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1.
FASEB J ; 35(9): e21837, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34383985

RESUMO

Overwhelming evidence indicates that excessive stimulation of innate immune receptors of the NOD-like receptor (NLR) family causes significant damage to multiple tissues, yet the role of these proteins in bone metabolism is not well known. Here, we studied the interaction between the NLRP3 and NLRC4 inflammasomes in bone homeostasis and disease. We found that loss of NLRP3 or NLRC4 inflammasome attenuated osteoclast differentiation in vitro. At the tissue level, lack of NLRP3, or NLRC4 to a lesser extent, resulted in higher baseline bone mass compared to wild-type (WT) mice, and conferred protection against LPS-induced inflammatory osteolysis. Bone mass accrual in mutant mice correlated with lower serum IL-1ß levels in vivo. Unexpectedly, the phenotype of Nlrp3-deficient mice was reversed upon loss of NLRC4 as bone mass was comparable between WT mice and Nlrp3;Nlrc4 knockout mice. Thus, although bone homeostasis is perturbed to various degrees by the lack of NLRP3 or NLRC4, this tissue appears to function normally upon compound loss of the inflammasomes assembled by these receptors.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Diferenciação Celular/fisiologia , Homeostase/fisiologia , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/metabolismo , Osteólise/metabolismo
2.
FASEB J ; 35(9): e21810, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34390520

RESUMO

Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.


Assuntos
Cobre/metabolismo , Homeostase/fisiologia , Animais , Transporte Biológico/fisiologia , ATPases Transportadoras de Cobre/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Neurodegenerativas/metabolismo
3.
FASEB J ; 35(9): e21816, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34396583

RESUMO

Proper physiological function of mammalian airways requires the differentiation of basal stem cells into secretory or multiciliated cells, among others. In addition, the self-renewal ability of these basal stem cells is crucial for developing a quick response to toxic agents in order to re-establish the epithelial barrier function of the airways. Although these epithelial missions are vital, little is known about those mechanism controlling airway epithelial regeneration in health and disease. p53 has been recently proposed as the guardian of homeostasis, promoting differentiation programs, and antagonizing a de-differentiation program. Here, we exploit mouse and human tracheal epithelial cell culture models to study the role of MDM2-p53 signaling in self-renewal and differentiation in the airway epithelium. We show that p53 protein regulation by MDM2 is crucial for basal stem cell differentiation and to keep proper cell proliferation. Therefore, we suggest that MDM2/p53 interaction modulation is a potential target to control regeneration of the mammalian airway epithelia without massively affecting the epithelium integrity and differentiation potential.


Assuntos
Diferenciação Celular/fisiologia , Epitélio/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Mucosa Respiratória/metabolismo , Células-Tronco/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Proliferação de Células/fisiologia , Células Epiteliais/metabolismo , Feminino , Homeostase/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regeneração/fisiologia , Transdução de Sinais/fisiologia , Traqueia/metabolismo
4.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361718

RESUMO

Several classes of polysaccharides have been described to have hypocholesterolemic potential, namely cholesterol bioaccessibility and bioavailability. This review will highlight the main mechanisms by which polysaccharides are known to affect cholesterol homeostasis at the intestine, namely the effect (i) of polysaccharide viscosity and its influence on cholesterol bioaccessibility; (ii) on bile salt sequestration and its dependence on the structural diversity of polysaccharides; (iii) of bio-transformations of polysaccharides and bile salts by the gut microbiota. Different quantitative structure-hypocholesterolemic activity relationships have been explored depending on the mechanism involved, and these were based on polysaccharide physicochemical properties, such as sugar composition and ramification degree, linkage type, size/molecular weight, and charge. The information gathered will support the rationalization of polysaccharides' effect on cholesterol homeostasis and highlight predictive rules towards the development of customized hypocholesterolemic functional food.


