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1.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803198

RESUMO

Extracellular matrix (ECM) remodeling plays important roles in both white adipose tissue (WAT) and the skeletal muscle (SM) metabolism. Excessive adipocyte hypertrophy causes fibrosis, inflammation, and metabolic dysfunction in adipose tissue, as well as impaired adipogenesis. Similarly, disturbed ECM remodeling in SM has metabolic consequences such as decreased insulin sensitivity. Most of described ECM molecular alterations have been associated with DNA sequence variation, alterations in gene expression patterns, and epigenetic modifications. Among others, the most important epigenetic mechanism by which cells are able to modulate their gene expression is DNA methylation. Epigenome-Wide Association Studies (EWAS) have become a powerful approach to identify DNA methylation variation associated with biological traits in humans. Likewise, Genome-Wide Association Studies (GWAS) and gene expression microarrays have allowed the study of whole-genome genetics and transcriptomics patterns in obesity and metabolic diseases. The aim of this review is to explore the molecular basis of ECM in WAT and SM remodeling in obesity and the consequences of metabolic complications. For that purpose, we reviewed scientific literature including all omics approaches reporting genetic, epigenetic, and transcriptomic (GWAS, EWAS, and RNA-seq or cDNA arrays) ECM-related alterations in WAT and SM as associated with metabolic dysfunction and obesity.


Assuntos
Tecido Adiposo Branco/metabolismo , Matriz Extracelular/metabolismo , Doenças Metabólicas/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Tecido Adiposo Branco/patologia , Animais , Matriz Extracelular/genética , Matriz Extracelular/patologia , Estudo de Associação Genômica Ampla , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Músculo Esquelético/patologia , Obesidade/genética , Obesidade/patologia
2.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809321

RESUMO

The revolutionary evolution in science and technology over the last few decades has made it possible to face more adequately three main challenges of modern medicine: changes in old diseases, the appearance of new diseases, and diseases that are unknown (mostly genetic), despite research efforts. In this paper we review the road travelled by pathologists in search of a method based upon the use of routine instruments and techniques which once were available for research only. The application to tissue studies of techniques from immunology, molecular biology, and genetics has allowed dynamic interpretations of biological phenomena with special regard to gene regulation and expression. That implies stepwise investigations, including light microscopy, immunohistochemistry, in situ hybridization, electron microscopy, molecular histopathology, protein crystallography, and gene sequencing, in order to progress from suggestive features detectable in routinely stained preparations to more characteristic, specific, and finally, pathognomonic features. Hematoxylin and Eosin (H&E)-stained preparations and appropriate immunohistochemical stains have enabled the recognition of phenotypic changes which may reflect genotypic alterations. That has been the case with hepatocytic inclusions detected in H&E-stained preparations, which appeared to correspond to secretory proteins that, due to genetic mutations, were retained within the rough endoplasmic reticulum (RER) and were deficient in plasma. The identification of this phenomenon affecting the molecules alpha-1-antitrypsin and fibrinogen has led to the discovery of a new field of cell organelle pathology, endoplasmic reticulum storage disease(s) (ERSD). Over fifty years, pathologists have wandered through a dark forest of complicated molecules with strange conformations, and by detailed observations in simple histopathological sections, accompanied by a growing background of molecular techniques and revelations, have been able to recognize and identify arrays of grotesque polypeptide arrangements.


Assuntos
Retículo Endoplasmático/genética , Imuno-Histoquímica , Doenças Metabólicas/patologia , alfa 1-Antitripsina/genética , Retículo Endoplasmático/patologia , Regulação da Expressão Gênica/genética , Genótipo , Humanos , Doenças Metabólicas/classificação , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Mutação/genética
3.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803491

RESUMO

Particulate matter (PM) is constituted by particles with sizes in the nanometer to micrometer scales. PM can be generated from natural sources such as sandstorms and wildfires, and from human activities, including combustion of fuels, manufacturing and construction or specially engineered for applications in biotechnology, food industry, cosmetics, electronics, etc. Due to their small size PM can penetrate biological tissues, interact with cellular components and induce noxious effects such as disruptions of the cytoskeleton and membranes and the generation of reactive oxygen species. Here, we provide an overview on the actions of PM on transient receptor potential (TRP) proteins, a superfamily of cation-permeable channels with crucial roles in cell signaling. Their expression in epithelial cells and sensory innervation and their high sensitivity to chemical, thermal and mechanical stimuli makes TRP channels prime targets in the major entry routes of noxious PM, which may result in respiratory, metabolic and cardiovascular disorders. On the other hand, the interactions between TRP channel and engineered nanoparticles may be used for targeted drug delivery. We emphasize in that much further research is required to fully characterize the mechanisms underlying PM-TRP channel interactions and their relevance for PM toxicology and biomedical applications.


