema Digestório/imunologia , Doenças do Sistema Digestório/metabolismo , Humanos , Inflamação/imunologia , Nefropatias/imunologia , Nefropatias/metabolismo , Pneumopatias/imunologia , Pneumopatias/metabolismo , Modelos MolecularesRESUMO
Opisthorchiasis caused by food-borne trematode Opisthorchis felineus is a substantial public health problem, with 17 million persons infected worldwide. This chronic disease is associated with hepatobiliary inflammation, cholangiocyte dysplasia, cholangiofibrosis, intraepithelial neoplasia, and even cholangiocarcinoma among chronically infected individuals. To provide first insights into the mechanism by which O. felineus infection causes precancerous liver lesions, we investigated the level of oxidative stress (lipid peroxidation byproducts and 8-hydroxy-2'-deoxyguanosine) as well as the time course profiles of chronic inflammation and fibrogenesis markers in the dynamics of opisthorchiasis from 1 month to 1.5 years postinfection in an experimental model based on golden hamsters Mesocricetus auratus. For the first time, we showed that O. felineus infection provokes time-dependent accumulation of oxidative hepatobiliary lesions in the injured liver of hamsters. In particular, over the course of infection, lipid peroxidation byproducts 4-hydroxynonenal and malondialdehyde were upregulated; these changes in general correlate with the dynamics of hepatic histopathological changes. We detected macrophages with various immunophenotypes and elevated levels of CD68, COX2, and CD163 in the O. felineus-infected animals. Meanwhile, there was direct time-dependent elevation of TNF-α (R = 0.79; p < 0.001) and CD163 protein levels (R = 0.58; p = 0.022). We also provide quantitative data about epithelial hyperplasia marker CK7 and a marker of myofibroblast activation (α smooth muscle actin). Our present data provide first insights into the histopathological mechanism by which O. felineus infection causes liver injuries. These findings support the inclusion of O. felineus in Group 1 of biological carcinogens.
Assuntos
Doenças do Sistema Digestório/complicações , Doenças do Sistema Digestório/metabolismo , Fígado/metabolismo , Fígado/patologia , Opistorquíase/complicações , Opisthorchis/fisiologia , Estresse Oxidativo , Animais , Biomarcadores/metabolismo , Cricetinae , Dano ao DNA , Doenças do Sistema Digestório/genética , Doenças do Sistema Digestório/patologia , Modelos Animais de Doenças , Peroxidação de Lipídeos , Fatores de TempoRESUMO
G-protein-coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. In the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication among cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of more than one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have shown that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs and has shown opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract.
Assuntos
Digestão/fisiologia , Doenças do Sistema Digestório/tratamento farmacológico , Doenças do Sistema Digestório/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Regulação Alostérica , Dimerização , Descoberta de Drogas , Endossomos/metabolismo , HumanosRESUMO
Precision medicine may significantly contribute to rapid disease diagnosis and targeted therapy, but relies on the availability of detailed, subject specific, clinical information. Proton nuclear magnetic resonance (¹Hâ»NMR) spectroscopy of body fluids can extract individual metabolic fingerprints. Herein, we studied 64 patients admitted to the Florence main hospital emergency room with severe abdominal pain. A blood sample was drawn from each patient at admission, and the corresponding sera underwent ¹Hâ»NMR metabolomics fingerprinting. Unsupervised Principal Component Analysis (PCA) analysis showed a significant discrimination between a group of patients with symptoms of upper abdominal pain and a second group consisting of patients with diffuse abdominal/intestinal pain. Prompted by this observation, supervised statistical analysis (Orthogonal Partial Least Squaresâ»Discriminant Analysis (OPLS-DA)) showed a very good discrimination (>90%) between the two groups of symptoms. This is a surprising finding, given that neither of the two symptoms points directly to a specific disease among those studied here. Actually herein, upper abdominal pain may result from either symptomatic gallstones, cholecystitis, or pancreatitis, while diffuse abdominal/intestinal pain may result from either intestinal ischemia, strangulated obstruction, or mechanical obstruction. Although limited by the small number of samples from each of these six conditions, discrimination of these diseases was attempted. In the first symptom group, >70% discrimination accuracy was obtained among symptomatic gallstones, pancreatitis, and cholecystitis, while for the second symptom group >85% classification accuracy was obtained for intestinal ischemia, strangulated obstruction, and mechanical obstruction. No single metabolite stands up as a possible biomarker for any of these diseases, while the contribution of the whole ¹Hâ»NMR serum fingerprint seems to be a promising candidate, to be confirmed on larger cohorts, as a first-line discriminator for these diseases.