Assuntos
Anticolesterolemiantes/química , Ácidos e Sais Biliares/química , Colesterol/química , Alimento Funcional/análise , Mucosa Intestinal/metabolismo , Polissacarídeos/química , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/uso terapêutico , Ácidos e Sais Biliares/metabolismo , Disponibilidade Biológica , Biotransformação , Colesterol/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estrutura Molecular , Peso Molecular , Polissacarídeos/metabolismo , Polissacarídeos/uso terapêutico , Eletricidade Estática
5.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445112

RESUMO

Brassinosteroids (BRs) are steroid phytohormones that are known to regulate plant growth and nutrient uptake and distribution. However, how BRs regulate nutrient uptake and balance in legume species is not fully understood. Here, we show that optimal BR levels are required for soybean (Glycine max L.) seedling growth, as treatments with both 24-epicastasterone (24-epiCS) and the BR biosynthesis inhibitor propiconazole (PPZ) inhibit root growth, including primary root elongation and lateral root formation and elongation. Specifically, 24-epiCS and PPZ reduced the total phosphorus and potassium levels in the shoot and affected several minor nutrients, such as magnesium, iron, manganese, and molybdenum. A genome-wide transcriptome analysis identified 3774 and 4273 differentially expressed genes in the root tip after brassinolide and PPZ treatments, respectively. The gene ontology (GO) analysis suggested that genes related to "DNA-replication", "microtubule-based movement", and "plant-type cell wall organization" were highly responsive to the brassinolide and PPZ treatments. Furthermore, consistent with the effects on the nutrient concentrations, corresponding mineral transporters were found to be regulated by BR levels, including the GmPHT1s, GmKTs, GmVIT2, GmZIPs, and GmMOT1 genes. Our study demonstrates that optimal BR levels are important for growth and mineral nutrient homeostasis in soybean seedlings.


Assuntos
Brassinosteroides/metabolismo , Homeostase/fisiologia , Minerais/metabolismo , Nutrientes/metabolismo , Soja/crescimento & desenvolvimento , Soja/metabolismo , Colestanóis/metabolismo , Fabaceae/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica de Plantas/fisiologia , Reguladores de Crescimento de Plantas/metabolismo , Proteínas de Plantas/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plântula/metabolismo , Esteroides Heterocíclicos/metabolismo
6.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445787

RESUMO

Mechanical stress is an important factor affecting bone tissue homeostasis. We focused on the interactions among mechanical stress, glucose uptake via glucose transporter 1 (Glut1), and the cellular energy sensor sirtuin 1 (SIRT1) in osteoblast energy metabolism, since it has been recognized that SIRT1, an NAD+-dependent deacetylase, may function as a master regulator of the mechanical stress response as well as of cellular energy metabolism (glucose metabolism). In addition, it has already been demonstrated that SIRT1 regulates the activity of the osteogenic transcription factor runt-related transcription factor 2 (Runx2). The effects of mechanical loading on cellular activities and the expressions of Glut1, SIRT1, and Runx2 were evaluated in osteoblasts and chondrocytes in a 3D cell-collagen sponge construct. Compressive mechanical loading increased osteoblast activity. Mechanical loading also significantly increased the expression of Glut1, significantly decreased the expression of SIRT1, and significantly increased the expression of Runx2 in osteoblasts in comparison with non-loaded osteoblasts. Incubation with a Glut1 inhibitor blocked mechanical stress-induced changes in SIRT1 and Runx2 in osteoblasts. In contrast with osteoblasts, the expressions of Glut1, SIRT1, and Runx2 in chondrocytes were not affected by loading. Our present study indicated that mechanical stress induced the upregulation of Glut1 following the downregulation of SIRT1 and the upregulation of Runx2 in osteoblasts but not in chondrocytes. Since SIRT1 is known to negatively regulate Runx2 activity, a mechanical stress-induced downregulation of SIRT1 may lead to the upregulation of Runx2, resulting in osteoblast differentiation. Incubation with a Glut1 inhibitor the blocked mechanical stress-induced downregulation of SIRT1 following the upregulation of Runx2, suggesting that Glut1 is necessary to mediate the responses of SIRT1 and Runx2 to mechanical loading in osteoblasts.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Osteoblastos/metabolismo , Osteogênese/fisiologia , Transdução de Sinais/fisiologia , Sirtuína 1/metabolismo , Idoso , Diferenciação Celular/fisiologia , Células Cultivadas , Condrócitos/metabolismo , Feminino , Regulação da Expressão Gênica/fisiologia , Homeostase/fisiologia , Humanos , NAD/metabolismo , Estresse Mecânico
7.
Nutrients ; 13(8)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34444890

RESUMO

Obesity prevention interventions generally have either not worked or had effects inadequate to mitigate the problem. They have been predicated on the simple energy balance model, which has been severely questioned by biological scientists. Numerous other etiological mechanisms have been proposed, including the intestinal microbiome, which has been related to childhood obesity in numerous ways. Public health research is needed in regard to diet and the microbiome, which hopefully will lead to effective child obesity prevention.