Assuntos
Doenças Cardiovasculares , Doenças Metabólicas , Material Particulado/efeitos adversos , Doenças Respiratórias , Canais de Receptores Transientes de Potencial/metabolismo , Animais , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Humanos , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Doenças Respiratórias/induzido quimicamente , Doenças Respiratórias/metabolismo , Doenças Respiratórias/patologia
4.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673357

RESUMO

The Wnt/ß-catenin signaling pathway plays a crucial role in early embryonic development. Wnt/ß-catenin signaling is a major regulator of cell proliferation and keeps embryonic stem cells (ESCs) in the pluripotent state. Dysregulation of Wnt signaling in the early developmental stages causes several hereditary diseases that lead to embryonic abnormalities. Several other signaling molecules are directly or indirectly activated in response to Wnt/ß-catenin stimulation. The crosstalk of these signaling factors either synergizes or opposes the transcriptional activation of ß-catenin/Tcf4-mediated target gene expression. Recently, the crosstalk between the peroxisome proliferator-activated receptor delta (PPARδ), which belongs to the steroid superfamily, and Wnt/ß-catenin signaling has been reported to take place during several aspects of embryonic development. However, numerous questions need to be answered regarding the function and regulation of PPARδ in coordination with the Wnt/ß-catenin pathway. Here, we have summarized the functional activation of the PPARδ in co-ordination with the Wnt/ß-catenin pathway during the regulation of several aspects of embryonic development, stem cell regulation and maintenance, as well as during the progression of several metabolic disorders.


Assuntos
Diferenciação Celular , Desenvolvimento Embrionário , Células-Tronco Embrionárias Humanas/metabolismo , Doenças Metabólicas/embriologia , PPAR delta/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Células-Tronco Embrionárias Humanas/patologia , Humanos , Doenças Metabólicas/patologia , Fator de Transcrição 4/metabolismo
5.
PLoS One ; 16(3): e0248995, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33750990

RESUMO

The COVID-19 pandemic forced healthcare services organization to adjust to mutating healthcare needs. Not exhaustive data are available on the consequences of this on non-COVID-19 patients. The aim of this study was to assess the impact of the pandemic on non-COVID-19 patients living in a one-million inhabitants' area in Northern Italy (Bologna Metropolitan Area-BMA), analyzing time trends of Emergency Department (ED) visits, hospitalizations and mortality. We conducted a retrospective observational study using data extracted from BMA healthcare informative systems. Weekly trends of ED visits, hospitalizations, in- and out-of-hospital, all-cause and cause-specific mortality between December 1st, 2019 to May 31st, 2020, were compared with those of the same period of the previous year. Non-COVID-19 ED visits and hospitalizations showed a stable trend until the first Italian case of COVID-19 has been recorded, on February 19th, 2020, when they dropped simultaneously. The reduction of ED visits was observed in all age groups and across all severity and diagnosis groups. In the lockdown period a significant increase was found in overall out-of-hospital mortality (43.2%) and cause-specific out-of-hospital mortality related to neoplasms (76.7%), endocrine, nutritional and metabolic (79.5%) as well as cardiovascular (32.7%) diseases. The pandemic caused a sudden drop of ED visits and hospitalizations of non-COVID-19 patients during the lockdown period, and a concurrent increase in out-of-hospital mortality mainly driven by deaths for neoplasms, cardiovascular and endocrine diseases. As recurrencies of the COVID-19 pandemic are underway, the scenario described in this study might be useful to understand both the population reaction and the healthcare system response at the early phases of the pandemic in terms of reduced demand of care and systems capability in intercepting it.


