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1.
Semin Cancer Biol ; 73: 76-85, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32805396

RESUMO

Cholesterol is a crucial component of membrane bilayers that determines their physical and functional properties. Cells largely satisfy their need for cholesterol through the novo synthesis from acetyl-CoA and this demand is particularly critical for cancer cells to sustain dysregulated cell proliferation. However, the association between serum or tissue cholesterol levels and cancer development is not well established as epidemiologic data do not consistently support this link. While most preclinical studies focused on the role of total celular cholesterol, the specific contribution of the mitochondrial cholesterol pool to alterations in cancer cell biology has been less explored. Although low compared to other bilayers, the mitochondrial cholesterol content plays an important physiological function in the synthesis of steroid hormones in steroidogenic tissues or bile acids in the liver and controls mitochondrial function. In addition, mitochondrial cholesterol metabolism generates oxysterols, which in turn, regulate multiple pathways, including cholesterol and lipid metabolism as well as cell proliferation. In the present review, we summarize the regulation of mitochondrial cholesterol, including its role in mitochondrial routine performance, cell death and chemotherapy resistance, highlighting its potential contribution to cancer. Of particular relevance is hepatocellular carcinoma, whose incidence in Western countries had tripled in the past decades due to the obesity and type II diabetes epidemic. A better understanding of the role of mitochondrial cholesterol in cancer development may open up novel opportunities for cancer therapy.


Assuntos
Colesterol/metabolismo , Metabolismo dos Lipídeos/fisiologia , Mitocôndrias/metabolismo , Neoplasias , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
2.
J Hepatol ; 74(6): 1429-1441, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33515644

RESUMO

BACKGROUND & AIMS: Besides their physiological role in bile formation and fat digestion, bile acids (BAs) synthesised from cholesterol in hepatocytes act as signalling molecules that modulate hepatocellular carcinoma (HCC). Trafficking of cholesterol to mitochondria through steroidogenic acute regulatory protein 1 (STARD1) is the rate-limiting step in the alternative pathway of BA generation, the physiological relevance of which is not well understood. Moreover, the specific contribution of the STARD1-dependent BA synthesis pathway to HCC has not been previously explored. METHODS: STARD1 expression was analyzed in a cohort of human non-alcoholic steatohepatitis (NASH)-derived HCC specimens. Experimental NASH-driven HCC models included MUP-uPA mice fed a high-fat high-cholesterol (HFHC) diet and diethylnitrosamine (DEN) treatment in wild-type (WT) mice fed a HFHC diet. Molecular species of BAs and oxysterols were analyzed by mass spectrometry. Effects of NASH-derived BA profiles were investigated in tumour-initiated stem-like cells (TICs) and primary mouse hepatocytes (PMHs). RESULTS: Patients with NASH-associated HCC exhibited increased hepatic expression of STARD1 and an enhanced BA pool. Using NASH-driven HCC models, STARD1 overexpression in WT mice increased liver tumour multiplicity, whereas hepatocyte-specific STARD1 deletion (Stard1ΔHep) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, ß-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1ΔHep mice. Incubation of TICs or PMHs with a mix of BAs mimicking this profile stimulated expression of genes involved in pluripotency, stemness and inflammation. CONCLUSIONS: The study reveals a previously unrecognised role of STARD1 in HCC pathogenesis, wherein it promotes the synthesis of primary BAs through the mitochondrial pathway, the products of which act in TICs to stimulate self-renewal, stemness and inflammation. LAY SUMMARY: Effective therapy for hepatocellular carcinoma (HCC) is limited because of our incomplete understanding of its pathogenesis. The contribution of the alternative pathway of bile acid (BA) synthesis to HCC development is unknown. We uncover a key role for steroidogenic acute regulatory protein 1 (STARD1) in non-alcoholic steatohepatitis-driven HCC, wherein it stimulates the generation of BAs in the mitochondrial acidic pathway, the products of which stimulate hepatocyte pluripotency and self-renewal, as well as inflammation.