Assuntos
Dieta Saudável/métodos , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Microbioma Gastrointestinal/fisiologia , Obesidade Pediátrica/prevenção & controle , Criança , Feminino , Homeostase/fisiologia , Humanos , Masculino
8.
Nat Neurosci ; 24(9): 1198-1209, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34354283

RESUMO

The brain is supplied by an elaborate vascular network that originates extracranially and reaches deep into the brain. The concept of the neurovascular unit provides a useful framework to investigate how neuronal signals regulate nearby microvessels to support the metabolic needs of the brain, but it does not consider the role of larger cerebral arteries and systemic vasoactive signals. Furthermore, the recently emerged molecular heterogeneity of cerebrovascular cells indicates that there is no prototypical neurovascular unit replicated at all levels of the vascular network. Here, we examine the cellular and molecular diversity of the cerebrovascular tree and the relative contribution of systemic and brain-intrinsic factors to neurovascular function. Evidence supports the concept of a 'neurovascular complex' composed of segmentally diverse functional modules that implement coordinated vascular responses to central and peripheral signals to maintain homeostasis of the brain. This concept has major implications for neurovascular regulation in health and disease and for brain imaging.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Circulação Cerebrovascular/fisiologia , Homeostase/fisiologia , Acoplamento Neurovascular/fisiologia , Animais , Humanos
9.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360917

RESUMO

Although once perceived as inert structures that merely serve for lipid storage, lipid droplets (LDs) have proven to be the dynamic organelles that hold many cellular functions. The LDs' basic structure of a hydrophobic core consisting of neutral lipids and enclosed in a phospholipid monolayer allows for quick lipid accessibility for intracellular energy and membrane production. Whereas formed at the peripheral and perinuclear endoplasmic reticulum, LDs are degraded either in the cytosol by lipolysis or in the vacuoles/lysosomes by autophagy. Autophagy is a regulated breakdown of dysfunctional, damaged, or surplus cellular components. The selective autophagy of LDs is called lipophagy. Here, we review LDs and their degradation by lipophagy in yeast, which proceeds via the micrometer-scale raft-like lipid domains in the vacuolar membrane. These vacuolar microdomains form during nutrient deprivation and facilitate internalization of LDs via the vacuolar membrane invagination and scission. The resultant intra-vacuolar autophagic bodies with LDs inside are broken down by vacuolar lipases and proteases. This type of lipophagy is called microlipophagy as it resembles microautophagy, the type of autophagy when substrates are sequestered right at the surface of a lytic compartment. Yeast microlipophagy via the raft-like vacuolar microdomains is a great model system to study the role of lipid domains in microautophagic pathways.


Assuntos
Autofagia/fisiologia , Gotículas Lipídicas/metabolismo , Microdomínios da Membrana/metabolismo , Saccharomyces cerevisiae/metabolismo , Vacúolos/metabolismo , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Homeostase/fisiologia , Lipólise/fisiologia , Lisossomos/metabolismo , Fosfolipídeos/metabolismo
10.
Immunity ; 54(7): 1511-1526.e8, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34260887

RESUMO

Myeloid cells encounter stromal cells and their matrix determinants on a continual basis during their residence in any given organ. Here, we examined the impact of the collagen receptor LAIR1 on myeloid cell homeostasis and function. LAIR1 was highly expressed in the myeloid lineage and enriched in non-classical monocytes. Proteomic definition of the LAIR1 interactome identified stromal factor Colec12 as a high-affinity LAIR1 ligand. Proteomic profiling of LAIR1 signaling triggered by Collagen1 and Colec12 highlighted pathways associated with survival, proliferation, and differentiation. Lair1-/- mice had reduced frequencies of Ly6C- monocytes, which were associated with altered proliferation and apoptosis of non-classical monocytes from bone marrow and altered heterogeneity of interstitial macrophages in lung. Myeloid-specific LAIR1 deficiency promoted metastatic growth in a melanoma model and LAIR1 expression associated with improved clinical outcomes in human metastatic melanoma. Thus, monocytes and macrophages rely on LAIR1 sensing of stromal determinants for fitness and function, with relevance in homeostasis and disease.


