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1.
Cell Mol Life Sci ; 81(1): 50, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38252148

RESUMO

Pancreatic neuroendocrine neoplasms (PanNENs) are a group of highly heterogeneous neoplasms originating from the endocrine islet cells of the pancreas with characteristic neuroendocrine differentiation, more than 60% of which represent metastases when diagnosis, causing major tumor-related death. Metabolic alterations have been recognized as one of the hallmarks of tumor metastasis, providing attractive therapeutic targets. However, little is known about the molecular mechanism of metabolic changes regulating PanNEN progression. In this study, we first identified methylmalonic acid (MMA) as an oncometabolite for PanNEN progression, based on serum metabolomics of metastatic PanNEN compared with non-metastatic PanNEN patients. One of the key findings was the potentially novel mechanism of epithelial-mesenchymal transition (EMT) triggered by MMA. Inhibin ßA (INHBA) was characterized as a key regulator of MMA-induced PanNEN progression according to transcriptomic analysis, which has been validated in vitro and in vivo. Mechanistically, INHBA was activated by FOXA2, a neuroendocrine (NE) specific transcription factor, which was initiated during MMA-induced progression. In addition, MMA-induced INHBA upregulation activated downstream MITF to regulate EMT-related genes in PanNEN cells. Collectively, these data suggest that activation of INHBA via FOXA2 promotes MITF-mediated EMT during MMA inducing PanNEN progression, which puts forward a novel therapeutic target for PanNENs.


Assuntos
Fator 3-beta Nuclear de Hepatócito , Subunidades beta de Inibinas , Ácido Metilmalônico , Neoplasias Pancreáticas , Humanos , Fator 3-beta Nuclear de Hepatócito/genética , Subunidades beta de Inibinas/genética , Pâncreas , Neoplasias Pancreáticas/genética , Ativação Transcricional
2.
Metabolomics ; 20(6): 116, 2024 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-39397188

RESUMO

BACKGROUND: Dopaminergic neurons from the substantia nigra pars compacta (SNc) have a higher susceptibility to aging-related degeneration, compared to midbrain dopaminergic cells present in the ventral tegmental area (VTA); the death of dopamine neurons in the SNc results in Parkinson´s disease (PD). In addition to increased loss by aging, dopaminergic neurons from the SNc are more prone to cell death when exposed to genetic or environmental factors, that either interfere with mitochondrial function, or cause an increase of oxidative stress. The oxidation of dopamine is a contributing source of reactive oxygen species (ROS), but this production is not enough to explain the differences in susceptibility to degeneration between SNc and VTA neurons. AIM OF REVIEW: In this review we aim to highlight the intrinsic differences between SNc and VTA dopamine neurons, in terms of gene expression, calcium oscillations, bioenergetics, and ROS responses. Also, to describe the changes in the pentose phosphate pathway and the induction of apoptosis in SNc neurons during aging, as related to the development of PD. KEY SCIENTIFIC CONCEPTS OF REVIEW: Recent work showed that neurons from the SNc possess intrinsic characteristics that result in metabolic differences, related to their intricate morphology, that render them more susceptible to degeneration. In particular, these neurons have an elevated basal energy metabolism, that is required to fulfill the demands of the constant firing of action potentials, but at the same time, is associated to higher ROS production, compared to VTA cells. Finally, we discuss how mutations related to PD affect metabolic pathways, and the related mechanisms, as revealed by metabolomics.