Assuntos
Causas de Morte , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , /epidemiologia , /virologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/patologia , Humanos , Itália/epidemiologia , Doenças Metabólicas/mortalidade , Doenças Metabólicas/patologia , Neoplasias/mortalidade , Neoplasias/patologia , Pandemias , Quarentena , Estudos Retrospectivos , /isolamento & purificação
6.
Cell Metab ; 33(3): 479-498, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33529600

RESUMO

The increased prevalence of obesity, diabetes, and cardiovascular risk factors in people hospitalized with severe COVID-19 illness has engendered considerable interest in the metabolic aspects of SARS-CoV-2-induced pathophysiology. Here, I update concepts informing how metabolic disorders and their co-morbidities modify the susceptibility to, natural history, and potential treatment of SARS-CoV-2 infection, with a focus on human biology. New data informing genetic predisposition, epidemiology, immune responses, disease severity, and therapy of COVID-19 in people with obesity and diabetes are highlighted. The emerging relationships of metabolic disorders to viral-induced immune responses and viral persistence, and the putative importance of adipose and islet ACE2 expression, glycemic control, cholesterol metabolism, and glucose- and lipid-lowering drugs is reviewed, with attention to controversies and unresolved questions. Rapid progress in these areas informs our growing understanding of SARS-CoV-2 infection in people with diabetes and obesity, while refining the therapeutic strategies and research priorities in this vulnerable population.


Assuntos
/patologia , Diabetes Mellitus/patologia , Doenças Metabólicas/patologia , Obesidade/patologia , /metabolismo , Glicemia/análise , /epidemiologia , Colesterol/metabolismo , Comorbidade , Predisposição Genética para Doença/genética , Glucose/metabolismo , Humanos , Hiperglicemia/patologia
7.
RNA ; 27(4): 367-389, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33376192

RESUMO

RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.


Assuntos
Doenças Metabólicas/genética , Neoplasias/genética , Doenças do Sistema Nervoso/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA não Traduzido/genética , Apoptose/genética , Ciclo Celular/genética , Epigênese Genética , Marcadores Genéticos , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , RNA Mensageiro/metabolismo , RNA não Traduzido/metabolismo
8.
Mol Immunol ; 130: 142-147, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33358570

RESUMO

MAIT cells are innate-like T cells that are enriched in mucosal sites and tissues including adipose tissue and liver. They play an important role in immunity against microbial pathogens. Recently, it has been reported that MAIT cells could also be important in metabolic diseases and can be involved in setting up and maintaining chronic inflammation. In this review, we give an overview of recent advances in understanding MAIT cells role in the ethology of this diseases.


Assuntos
Doenças Metabólicas/etiologia , Células T Invariáveis Associadas à Mucosa/fisiologia , Tecido Adiposo/imunologia , Tecido Adiposo/fisiologia , Animais , Humanos , Imunidade nas Mucosas/fisiologia , Fígado/imunologia , Fígado/fisiologia , Doenças Metabólicas/imunologia , Doenças Metabólicas/patologia
9.
Food Chem ; 338: 127535, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798817

RESUMO

Polyphenols are compounds naturally present in fruits and vegetables that are gaining more and more attention due to their therapeutic effects and their potential technological applications. In this review, we intend to demonstrate the importance of some phenolic compounds, addressing their biological effects and potential for applications in various industrial fields. The intake of these compounds in appropriate concentrations can present promising effects in the prevention of diseases such as diabetes, obesity, Parkinson's, Alzheimer's, and others. They can also be used to improve the physicochemical properties of starch, in the preservation of foods, as natural dyes, prebiotic ingredients, hydrogels and nanocomplexes. In addition, these compounds have potential for innovation in the most diverse technological fields, including organic fine chemistry, basic materials chemistry, pharmaceuticals, food chemistry, chemical engineering, etc.


Assuntos
Conservantes de Alimentos/química , Polifenóis/química , Antioxidantes/química , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/patologia , Corantes/química , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/patologia , Obesidade/tratamento farmacológico , Obesidade/patologia , Fenóis/química , Fenóis/uso terapêutico , Polifenóis/uso terapêutico
10.
Am J Physiol Cell Physiol ; 320(3): C375-C391, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33356944

RESUMO

Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease and organ tissue complications in the overweight and obese organism. Despite this widely confirmed paradigm, numerous open questions and knowledge gaps remain to be investigated. This is mainly due to the intricately intertwined cross-talk of various pro- and anti-inflammatory signaling cascades involved in the immune response of expanding adipose depots, particularly the visceral adipose tissue. Adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone marrow-derived immune cells that signal via production of cytokines and chemokines. Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity. The aim of this review is to broadly present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing our overall understanding of the field. We also discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of adipose tissue inflammation. In doing so, we hope to stimulate studies to uncover novel physiological, cellular, and molecular targets for the treatment of obesity.