Assuntos
Ácidos e Sais Biliares/biossíntese , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/metabolismo , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais/genética , Adulto , Idoso , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Células Cultivadas , Estudos de Coortes , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Deleção de Genes , Hepatócitos/metabolismo , Humanos , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Fosfoproteínas/genética , Adulto Jovem
3.
Gastroenterology ; 157(2): 552-568, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31029706

RESUMO

BACKGROUND & AIMS: Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. METHODS: Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah-/-/Rag2-/-/Il2rg-/-/NOD (FRGN) mice to create mice with humanized livers. RESULTS: Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. CONCLUSIONS: In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/patologia , Fosfoproteínas/metabolismo , Adulto , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Modelos Animais de Doenças , Overdose de Drogas/complicações , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/transplante , Humanos , Lipogênese/efeitos dos fármacos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfoproteínas/genética , Esteroides/metabolismo , Quimeras de Transplante , Regulação para Cima , Ácido Valproico/administração & dosagem
4.
J Biol Chem ; 293(13): 4735-4751, 2018 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-29378845

RESUMO

Estrogen receptor α (ERα) action plays an important role in pancreatic ß-cell function and survival; thus, it is considered a potential therapeutic target for the treatment of type 2 diabetes in women. However, the mechanisms underlying the protective effects of ERα remain unclear. Because ERα regulates mitochondrial metabolism in other cell types, we hypothesized that ERα may act to preserve insulin secretion and promote ß-cell survival by regulating mitochondrial-endoplasmic reticulum (EndoRetic) function. We tested this hypothesis using pancreatic islet-specific ERα knockout (PERαKO) mice and Min6 ß-cells in culture with Esr1 knockdown (KD). We found that Esr1-KD promoted reactive oxygen species production that associated with reduced fission/fusion dynamics and impaired mitophagy. Electron microscopy showed mitochondrial enlargement and a pro-fusion phenotype. Mitochondrial cristae and endoplasmic reticulum were dilated in Esr1-KD compared with ERα replete Min6 ß-cells. Increased expression of Oma1 and Chop was paralleled by increased oxygen consumption and apoptosis susceptibility in ERα-KD cells. In contrast, ERα overexpression and ligand activation reduced both Chop and Oma1 expression, likely by ERα binding to consensus estrogen-response element sites in the Oma1 and Chop promoters. Together, our findings suggest that ERα promotes ß-cell survival and insulin secretion through maintenance of mitochondrial fission/fusion-mitophagy dynamics and EndoRetic function, in part by Oma1 and Chop repression.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Receptor alfa de Estrogênio/metabolismo , Células Secretoras de Insulina/metabolismo , Mitocôndrias/metabolismo , Mitofagia , Animais , Sobrevivência Celular , Receptor alfa de Estrogênio/genética , Feminino , Insulina/genética , Insulina/metabolismo , Metaloproteases/biossíntese , Metaloproteases/genética , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Proteínas Mitocondriais/biossíntese , Proteínas Mitocondriais/genética , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição CHOP/biossíntese , Fator de Transcrição CHOP/genética
5.
Biomed Eng Online ; 17(Suppl 1): 135, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458795

RESUMO

BACKGROUND: Like other scientific fields, such as cosmology, high-energy physics, or even the life sciences, medicine and healthcare face the challenge of an extremely quick transformation into data-driven sciences. This challenge entails the daunting task of extracting usable knowledge from these data using algorithmic methods. In the medical context this may for instance realized through the design of medical decision support systems for diagnosis, prognosis and patient management. The intensive care unit (ICU), and by extension the whole area of critical care, is becoming one of the most data-driven clinical environments. RESULTS: The increasing availability of complex and heterogeneous data at the point of patient attention in critical care environments makes the development of fresh approaches to data analysis almost compulsory. Computational Intelligence (CI) and Machine Learning (ML) methods can provide such approaches and have already shown their usefulness in addressing problems in this context. The current study has a dual goal: it is first a review of the state-of-the-art on the use and application of such methods in the field of critical care. Such review is presented from the viewpoint of the different subfields of critical care, but also from the viewpoint of the different available ML and CI techniques. The second goal is presenting a collection of results that illustrate the breath of possibilities opened by ML and CI methods using a single problem, the investigation of septic shock at the ICU. CONCLUSION: We have presented a structured state-of-the-art that illustrates the broad-ranging ways in which ML and CI methods can make a difference in problems affecting the manifold areas of critical care. The potential of ML and CI has been illustrated in detail through an example concerning the sepsis pathology. The new definitions of sepsis and the relevance of using the systemic inflammatory response syndrome (SIRS) in its diagnosis have been considered. Conditional independence models have been used to address this problem, showing that SIRS depends on both organ dysfunction measured through the Sequential Organ Failure (SOFA) score and the ICU outcome, thus concluding that SIRS should still be considered in the study of the pathophysiology of Sepsis. Current assessment of the risk of dead at the ICU lacks specificity. ML and CI techniques are shown to improve the assessment using both indicators already in place and other clinical variables that are routinely measured. Kernel methods in particular are shown to provide the best performance balance while being amenable to representation through graphical models, which increases their interpretability and, with it, their likelihood to be accepted in medical practice.