Assuntos
Homeostase/fisiologia , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Monócitos/metabolismo , Receptores Imunológicos/metabolismo , Animais , Apoptose/fisiologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Células COS , Diferenciação Celular/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Linhagem da Célula/fisiologia , Proliferação de Células/fisiologia , Chlorocebus aethiops , Feminino , Humanos , Pulmão/patologia , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/patologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Metástase Neoplásica/patologia , Proteômica/métodos , Transdução de Sinais/fisiologia
11.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299236

RESUMO

Inflammatory bowel disease (IBD) is a heterogeneous state of chronic intestinal inflammation of unknown cause encompassing Crohn's disease (CD) and ulcerative colitis (UC). IBD has been linked to genetic and environmental factors, microbiota dysbiosis, exacerbated innate and adaptive immunity and epithelial intestinal barrier dysfunction. IBD is classically associated with gut accumulation of proinflammatory Th1 and Th17 cells accompanied by insufficient Treg numbers and Tr1 immune suppression. Inflammatory T cells guide innate cells to perpetuate a constant hypersensitivity to microbial antigens, tissue injury and chronic intestinal inflammation. Recent studies of intestinal mucosal homeostasis and IBD suggest involvement of innate lymphoid cells (ILCs). These lymphoid-origin cells are innate counterparts of T cells but lack the antigen receptors expressed on B and T cells. ILCs play important roles in the first line of antimicrobial defense and contribute to organ development, tissue protection and regeneration, and mucosal homeostasis by maintaining the balance between antipathogen immunity and commensal tolerance. Intestinal homeostasis requires strict regulation of the quantity and activity of local ILC subpopulations. Recent studies demonstrated that changes to ILCs during IBD contribute to disease development. A better understanding of ILC behavior in gastrointestinal homeostasis and inflammation will provide valuable insights into new approaches to IBD treatment. This review summarizes recent research into ILCs in intestinal homeostasis and the latest advances in the understanding of the role of ILCs in IBD, with particular emphasis on the interaction between microbiota and ILC populations and functions.


Assuntos
Imunidade Inata/imunologia , Mucosa Intestinal/metabolismo , Linfócitos/metabolismo , Imunidade Adaptativa/imunologia , Animais , Colite , Colite Ulcerativa , Doença de Crohn , Trato Gastrointestinal , Homeostase/fisiologia , Humanos , Tolerância Imunológica , Inflamação , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/fisiopatologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Linfócitos/imunologia , Microbiota , Células Th17
12.
Cell Mol Life Sci ; 78(16): 5925-5951, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34228161

RESUMO

Mitochondrial fidelity is a key determinant of longevity and was found to be perturbed in a multitude of disease contexts ranging from neurodegeneration to heart failure. Tight homeostatic control of the mitochondrial proteome is a crucial aspect of mitochondrial function, which is severely complicated by the evolutionary origin and resulting peculiarities of the organelle. This is, on one hand, reflected by a range of basal quality control factors such as mitochondria-resident chaperones and proteases, that assist in import and folding of precursors as well as removal of aggregated proteins. On the other hand, stress causes the activation of several additional mechanisms that counteract any damage that may threaten mitochondrial function. Countermeasures depend on the location and intensity of the stress and on a range of factors that are equipped to sense and signal the nature of the encountered perturbation. Defective mitochondrial import activates mechanisms that combat the accumulation of precursors in the cytosol and the import pore. To resolve proteotoxic stress in the organelle interior, mitochondria depend on nuclear transcriptional programs, such as the mitochondrial unfolded protein response and the integrated stress response. If organelle damage is too severe, mitochondria signal for their own destruction in a process termed mitophagy, thereby preventing further harm to the mitochondrial network and allowing the cell to salvage their biological building blocks. Here, we provide an overview of how different types and intensities of stress activate distinct pathways aimed at preserving mitochondrial fidelity.