Assuntos
Neurônios Dopaminérgicos , Doença de Parkinson , Espécies Reativas de Oxigênio , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Neurônios Dopaminérgicos/metabolismo , Animais , Espécies Reativas de Oxigênio/metabolismo , Metabolismo Energético , Estresse Oxidativo , Área Tegmentar Ventral/metabolismo , Mitocôndrias/metabolismo , Dopamina/metabolismo , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-39425884

RESUMO

Hyper and hypoprolactinemia seem to be related to the occurrence of metabolic alterations in PCOS patients. In contrast, between significantly elevated and significantly low, prolactin levels seem to be protective against metabolic consequences. In the present review, we found 4 studies investigating hypoprolactinemia in patients with PCOS. We also identified 6 additional studies that reported low levels of PRL in PCOS patients. Although its prevalence is not considered high (13.2-13.9%), its contribution is certainly significant to the metabolic alterations observed in PCOS (insulin resistance, obesity, diabetes mellitus, and fatty liver disease). Dopamine inhibits the secretion of prolactin and GnRH. If dopamine levels are low or the dopamine receptor is less expressed or mutated, the levels of prolactin and GnRH increase, and consequently, LH also increases. On the other hand, hyperprolactinemia, in prolactinomas-typical levels, acting through kisspeptin inhibition causes GnRH suppression and hypogonadotropic hypogonadism. In situations of hypoprolactinemia due to excessive dopamine agonist treatment, dosage reduction is important to minimize the decrease in prolactin levels. Nevertheless, there is a lack of prospective studies confirming these hypotheses, as well as randomized clinical trials with appropriate drugs targeting both hyperprolactin and hypoprolactin in patients with PCOS.

4.
J Nutr ; 154(10): 2963-2975, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39163971

RESUMO

BACKGROUND: Maple syrup, a minimally transformed sweetener rich in polyphenols, can exert a action and improve metabolic parameters in animal models. However, no randomized clinical trial has investigated this. OBJECTIVES: This study aims to determine whether replacing refined sugars with an equivalent quantity of maple syrup could decrease key cardiometabolic risk factors in individuals with mild metabolic alterations. METHODS: In a randomized, double-blind, controlled crossover trial with 42 overweight adults with mild cardiometabolic alterations, participants were instructed to substitute 5% of their total caloric intake from added sugars with either maple syrup or an artificially flavored sucrose syrup for 8 wk. The primary outcome included changes in glucose homeostasis, whereas secondary outcomes were changes in other cardiometabolic risk factors such as blood pressure, anthropometric indices, and blood lipid profiles. Exploratory outcomes involved analyzing changes in gut microbiota composition. RESULTS: Replacing refined sugars with maple syrup over 8 wk decreased the glucose area under the curve when compared with substituting refined sugars with sucrose syrup, as determined during the oral glucose tolerance test, leading to a significant difference between the intervention arms (-50.59 ± 201.92 compared with 29.93 ± 154.90; P < 0.047). Substituting refined sugar with maple syrup also significantly decreased android fat mass (-7.83 ± 175.05 g compared with 67.61 ± 206.71 g; P = 0.02) and systolic blood pressure (-2.72 ± 8.73 mm Hg compared with 0.87 ± 8.99 mm Hg; P = 0.03). No changes in the blood lipid profile were observed. As an exploratory outcome, we further observed that substituting refined sugars with maple syrup promoted selective taxonomic changes in the gut microbiota such as a significant reduction in the abundance of Klebsiella species and decreased microbial functions associated with bacterial-induced cytokine response, when compared with substitution with sucrose syrup. CONCLUSIONS: Substituting refined sugars with maple syrup in individuals with mild metabolic alterations result in a significantly greater reduction of key cardiometabolic risk factors compared with substitution with sucrose syrup, in association with specific changes in gut microbiota. The role of the gut microbiota in these effects remains to be further explored. This trial was registered at clinicaltrials.gov as NCT04117802.