Assuntos
Cuidados Críticos/métodos , Aprendizado de Máquina , Sepse/terapia , Inteligência Artificial , Gráficos por Computador , Análise de Dados , Sistemas Inteligentes , Humanos , Unidades de Terapia Intensiva , Informática Médica , Probabilidade , Prognóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Software
6.
Adv Exp Med Biol ; 1043: 257-284, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29224099

RESUMO

Women in the modern era are challenged with facing menopausal symptoms as well as heightened disease risk associated with increasing adiposity and metabolic dysfunction for up to three decades of life. Treatment strategies to combat metabolic dysfunction and associated pathologies have been hampered by our lack of understanding regarding the biological causes of these clinical conditions and our incomplete understanding regarding the effects of estrogens and the tissue-specific functions and molecular actions of its receptors. In this chapter we provide evidence supporting a critical and protective role for skeletal muscle estrogen receptor α in the maintenance of metabolic homeostasis and insulin sensitivity. Studies identifying the critical ER-regulated pathways essential for disease prevention will lay the important foundation for the rational design of novel therapeutic strategies to improve the health of women while limiting secondary complications that have plagued traditional hormone replacement interventions.


Assuntos
Metabolismo Energético , Estrogênios/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Metabolismo Energético/efeitos dos fármacos , Terapia de Reposição de Estrogênios , Feminino , Homeostase , Humanos , Masculino , Menopausa/metabolismo , Doenças Metabólicas/metabolismo , Doenças Metabólicas/fisiopatologia , Doenças Metabólicas/prevenção & controle , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Receptores de Estrogênio/efeitos dos fármacos , Transdução de Sinais
7.
J Biol Chem ; 290(9): 5566-81, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25468909

RESUMO

Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissue-specific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knock-out (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3-hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity.


Assuntos
Proteínas de Fase Aguda/metabolismo , Tecido Adiposo/metabolismo , Receptor alfa de Estrogênio/metabolismo , Lipocalinas/metabolismo , Obesidade/metabolismo , Proteínas Oncogênicas/metabolismo , Células 3T3-L1 , Proteínas de Fase Aguda/genética , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo/citologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Receptor alfa de Estrogênio/genética , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Immunoblotting , Lipocalina-2 , Lipocalinas/sangue , Lipocalinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/genética , Proteínas Oncogênicas/sangue , Proteínas Oncogênicas/genética , Regiões Promotoras Genéticas/genética , Ligação Proteica , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
PLoS Genet ; 8(12): e1003046, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23236286

RESUMO

Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein-protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10(-5)). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases.


Assuntos
Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Resistência à Insulina/genética , Mitocôndrias , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica , Predisposição Genética para Doença , Glucose/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Redes e Vias Metabólicas , Mitocôndrias/genética , Mitocôndrias/metabolismo , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Biologia de Sistemas
9.
Proc Natl Acad Sci U S A ; 108(39): 16457-62, 2011 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-21900603

RESUMO

ERα is expressed in macrophages and other immune cells known to exert dramatic effects on glucose homeostasis. We investigated the impact of ERα expression on macrophage function to determine whether hematopoietic or myeloid-specific ERα deletion manifests obesity-induced insulin resistance in mice. Indeed, altered plasma adipokine and cytokine levels, glucose intolerance, insulin resistance, and increased adipose tissue mass were observed in animals harboring a hematopoietic or myeloid-specific deletion of ERα. A similar obese phenotype and increased atherosclerotic lesion area was displayed in LDL receptor-KO mice transplanted with ERα(-/-) bone marrow. In isolated macrophages, ERα was necessary for repression of inflammation, maintenance of oxidative metabolism, IL-4-mediated induction of alternative activation, full phagocytic capacity in response to LPS, and oxidized LDL-induced expression of ApoE and Abca1. Furthermore, we identified ERα as a direct regulator of macrophage transglutaminase 2 expression, a multifunctional atheroprotective enzyme. Our findings suggest that diminished ERα expression in hematopoietic/myeloid cells promotes aspects of the metabolic syndrome and accelerates atherosclerosis in female mice.