Assuntos
Mitocôndrias/fisiologia , Transdução de Sinais/fisiologia , Animais , Homeostase/fisiologia , Humanos , Mitocôndrias/metabolismo , Mitofagia/fisiologia , Proteoma/metabolismo , Resposta a Proteínas não Dobradas/fisiologia
13.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298870

RESUMO

The liver is an essential immunological organ due to its gatekeeper position to bypassing antigens from the intestinal blood flow and microbial products from the intestinal commensals. The tissue-resident liver macrophages, termed Kupffer cells, represent key phagocytes that closely interact with local parenchymal, interstitial and other immunological cells in the liver to maintain homeostasis and tolerance against harmless antigens. Upon liver injury, the pool of hepatic macrophages expands dramatically by infiltrating bone marrow-/monocyte-derived macrophages. The interplay of the injured microenvironment and altered macrophage pool skews the subsequent course of liver injuries. It may range from complete recovery to chronic inflammation, fibrosis, cirrhosis and eventually hepatocellular cancer. This review summarizes current knowledge on the classification and role of hepatic macrophages in the healthy and injured liver.


Assuntos
Hepatopatias/patologia , Fígado/patologia , Macrófagos/patologia , Animais , Homeostase/fisiologia , Humanos , Macrófagos do Fígado/patologia , Monócitos/patologia
14.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298886

RESUMO

Interaction between endothelial cells and osteoblasts is essential for bone development and homeostasis. This process is mediated in large part by osteoblast angiotropism, the migration of osteoblasts alongside blood vessels, which is crucial for the homing of osteoblasts to sites of bone formation during embryogenesis and in mature bones during remodeling and repair. Specialized bone endothelial cells that form "type H" capillaries have emerged as key interaction partners of osteoblasts, regulating osteoblast differentiation and maturation and ensuring their migration towards newly forming trabecular bone areas. Recent revolutions in high-resolution imaging methodologies for bone as well as single cell and RNA sequencing technologies have enabled the identification of some of the signaling pathways and molecular interactions that underpin this regulatory relationship. Similarly, the intercellular cross talk between endothelial cells and entombed osteocytes that is essential for bone formation, repair, and maintenance are beginning to be uncovered. This is a relatively new area of research that has, until recently, been hampered by a lack of appropriate analysis tools. Now that these tools are available, greater understanding of the molecular relationships between these key cell types is expected to facilitate identification of new drug targets for diseases of bone formation and remodeling.


Assuntos
Desenvolvimento Ósseo/fisiologia , Osso e Ossos/fisiologia , Homeostase/fisiologia , Osteoblastos/fisiologia , Animais , Remodelação Óssea/fisiologia , Células Endoteliais/fisiologia , Humanos , Osteogênese/fisiologia , Transdução de Sinais/fisiologia
15.
Nutrients ; 13(6)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34200102