Assuntos
Tecido Adiposo/patologia , Inflamação/patologia , Doenças Metabólicas/patologia , Obesidade/patologia , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/metabolismo , Animais , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Doenças Metabólicas/metabolismo , Obesidade/metabolismo
11.
BMC Med Genomics ; 13(Suppl 11): 191, 2020 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-33371893

RESUMO

BACKGROUND: Understanding gene regulation is important but difficult. Elucidating tissue-specific gene regulation mechanism is even more challenging and requires gene co-expression network assembled from protein-protein interaction, transcription factor and gene binding, and post-transcriptional regulation (e.g., miRNA targeting) information. The miRNA binding affinity could therefore be changed by SNP(s) located at the 3' untranslated regions (3'UTR) of the target messenger RNA (mRNA) which miRNA(s) interacts with. Genome-wide association study (GWAS) has reported significant numbers of loci hosting SNPs associated with many traits. The goal of this study is to pinpoint GWAS functional variants located in 3'UTRs and elucidate if the genes harboring these variants along with their targeting miRNAs are associated with genetic traits relevant to certain tissues. METHODS: By applying MIGWAS, CoCoNet, ANNOVAR, and DAVID bioinformatics software and utilizing the gene expression database (e.g. GTEx data) to study GWAS summary statistics for 43 traits from 28 GWAS studies, we have identified a list of miRNAs and targeted genes harboring 3'UTR variants, which could contribute to trait-relevant tissue over miRNA-target gene network. RESULTS: Our result demonstrated that strong association between traits and tissues exists, and in particular, the Primary Biliary Cirrhosis (PBC) trait has the most significant p-value for all 180 tissues among all 43 traits used for this study. We reported SNPs located in 3'UTR regions of genes (SFMBT2, ZC3HAV1, and UGT3A1) targeted by miRNAs for PBC trait and its tissue association network. After employing Gene Ontology (GO) analysis for PBC trait, we have also identified a very important miRNA targeted gene over miRNA-target gene network, PFKL, which encodes the liver subunit of an enzyme. CONCLUSIONS: The non-coding variants identified from GWAS studies are casually assumed to be not critical to translated protein product. However, 3' untranslated regions (3'UTRs) of genes harbor variants can often change the binding affinity of targeting miRNAs playing important roles in protein translation degree. Our study has shown that GWAS variants could play important roles on miRNA-target gene networks by contributing the association between traits and tissues. Our analysis expands our knowledge on trait-relevant tissue network and paves way for future human disease studies.


Assuntos
Doenças Autoimunes/genética , Redes Reguladoras de Genes , Doenças Metabólicas/genética , MicroRNAs/genética , Doenças do Sistema Nervoso/genética , Locos de Características Quantitativas , RNA Mensageiro/genética , Doenças Autoimunes/patologia , Biologia Computacional , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Doenças Metabólicas/patologia , Doenças do Sistema Nervoso/patologia , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Software
12.
Nat Metab ; 2(12): 1482-1497, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33324010

RESUMO

White and beige adipocytes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are maintained by proliferation and differentiation of adipose progenitor cells (APCs). Here we use mice with tissue-specific telomerase reverse transcriptase (TERT) gene knockout (KO), which undergo premature telomere shortening and proliferative senescence in APCs, to investigate the effect of over-nutrition on APC exhaustion and metabolic dysfunction. We find that TERT KO in the Pdgfra+ cell lineage results in adipocyte hypertrophy, inflammation and fibrosis in SAT, while TERT KO in the Pdgfrb+ lineage leads to adipocyte hypertrophy in both SAT and VAT. Systemic insulin resistance is observed in both KO models and is aggravated by a high-fat diet. Analysis of human biopsies demonstrates that telomere shortening in SAT is associated with metabolic disease progression after bariatric surgery. Our data indicate that over-nutrition can promote APC senescence and provide a mechanistic link between ageing, obesity and diabetes.