Assuntos
Aterosclerose/patologia , Medula Óssea/metabolismo , Receptor alfa de Estrogênio/fisiologia , Homeostase , Adiposidade , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Glucose/metabolismo , Resistência à Insulina , Interleucina-4/fisiologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
10.
Diabetes Res Clin Pract ; 211: 111655, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38574895

RESUMO

AIMS: We aimed to assess physical activity (PA) levels, adherence to PA guidelines, and fitness capacity in individuals with type 1 diabetes (T1D) and control population. METHODS: This cross-sectional study included 232 T1D and 248 controls. PA levels (IPAQ-SF questionnaire), adherence to guidelines (>150 min/week of moderate-to-vigorous PA), fitness capacity (VO2max, maximal incremental test on a cycle ergometer and 1RM test) were assessed, along with other clinical variables. RESULTS: Total PA levels (T1D 2202 ± 1839 vs. controls 2357 ± 2189 METs/min/week), adherence (T1D 53.1 % vs controls 53.2 %), and sedentariness (T1D 27.3 % vs. controls 25.1 %) were similar between groups. However, participants with T1D exhibited significantly lower levels of VO2max (29.1 ± 10.5 vs. 32.5 ± 11.5 mlO2/kg/min, p < 0.001), work capacity (2.73 ± 1.03 vs. 3 ± 10 W/kg of body weight, p = 0.004) and strength capacity (2.29 ± 0.53 vs. 2.41 ± 0.79 kg/kg body weight in 1RM, p = 0.01) than controls, after adjusting for sex and age. CONCLUSIONS: Individuals with T1D exhibit lower fitness capacity compared to a control population, regardless of age and sex, even when presenting similar levels of total physical activity and adherence to guidelines.


Assuntos
Diabetes Mellitus Tipo 1 , Tolerância ao Exercício , Exercício Físico , Humanos , Diabetes Mellitus Tipo 1/fisiopatologia , Masculino , Feminino , Estudos Transversais , Exercício Físico/fisiologia , Adulto , Tolerância ao Exercício/fisiologia , Pessoa de Meia-Idade , Aptidão Física/fisiologia , Consumo de Oxigênio/fisiologia , Adulto Jovem , Estudos de Casos e Controles , Inquéritos e Questionários
11.
Antibiotics (Basel) ; 13(2)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38391573

RESUMO

Streptococcal toxic shock syndrome (STTS) is a critical medical emergency marked by high morbidity and mortality, necessitating swift awareness, targeted treatment, and early source control due to its rapid symptom manifestation. This report focuses on a cohort of 13 patients admitted to Vall d'Hebron University Hospital Intensive Care Unit, Barcelona, from November 2022 to March 2023, exhibiting invasive Streptococcus pyogenes infections and meeting institutional sepsis code activation criteria. The primary infections were community-acquired pneumonia (61.5%) and skin/soft tissue infection (30.8%). All patients received prompt antibiotic treatment, with clinical source control through thoracic drainage (30.8%) or surgical means (23.1%). Organ support involved invasive mechanical ventilation, vasopressors, and continuous renal replacement therapy as per guidelines. Of note, 76.9% of patients experienced septic cardiomyopathy, and 53.8% required extracorporeal membrane oxygenation (ECMO). The study identified three distinct phenotypic profiles-hyperinflammatory, low perfusion, and hypogammaglobulinemic-which could guide personalized therapeutic approaches. STTS, with a mean SOFA score of 17 (5.7) and a 53.8% requiring ECMO, underscores the need for precision medicine-based rescue therapies and sepsis phenotype identification. Integrating these strategies with prompt antibiotics and efficient source control offers a potential avenue to mitigate organ failure, enhancing patient survival and recovery in the face of this severe clinical condition.