RESUMO

Transcription factor-7-like 2 (TCF7L2) is one of the most important susceptibility genes for type 2 diabetes mellitus (T2DM). The aim of our cross-sectional population-based study was to analyze whether daily macronutrient intake may influence the effects of the TCF7L2 rs7901695 genotype on glucose homeostasis and obesity-related parameters. We recruited 810 participants (47.5% men and 52.5% women), 18-79 years old (mean age, 42.1 (±14.5) years), who were genotyped for the common TCF7L2 rs7901695 single-nucleotide polymorphism (SNP), and anthropometric measurements, body composition, body fat distribution (visceral (VAT) and subcutaneous adipose tissue (SAT) content), blood glucose and insulin concentrations after fasting and during OGTTs, and HbA1c were assessed. The VAT/SAT ratio, HOMA-IR (homeostatic model assessment of insulin resistance), HOMA-B (homeostatic model assessment of ß-cell function), and CIR30 (corrected insulin response) were calculated. The daily macronutrient intake was evaluated based on 3-day food-intake diaries. Daily physical activity was evaluated based on a validated questionnaire. We performed ANOVA or Kruskal-Wallis tests, and multivariate linear regression models were created to evaluate the effects of dietary macronutrient intake on glucose homeostasis and obesity-related parameters in carriers of the investigated genotypes. This study was registered at ClinicalTrials.gov as NCT03792685. The TT-genotype carriers stratified to the upper protein intake quantiles presented higher HbA1c levels than the CT- and CC-genotype participants in the same quantiles (p = 0.038 and p = 0.022, respectively). Moreover, we observed higher HOMA-IR (p = 0.014), as well as significantly higher blood glucose and insulin concentrations, during the OGTTs for those in the upper quantiles, when compared to subjects from the lower quantiles of protein intake, while the CC-genotype carriers presented significantly lower HbA1c (p = 0.033) and significantly higher CIR30 (p = 0.03). The linear regression models revealed that an increase in energy derived from proteins in TT carriers was associated with higher HbA1c levels (ß = 0.37 (95% CI: 0.01-0.74, p = 0.05)), although, in general, carrying the TT genotype, but without considering protein intake, showed an opposite tendency-to lower HbA1c levels (ß = -0.22 (95% CI: 0.47 to -0.01, p = 0.05). Among the subjects stratified to the lower quantile of carbohydrate intake, the TT-genotype individuals presented higher HbA1c (p = 0.041), and the CC-genotype subjects presented higher VAT (p = 0.033), lower SAT (p = 0.033), and higher VAT/SAT ratios (p = 0.034). In both the CC- and TT-genotype carriers, we noted higher VAT (p = 0.012 and p = 0.0006, respectively), lower SAT (p = 0.012 and p = 0.0006, respectively) and higher VAT/SAT ratios (p = 0.016 and p = 0.00062, respectively) when dietary fat provided more than 30% of total daily energy intake, without any differences in total body fat content. Our findings suggest that associations of the common TCF7L2 SNP with glucose homeostasis and obesity-related parameters may be dependent on daily macronutrient intake, which warrants further investigations in a larger population, as well as interventional studies.


Assuntos
Ingestão de Alimentos , Glucose/metabolismo , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Adolescente , Adulto , Idoso , Glicemia/análise , Composição Corporal , Distribuição da Gordura Corporal , Estudos Transversais , Ingestão de Alimentos/fisiologia , Feminino , Genótipo , Homeostase/fisiologia , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/dietoterapia , Obesidade/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/fisiologia , Adulto Jovem
16.
Nutrients ; 13(7)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206629

RESUMO

A perinatal high-salt (HS) diet was reported to elevate plasma triglycerides. This study aimed to investigate the hypothesis that a perinatal HS diet predisposed offspring to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of abnormal lipid metabolism, and the possible mechanism. Female C57BL/6 mice were fed a control diet (0.5% NaCl) or HS diet (4% NaCl) during pregnancy and lactation and their offspring were sacrificed at weaning. The perinatal HS diet induced greater variation in fecal microbial beta-diversity (ß-diversity) and increased bacteria abundance of Proteobacteria and Bacteroides. The gut microbiota dysbiosis promoted bile acid homeostasis disbalance, characterized by the accumulation of lithocholic acid (LCA) and deoxycholic acid (DCA) in feces. These alterations disturbed gut barrier by increasing the expression of tight junction protein (Tjp) and occludin (Ocln), and increased systemic lipopolysaccharide (LPS) levels and hepatic inflammatory cytokine secretion (TNF-α and IL-6) in the liver. The perinatal HS diet also inhibited hepatic expression of hepatic FXR signaling (CYP7A1 and FXR), thus triggering increased hepatic expression of pro-inflammatory cytokines (TNF-α and IL-6) and hepatic lipid metabolism-associated genes (SREBP-1c, FAS, ACC), leading to unique characteristics of NAFLD. In conclusion, a perinatal HS diet induced NAFLD in weanling mice offspring; the possible mechanism was related to increased bacteria abundance of Proteobacteria and Bacteroides, increased levels of LCA and DCA in feces, and increased expressions of hepatic FXR signaling.