Assuntos
Acer , Fatores de Risco Cardiometabólico , Estudos Cross-Over , Humanos , Método Duplo-Cego , Masculino , Feminino , Acer/química , Adulto , Pessoa de Meia-Idade , Glicemia/metabolismo , Edulcorantes/farmacologia , Edulcorantes/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Sobrepeso , Açúcares da Dieta/administração & dosagem
5.
Pharmacol Res ; 208: 107382, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39218420

RESUMO

It is now recognized that tumors are not merely masses of transformed cells but are intricately interconnected with healthy cells in the tumor microenvironment (TME), forming complex and heterogeneous structures. Recent studies discovered that cancer cells can steal mitochondria from healthy cells to empower themselves, while reducing the functions of their target organ. Mitochondrial transfer, i.e. the intercellular movement of mitochondria, is recently emerging as a novel process in cancer biology, contributing to tumor growth, metastasis, and resistance to therapy by shaping the metabolic landscape of the tumor microenvironment. This review highlights the influence of transferred mitochondria on cancer bioenergetics, redox balance and apoptotic resistance, which collectively foster aggressive cancer phenotype. Furthermore, the therapeutic implications of mitochondrial transfer are discussed, emphasizing the potential of targeting these pathways to overcome drug resistance and improve treatment efficacy.


Assuntos
Mitocôndrias , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Mitocôndrias/metabolismo , Animais , Metabolismo Energético , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos
6.
Cell Mol Biol Lett ; 29(1): 80, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38811901

RESUMO

BACKGROUND: Sodium-glucose transporter 2 (SGLT2) inhibitors (iSGLT2) are approved medications for type 2 diabetes. Recent studies indicate that iSGLT2 inhibit the growth of some cancer cells. However, the mechanism(s) remains to be fully elucidated. METHODS: The SGLT2 levels were determined in normal colon CCD 841 CoN and, HCT 116, HT-29, SW480 and LoVo colorectal cancer (CRC) cell lines by quantitative real-time PCR and western blot. The effect of iSGLT2 canagliflozin on cell proliferation was examined using CCK-8, as its role on CRC cells metabolism and tumorigenesis has been evaluated by XF HS Seahorse Bioanalyzer and flow cytometric analyses. Transient gene silencing experiments and analysis of protein-protein interaction network were conducted to evaluate the SGLT2 molecular targets in CRC cells. RESULTS: Data showed that the treatment with iSGLT2 (50 µM) for 72 h induced cell cycle arrest (p < 0.001), impaired glucose and energetic metabolism (p < 0.001), promoted apoptotic cell death and ER stress flowing into autophagy (p < 0.001) in HCT 116 and HT-29 cells. These cellular events were accompanied by sirtuin 3 (SIRT3) upregulation (p < 0.01), as also supported by SIRT3 transient silencing experiments resulting in the attenuation of the effects of iSGLT2 on the cellular metabolic/energetic alterations and the induction of programmed cell death. The identification and validation of dipeptidyl peptidase 4 (DPP4) as potential common target of SGLT2 and SIRT3 were also assessed. CONCLUSIONS: These results deepened knowledge on the iSGLT2 contribution in limiting CRC tumorigenesis unveiling the SGLT2/SIRT3 axis in the cytotoxic mechanisms.


Assuntos
Apoptose , Proliferação de Células , Neoplasias Colorretais , Estresse do Retículo Endoplasmático , Mitocôndrias , Inibidores do Transportador 2 de Sódio-Glicose , Transportador 2 de Glucose-Sódio , Humanos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/genética , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Canagliflozina/farmacologia , Células HT29 , Células HCT116 , Sirtuína 3/metabolismo , Sirtuína 3/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Glucose/metabolismo
7.
Endocr Res ; 49(1): 12-21, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-37864464