12.
Cancers (Basel) ; 15(13)2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37444479

RESUMO

Glioma is the most common type of tumor in humans originating in the brain. According to the World Health Organization, gliomas can be graded on a four-stage scale, ranging from the most benign to the most malignant. The grading of these tumors from image information is a far from trivial task for radiologists and one in which they could be assisted by machine-learning-based decision support. However, the machine learning analytical pipeline is also fraught with perils stemming from different sources, such as inadvertent data leakage, adequacy of 2D image sampling, or classifier assessment biases. In this paper, we analyze a glioma database sourced from multiple datasets using a simple classifier, aiming to obtain a reliable tumor grading and, on the way, we provide a few guidelines to ensure such reliability. Our results reveal that by focusing on the tumor region of interest and using data augmentation techniques we significantly enhanced the accuracy and confidence in tumor classifications. Evaluation on an independent test set resulted in an AUC-ROC of 0.932 in the discrimination of low-grade gliomas from high-grade gliomas, and an AUC-ROC of 0.893 in the classification of grades 2, 3, and 4. The study also highlights the importance of providing, beyond generic classification performance, measures of how reliable and trustworthy the model's output is, thus assessing the model's certainty and robustness.

13.
Front Med (Lausanne) ; 10: 1301001, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38188336

RESUMO

Objectives: To determine vitamin C plasma kinetics, through the measurement of vitamin C plasma concentrations, in critically ill Coronavirus infectious disease 2019 (COVID-19) patients, identifying eventually the onset of vitamin C deficiency. Design: Prospective, observational, single-center study. Setting: Intensive Care Unit (ICU), Vall d'Hebron University Hospital, Barcelona. Study period from November 12th, 2020, to February 24th, 2021. Patients: Patients who had a severe hypoxemic acute respiratory failure due to COVID-19 were included. Interventions: Plasma vitamin C concentrations were measured on days 1, 5, and 10 of ICU admission. There were no vitamin C enteral nor parenteral supplementation. The supportive treatment was performed following the standard of care or acute respiratory distress syndrome (ARDS) patients. Measurement: Plasma vitamin C concentrations were analyzed using an ultra-performance liquid chromatography (UPLC) system with a photodiode array detector (wavelength set to 245 nm). We categorized plasmatic levels of vitamin C as follows: undetectable: < 1,5 mg/L, deficiency: <2 mg/L. Low plasma concentrations: 2-5 mg/L; (normal plasma concentration: > 5 mg/L). Main results: Forty-three patients were included (65% men; mean age 62 ± 10 years). The median Sequential Organ Failure Assessment (SOFA) score was 3 (1-4), and the Acute Physiology and Chronic Health disease Classification System (APACHE II) score was 13 (10-22). Five patients had shock. Bacterial coinfection was documented in 7 patients (16%). Initially all patients required high-flow oxygen therapy, and 23 (53%) further needed invasive mechanical ventilation during 21 (± 10) days. The worst PaO2/FIO2 registered was 93 (± 29). ICU and hospital survival were 77 and 74%, respectively. Low or undetectable levels remained constant throughout the study period in the vast majority of patients. Conclusion: This observational study showed vitamin C plasma levels were undetectable on ICU admission in 86% of patients with acute respiratory failure due to COVID-19 pneumonia requiring respiratory support. This finding remained consistent throughout the study period.

14.
EMBO Rep ; 11(1): 37-44, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20010805

RESUMO

The regulation of autophagy in metazoans is only partly understood, and there is a need to identify the proteins that control this process. The diabetes- and obesity-regulated gene (DOR), a recently reported nuclear cofactor of thyroid hormone receptors, is expressed abundantly in metabolically active tissues such as muscle. Here, we show that DOR shuttles between the nucleus and the cytoplasm, depending on cellular stress conditions, and re-localizes to autophagosomes on autophagy activation. We demonstrate that DOR interacts physically with autophagic proteins Golgi-associated ATPase enhancer of 16 kDa (GATE16) and microtubule-associated protein 1A/1B-light chain 3. Gain-of-function and loss-of-function studies indicate that DOR stimulates autophagosome formation and accelerates the degradation of stable proteins. CG11347, the DOR Drosophila homologue, has been predicted to interact with the Drosophila Atg8 homologues, which suggests functional conservation in autophagy. Flies lacking CG11347 show reduced autophagy in the fat body during pupal development. All together, our data indicate that DOR regulates autophagosome formation and protein degradation in mammalian and Drosophila cells.