Assuntos
Adipócitos/patologia , Envelhecimento/patologia , Doenças Metabólicas/patologia , Células-Tronco/patologia , Homeostase do Telômero , Adipócitos Bege/metabolismo , Adipócitos Brancos/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula/genética , Proliferação de Células , Dieta Hiperlipídica , Feminino , Humanos , Resistência à Insulina/genética , Gordura Intra-Abdominal , Masculino , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Gordura Subcutânea/metabolismo , Gordura Subcutânea/patologia , Telomerase/genética , Telomerase/metabolismo
13.
Nat Commun ; 11(1): 5165, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057007

RESUMO

Angiotensin-converting enzyme 2 (ACE2) has been identified as the host entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the COVID-19 pandemic. ACE2 is a regulatory enzyme of the renin-angiotensin system and has protective functions in many cardiovascular, pulmonary and metabolic diseases. This review summarizes available murine models with systemic or organ-specific deletion of ACE2, or with overexpression of murine or human ACE2. The purpose of this review is to provide researchers with the genetic tools available for further understanding of ACE2 biology and for the investigation of ACE2 in the pathogenesis and treatment of COVID-19.


Assuntos
Doenças Cardiovasculares/patologia , Modelos Animais de Doenças , Pneumopatias/patologia , Peptidil Dipeptidase A/metabolismo , Animais , Betacoronavirus/fisiologia , Doenças Cardiovasculares/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Pneumopatias/metabolismo , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Camundongos , Camundongos Mutantes , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia
14.
Metabolism ; 111S: 154337, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32795560

RESUMO

All living organisms including humans, experience changes in the light exposure generated by the Earth's rotation. In anticipation of this unavoidable geo-physical variability, and to generate an appropriate biochemical response, species of many phyla, including mammals have evolved a nearly 24-hour endogenous timing device known as the circadian clock (CC), which is self-sustained, cell autonomous and is present in every cell type. At the heart of the 'clock' functioning resides the CC-oscillator, an elegantly designed transcriptional-translational feedback system. Notably, the core components of the CC-oscillator not only drive daily rhythmicity of their own synthesis, but also generate circadian phase-specific variability in the expression levels of thousands of target genes through transcriptional, post-transcriptional and post-translational mechanisms. Thereby, this 'clock'-system provides proper chronological coordination in the functioning of cells, tissues and organs. The CC governs many physiologically critical functions. Among these functions, the key role of the CC in maintaining metabolic homeostasis deserves special emphasis. Indeed, the several features of the modern lifestyle (e.g. travel-induced jet lag, rotating shift work, energy-dense food) which, force disruption of circadian rhythms have recently emerged as a major driver to global health problems like obesity, cardiovascular disease and metabolic liver disease such as non-alcoholic fatty liver disease (NAFLD). Here we review, the CC-dependent pathways in different tissues which play critical roles in mediating several critical metabolic functions under physiological conditions and discuss their impact for the development of metabolic disease with a focus on the liver.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Homeostase/fisiologia , Humanos , Doenças Metabólicas/patologia
15.
Nat Commun ; 11(1): 3861, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737316

RESUMO

Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank.


Assuntos
Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Análise da Randomização Mendeliana/estatística & dados numéricos , Modelos Genéticos , Transcriptoma , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Simulação por Computador , Bases de Dados Factuais , Gastroenteropatias/diagnóstico , Gastroenteropatias/genética , Gastroenteropatias/patologia , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Funções Verossimilhança , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Herança Multifatorial , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
17.
Clin Sci (Lond) ; 134(12): 1357-1376, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32490513

RESUMO

Non-specific inhibition of Rho-associated kinases (ROCKs) alleviated renal fibrosis in the unilateral ureteral obstruction (UUO) model, while genetic deletion of ROCK1 did not affect renal pathology in mice. Thus, whether ROCK2 plays a role in renal tubulointerstitial fibrosis needs to be clarified. In the present study, a selective inhibitor against ROCK2 or genetic approach was used to investigate the role of ROCK2 in renal tubulointerstitial fibrosis. In the fibrotic kidneys of chronic kidney diseases (CKDs) patients, we observed an enhanced expression of ROCK2 with a positive correlation with interstitial fibrosis. In mice, the ROCK2 protein level was time-dependently increased in the UUO model. By treating CKD animals with KD025 at the dosage of 50 mg/kg/day via intraperitoneal injection, the renal fibrosis shown by Masson's trichrome staining was significantly alleviated along with the reduced expression of fibrotic genes. In vitro, inhibiting ROCK2 by KD025 or ROCK2 knockdown/knockout significantly blunted the pro-fibrotic response in transforming growth factor-ß1 (TGF-ß1)-stimulated mouse renal proximal tubular epithelial cells (mPTCs). Moreover, impaired cellular metabolism was reported as a crucial pathogenic factor in CKD. By metabolomics analysis, we found that KD025 restored the metabolic disturbance, including the impaired glutathione metabolism in TGF-ß1-stimulated tubular epithelial cells. Consistently, KD025 increased antioxidative stress enzymes and nuclear erythroid 2-related factor 2 (Nrf2) in fibrotic models. In addition, KD025 decreased the infiltration of macrophages and inflammatory response in fibrotic kidneys and blunted the activation of macrophages in vitro. In conclusion, inhibition of ROCK2 may serve as a potential novel therapy for renal tubulointerstitial fibrosis in CKD.