RESUMO

BACKGROUND AND AIMS: Patients with obesity and type 2 diabetes (T2D) have shown alterations in the affinity of IgG anti-leptin antibodies which are possibly related to metabolic alterations. In the present exploratory study, we analyzed serum samples from adults with T2D classified by body mass index (BMI) and evaluated the relationship of IgG anti-leptin antibodies with body composition, metabolic and cardiovascular risk parameters. METHODS: Serum IgG anti-leptin antibodies (total, free and immune complexes fractions) were measured by in-house ELISA. Body composition, metabolic biomarkers (glucose, glycated hemoglobin, lipid profile, insulin, leptin) and cardiometabolic risk indexes (AIP, HOMA-IR, HOMA-ß) were evaluated in one hundred T2D patients. RESULTS: Patients with T2D and obesity presented a decrease in the percentage of IgG anti-leptin immune complexes compared to patients with T2D and overweight (p < 0.0053). Negative correlations of IgG anti-leptin immune complexes with triglycerides (TG) (r=-0.412, p = 0.023) and VLDL-C (r=-0.611, p = 0.017) were found in normal weight T2D patients. Free IgG anti-leptin antibodies correlated positively with TC (r = 0.390, p = 0.032) and LDL-C (r = 0.458, p = 0.011) in overweight individuals with T2D. Finally, total IgG anti-leptin antibodies correlated positively with leptin hormone levels (r = 0.409, p = 0.024) and negatively with HOMA-IR (r =-0.459, p = 0.012) in T2D patients with obesity. CONCLUSIONS: The decrease of IgG anti-leptin immune complexes observed in patients with T2D and obesity suggests a reduction in antibody affinity to the hormone that may impact its transport and signaling, lipid, lipoprotein and insulin metabolism.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adulto , Humanos , Leptina , Sobrepeso , Complexo Antígeno-Anticorpo , Doenças Cardiovasculares/etiologia , Fatores de Risco , Obesidade/complicações , Insulina , Triglicerídeos , Fatores de Risco de Doenças Cardíacas , Imunoglobulina G , Índice de Massa Corporal
8.
Br J Nutr ; 130(5): 783-792, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36412162

RESUMO

Obese mothers' offspring develop obesity and metabolic alterations in adulthood. Poor postnatal dietary patterns also contribute to obesity and its comorbidities. We aimed to determine whether in obese mothers' offspring an adverse postnatal environment, such as high-fat diet (HFD) consumption (second hit) exacerbates body fat accumulation, metabolic alterations and adipocyte size distribution. Female Wistar rats ate chow (C-5 %-fat) or HFD (maternal obesity (MO)-25 %-fat) from weaning until the end of lactation. Male offspring were weaned on either control (C/C and MO/C, maternal diet/offspring diet) or HFD (C/HF and MO/HF) diet. At 110 postnatal days, offspring were killed. Fat depots were excised to estimate adiposity index (AI). Serum glucose, triglyceride, leptin, insulin, insulin resistance index (HOMA-IR), corticosterone and dehydroepiandrosterone (DHEA) were determined. Adipocyte size distribution was evaluated in retroperitoneal fat. Body weight was similar in C/C and MO/C but higher in C/HF and MO/HF. AI, leptin, insulin and HOMA-IR were higher in MO/C and C/HF v. C/C but lower than MO/HF. Glucose increased in MO/HF v. MO/C. C/HF and MO/C had higher triglyceride and corticosterone than C/C, but lower corticosterone than MO/HF. DHEA and the DHEA/corticosterone ratio were lower in C/HF and MO/C v. C/C, but higher than MO/HF. Small adipocyte proportion decreased while large adipocyte proportions increased in MO/C and C/HF v. C/C and exacerbated in MO/HF v. C/HF. Postnatal consumption of a HFD by the offspring of obese mothers exacerbates body fat accumulation as well as the decrease of small and the increase of large adipocytes, which leads to larger metabolic abnormalities.