Assuntos
Autofagia/fisiologia , Diabetes Mellitus , Proteínas de Drosophila/metabolismo , Proteínas Nucleares/metabolismo , Obesidade , Receptores dos Hormônios Tireóideos/metabolismo , Animais , Autofagia/genética , Linhagem Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Drosophila/anatomia & histologia , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Drosophila/metabolismo , Proteínas de Drosophila/genética , Corpo Adiposo/metabolismo , Imunofluorescência , Células HeLa , Humanos , Proteínas dos Microfilamentos/metabolismo , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Nucleares/genética , Fagossomos/metabolismo , Ligação Proteica , Transporte Proteico , Estresse Fisiológico
15.
Diagnostics (Basel) ; 12(11)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36359482

RESUMO

Predicting whether a lung nodule will grow, remain stable or regress over time, especially early in its follow-up, would help doctors prescribe personalized treatments and better surgical planning. However, the multifactorial nature of lung tumour progression hampers the identification of growth patterns. In this work, we propose a deep hierarchical generative and probabilistic network that, given an initial image of the nodule, predicts whether it will grow, quantifies its future size and provides its expected semantic appearance at a future time. Unlike previous solutions, our approach also estimates the uncertainty in the predictions from the intrinsic noise in medical images and the inter-observer variability in the annotations. The evaluation of this method on an independent test set reported a future tumour growth size mean absolute error of 1.74 mm, a nodule segmentation Dice's coefficient of 78% and a tumour growth accuracy of 84% on predictions made up to 24 months ahead. Due to the lack of similar methods for providing future lung tumour growth predictions, along with their associated uncertainty, we adapted equivalent deterministic and alternative generative networks (i.e., probabilistic U-Net, Bayesian test dropout and Pix2Pix). Our method outperformed all these methods, corroborating the adequacy of our approach.

16.
PLoS One ; 17(12): e0278708, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36459524

RESUMO

INTRODUCTION: The search for new biomarkers that allow an early diagnosis in sepsis and predict its evolution has become a necessity in medicine. The objective of this study is to identify, through omics techniques, potential protein biomarkers that are expressed in patients with sepsis and their relationship with organ dysfunction and mortality. METHODS: Prospective, observational and single-center study that included adult patients (≥ 18 years) who were admitted to a tertiary hospital and who met the criteria for sepsis. A mass spectrometry-based approach was used to analyze the plasma proteins in the enrolled subjects. Subsequently, using recursive feature elimination classification and cross-validation with a vector classifier, an association of these proteins with mortality and organ dysfunction was established. The protein-protein interaction network was analyzed with String software. RESULTS: 141 patients were enrolled in this study. Mass spectrometry identified 177 proteins. Of all of them, and by recursive feature elimination, nine proteins (GPX3, APOB, ORM1, SERPINF1, LYZ, C8A, CD14, APOC3 and C1QC) were associated with organ dysfunction (SOFA > 6) with an accuracy of 0.82 ± 0.06, precision of 0.85 ± 0.093, sensitivity 0.81 ± 0.10, specificity 0.84 ± 0.10 and AUC 0.82 ± 0.06. Twenty-two proteins (CLU, LUM, APOL1, SAA1, CLEBC3B, C8A, ITIH4, KNG1, AGT, C7, SAA2, APOH, HRG, AFM, APOE, APOC1, C1S, SERPINC1, IGFALS, KLKB1, CFB and BTD) were associated with mortality with an accuracy of 0.86 ± 0.05, a precision of 0.91 ± 0.05, a sensitivity of 0.91 ± 0.05, a specificity of 0.72 ± 0.17, and an area under the curve (AUC) of 0.81 ± 0.08 with a confidence interval of 95%. CONCLUSION: In sepsis there are proteomic patterns associated with organ dysfunction and mortality.


Assuntos
Sepse , Choque Séptico , Adulto , Humanos , Proteômica , Insuficiência de Múltiplos Órgãos , Estudos Prospectivos , Apolipoproteína L1
17.
World J Crit Care Med ; 11(1): 1-21, 2022 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-35433311

RESUMO

Sepsis is a heterogeneous disease with variable clinical course and several clinical phenotypes. As it is associated with an increased risk of death, patients with this condition are candidates for receipt of a very well-structured and protocolized treatment. All patients should receive the fundamental pillars of sepsis management, which are infection control, initial resuscitation, and multiorgan support. However, specific subgroups of patients may benefit from a personalized approach with interventions targeted towards specific pathophysiological mechanisms. Herein, we will review the framework for identifying subpopulations of patients with sepsis, septic shock, and multiorgan dysfunction who may benefit from specific therapies. Some of these approaches are still in the early stages of research, while others are already in routine use in clinical practice, but together will help in the effective generation and safe implementation of precision medicine in sepsis.