Assuntos
Células Epiteliais/enzimologia , Túbulos Renais Proximais/patologia , Doenças Metabólicas/enzimologia , Quinases Associadas a rho/antagonistas & inibidores , Adolescente , Animais , Anti-Inflamatórios/farmacologia , Criança , Pré-Escolar , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Feminino , Fibrose , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Lactente , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Doenças Metabólicas/patologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Células RAW 264.7 , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Regulação para Cima/efeitos dos fármacos , Obstrução Ureteral/enzimologia , Obstrução Ureteral/patologia , Quinases Associadas a rho/metabolismo
18.
Sci Rep ; 10(1): 8842, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483283

RESUMO

The relationship between osteoblast-specific insulin signaling, osteocalcin activation and gluco-metabolic homeostasis has proven to be complex and potentially inconsistent across animal-model systems and in humans. Moreover, the impact of postnatally acquired, osteoblast-specific insulin deficiency on the pancreas-to-skeleton-to-pancreas circuit has not been studied. To explore this relationship, we created a model of postnatal elimination of insulin signaling in osteoprogenitors. Osteoprogenitor-selective ablation of the insulin receptor was induced after ~10 weeks of age in IRl°x/lox/Osx-Cre+/- genotypic male and female mice (designated postnatal-OIRKO). At ~21 weeks of age, mice were then phenotypically and metabolically characterized. Postnatal-OIRKO mice demonstrated a significant reduction in circulating concentrations of undercarboxylated osteocalcin (ucOC), in both males and females compared with control littermates. However, no differences were observed between postnatal-OIRKO and control mice in: body composition (lean or fat mass); fasting serum insulin; HbA1c; glucose dynamics during glucose tolerance testing; or in pancreatic islet area or islet morphology, demonstrating that while ucOC is impacted by insulin signaling in osteoprogenitors, there appears to be little to no relationship between osteocalcin, or its derivative (ucOC), and glucose homeostasis in this model.


Assuntos
Doenças Metabólicas/patologia , Receptor de Insulina/metabolismo , Animais , Composição Corporal , Peso Corporal , Feminino , Teste de Tolerância a Glucose , Hemoglobina A Glicada/análise , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteocalcina/genética , Osteocalcina/metabolismo , Fenótipo , Receptor de Insulina/deficiência , Receptor de Insulina/genética , Células-Tronco/citologia , Células-Tronco/metabolismo
19.
Int J Mol Sci ; 21(10)2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32429235

RESUMO

We live and to do so we must breathe and eat, so are we a combination of what we eat and breathe? Here, we will consider this question, and the role in this respect of the AMP-activated protein kinase (AMPK). Emerging evidence suggests that AMPK facilitates central and peripheral reflexes that coordinate breathing and oxygen supply, and contributes to the central regulation of feeding and food choice. We propose, therefore, that oxygen supply to the body is aligned with not only the quantity we eat, but also nutrient-based diet selection, and that the cell-specific expression pattern of AMPK subunit isoforms is critical to appropriate system alignment in this respect. Currently available information on how oxygen supply may be aligned with feeding and food choice, or vice versa, through our motivation to breathe and select particular nutrients is sparse, fragmented and lacks any integrated understanding. By addressing this, we aim to provide the foundations for a clinical perspective that reveals untapped potential, by highlighting how aberrant cell-specific changes in the expression of AMPK subunit isoforms could give rise, in part, to known associations between metabolic disease, such as obesity and type 2 diabetes, sleep-disordered breathing, pulmonary hypertension and acute respiratory distress syndrome.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Oxigênio/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Dieta , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Isoformas de Proteínas/metabolismo , Respiração , Transtornos Respiratórios/metabolismo , Transtornos Respiratórios/patologia , Termogênese
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