Assuntos
Dieta/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Efeitos Tardios da Exposição Pré-Natal/etiologia , Sódio na Dieta/efeitos adversos , Acidose/etiologia , Animais , Animais Recém-Nascidos , Ácidos e Sais Biliares/metabolismo , Dieta/métodos , Disbiose/etiologia , Feminino , Microbioma Gastrointestinal/fisiologia , Homeostase/fisiologia , Lactação/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Gravidez , Transdução de Sinais/fisiologia , Triglicerídeos/sangue , Desmame
17.
Biomed Pharmacother ; 139: 111667, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243608

RESUMO

Interactions between vascular smooth muscle cells (VSMCs), endothelial cells (ECs), pericytes (PCs) and macrophages (MФ), the major components of blood vessels, play a crucial role in maintaining vascular structural and functional homeostasis. Low-density lipoprotein (LDL) receptor-related protein-1 (LRP1), a transmembrane receptor protein belonging to the LDL receptor family, plays multifunctional roles in maintaining endocytosis, homeostasis, and signal transduction. Accumulating evidence suggests that LRP1 modulates vascular homeostasis mainly by regulating vasoactive substances and specific intracellular signaling pathways, including the plasminogen activator inhibitor 1 (PAI-1) signaling pathway, platelet-derived growth factor (PDGF) signaling pathway, transforming growth factor-ß (TGF-ß) signaling pathway and vascular endothelial growth factor (VEGF) signaling pathway. The aim of the present review is to focus on recent advances in the discovery and mechanism of vascular homeostasis regulated by LRP1-dependent signaling pathways. These recent discoveries expand our understanding of the mechanisms controlling LRP1 as a target for studies on vascular complications.


Assuntos
Homeostase/fisiologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Músculo Liso Vascular/metabolismo , Transdução de Sinais/fisiologia , Animais , Endocitose/fisiologia , Células Endoteliais/metabolismo , Humanos , Lipoproteínas LDL/metabolismo , Miócitos de Músculo Liso/metabolismo
18.
Biomed Pharmacother ; 139: 111603, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243596

RESUMO

The HtrA protein family is composed by evolutionally-conserved serine proteases, which are homologous to the HtrA protein of the model bacterium Escherichia coli. They are widely distributed in organisms including humans, prokaryotes and eukaryotes. Moreover, HtrA family proteins are important regulators of a variety of human physiological processes, which contains the maintenance of mitochondrial homeostasis, cellular signal transduction and apoptosis regulation. The HtrA family has been found to be associated with cancer and could be used as a target for future cancer treatments. The purpose of this article is to review the relationship between these HtrA and cancer and to summarize the latest researches on HtrA and cancer.


Assuntos
Neoplasias/metabolismo , Serina Proteases/metabolismo , Animais , Apoptose/fisiologia , Homeostase/fisiologia , Humanos , Mitocôndrias/metabolismo , Transdução de Sinais/fisiologia
19.
Nutrients ; 13(6)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072120

RESUMO

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a "privileged" organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood-brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood-CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.


Assuntos
Barreira Hematoencefálica , Encéfalo , Manganês , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Líquido Cefalorraquidiano/metabolismo , Líquido Cefalorraquidiano/fisiologia , Plexo Corióideo/metabolismo , Plexo Corióideo/fisiologia , Homeostase/fisiologia , Humanos , Manganês/metabolismo , Manganês/fisiologia , Camundongos , Ratos
20.
Am J Physiol Endocrinol Metab ; 321(1): E146-E155, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34097543

RESUMO

Cannabinoid 1 receptor (CB1R) inverse agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice.NEW & NOTEWORTHY Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.


Assuntos
Peso Corporal/fisiologia , Glucose/metabolismo , Homeostase/fisiologia , Neurônios/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Composição Corporal/fisiologia , Proteína 9 Associada à CRISPR , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Dieta Hiperlipídica , Metabolismo Energético/fisiologia , Feminino , Edição de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Receptor CB1 de Canabinoide/deficiência , Receptor CB1 de Canabinoide/genética
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