18.
Cell Metab ; 34(2): 269-284.e9, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35108514

RESUMO

Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone's effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders.


Assuntos
Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipotálamo/metabolismo , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pregnenolona/metabolismo , Pró-Opiomelanocortina/metabolismo
19.
Arterioscler Thromb Vasc Biol ; 30(2): 232-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19910634

RESUMO

INTRODUCTION: Apolipoprotein (apo) A-II is the second most abundant high-density lipoprotein (HDL) apolipoprotein. We assessed the mechanism involved in the altered postprandial triglyceride-rich lipoprotein metabolism of female human apoA-II-transgenic mice (hapoA-II-Tg mice), which results in up to an 11-fold increase in plasma triglyceride concentration. The relationships between apoA-II, HDL composition, and lipoprotein lipase (LPL) activity were also analyzed in a group of normolipidemic women. METHODS AND RESULTS: Triglyceride-rich lipoprotein catabolism was decreased in hapoA-II-Tg mice compared to control mice. This suggests that hapoA-II, which was mainly associated with HDL during fasting and postprandially, impairs triglyceride-rich lipoprotein lipolysis. HDL isolated from hapoA-II-Tg mice impaired bovine LPL activity. Two-dimensional gel electrophoresis, mass spectrometry, and immunonephelometry identified a marked deficiency in the HDL content of apoA-I, apoC-III, and apoE in these mice. In normolipidemic women, apoA-II concentration was directly correlated with plasma triglyceride and inversely correlated with the HDL-apoC-II+apoE/apoC-III ratio [corrected]. HDL-mediated induction of LPL activity was inversely correlated with apoA-II and directly correlated with the HDL-apoC-II+apoE/apoC-III ratio [corrected]. Purified hapoA-II displaced apoC-II, apoC-III, and apoE from human HDL2. Human HDL3 was, compared to HDL2, enriched in apoA-II but poorer in apoC-II, apoC-III, and apoE. CONCLUSIONS: ApoA-II plays a crucial role in triglyceride catabolism by regulating LPL activity, at least in part, through HDL proteome modulation.


Assuntos
Apolipoproteína A-II/sangue , Lipólise , Lipase Lipoproteica/sangue , Lipoproteínas HDL2/sangue , Lipoproteínas HDL3/sangue , Triglicerídeos/sangue , Animais , Apolipoproteína A-I/sangue , Apolipoproteína A-II/genética , Apolipoproteína C-II/sangue , Apolipoproteína C-III/sangue , Apolipoproteínas E/sangue , Biomarcadores/sangue , Gorduras na Dieta/metabolismo , Eletroforese em Gel Bidimensional , Feminino , Humanos , Intestinos/enzimologia , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nefelometria e Turbidimetria , Período Pós-Prandial , Proteoma , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Fatores de Tempo , Regulação para Cima
20.
Trends Mol Med ; 27(1): 31-46, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33020031

RESUMO

Decrements in metabolic health elevate disease risk, including type 2 diabetes, heart disease, and certain cancers. Thus, treatment strategies to combat metabolic dysfunction are needed. Reduced ESR1 (estrogen receptor, ERα) expression is observed in muscle from women, men, and animals presenting clinical features of the metabolic syndrome. Human studies of natural expression of ESR1 in metabolic tissues show that muscle expression of ESR1 is positively correlated with markers of metabolic health, including insulin sensitivity. Herein, we highlight the important impact of ERα on mitochondrial form and function and present how these actions of the receptor govern metabolic homeostasis. Studies identifying ERα-regulated pathways for disease prevention will lay the foundation for the design of novel therapeutics to improve the health of women while limiting secondary complications that have plagued traditional hormone replacement interventions.


Assuntos
Metabolismo Energético , Receptor alfa de Estrogênio/metabolismo , Homeostase , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Mitocôndrias/metabolismo , Animais , Suscetibilidade a Doenças , Receptor alfa de Estrogênio/genética , Humanos , Resistência à Insulina , Mitocôndrias/genética , Especificidade de Órgãos
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