Assuntos
Leptina , Efeitos Tardios da Exposição Pré-Natal , Humanos , Ratos , Feminino , Animais , Masculino , Gravidez , Dieta Hiperlipídica/efeitos adversos , Mães , Corticosterona/metabolismo , Ratos Wistar , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/etiologia , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Peso Corporal , Glucose/metabolismo , Triglicerídeos/metabolismo , Hipertrofia/metabolismo , Insulina/metabolismo , Desidroepiandrosterona/metabolismo
9.
Mar Drugs ; 21(5)2023 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-37233482

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the main aggressive types of cancer, characterized by late prognosis and drug resistance. Among the main factors sustaining PDAC progression, the alteration of cell metabolism has emerged to have a key role in PDAC cell proliferation, invasion, and resistance to standard chemotherapeutic agents. Taking into account all these factors and the urgency in evaluating novel options to treat PDAC, in the present work we reported the synthesis of a new series of indolyl-7-azaindolyl triazine compounds inspired by marine bis-indolyl alkaloids. We first assessed the ability of the new triazine compounds to inhibit the enzymatic activity of pyruvate dehydrogenase kinases (PDKs). The results showed that most of derivatives totally inhibit PDK1 and PDK4. Molecular docking analysis was executed to predict the possible binding mode of these derivatives using ligand-based homology modeling technique. Evaluation of the capability of new triazines to inhibit the cell growth in 2D and 3D KRAS-wild-type (BxPC-3) and KRAS-mutant (PSN-1) PDAC cell line, was carried out. The results showed the capacity of the new derivatives to reduce cell growth with a major selectivity against KRAS-mutant PDAC PSN-1 on both cell models. These data demonstrated that the new triazine derivatives target PDK1 enzymatic activity and exhibit cytotoxic effects on 2D and 3D PDAC cell models, thus encouraging further structure manipulation for analogs development against PDAC.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/uso terapêutico , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Triazinas/farmacologia , Proliferação de Células , Adenocarcinoma/metabolismo , Neoplasias Pancreáticas
10.
Biomed Chromatogr ; 37(8): e5658, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37080899

RESUMO

Colon cancer (CC) is a malignancy of the digestive tract, and computed tomography (CT)-guided radiofrequency ablation (RFA) has been extensively adopted in cancer treatment. We aimed to explore the changes in fecal metabolism after CT-guided RFA in CC mice. The orthotopic CC mice received CT-guided RFA upon modeling. Subsequently, we quantified tumor volumes and weights to assess treatment efficacy. Next, because metabolomics is useful for evaluating therapeutic validity, feces were collected for metabolomics analysis. CT-guided RFA inhibited tumor growth effectively. Additionally, metabolomics results showed that the contents of bile acids and fatty acids were downregulated in CC mouse feces. Moreover, the levels of amino acids and carbohydrates were decreased while the levels of fatty acids, organic acids, phenols, pyridines and short-chain fatty acids were elevated in feces after CC mice received CT-guided RFA. Pathway enrichment analysis revealed that those differential metabolites were closely related to fatty acids degradation and synthesis. CT-guided RFA possesses a strong ability to suppress CC development in mice, accompanied by a significant increase of fatty acid content in feces. This study proposes a novel approach and target for CC treatment, which provides hope for CC patients and establishes a solid basis for future in-depth studies.


Assuntos
Ablação por Cateter , Neoplasias do Colo , Ablação por Radiofrequência , Animais , Camundongos , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem , Ablação por Cateter/métodos , Tomografia Computadorizada por Raios X/métodos , Metabolômica , Ácidos Graxos
11.
Int J Mol Sci ; 24(6)2023 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-36982445

RESUMO

Aldosterone, a vital hormone of the human body, has various pathophysiological roles. The excess of aldosterone, also known as primary aldosteronism, is the most common secondary cause of hypertension. Primary aldosteronism is associated with an increased risk of cardiovascular disease and kidney dysfunction compared to essential hypertension. Excess aldosterone can lead to harmful metabolic and other pathophysiological alterations, as well as cause inflammatory, oxidative, and fibrotic effects in the heart, kidney, and blood vessels. These alterations can result in coronary artery disease, including ischemia and myocardial infarction, left ventricular hypertrophy, heart failure, arterial fibrillation, intracarotid intima thickening, cerebrovascular disease, and chronic kidney disease. Thus, aldosterone affects several tissues, especially in the cardiovascular system, and the metabolic and pathophysiological alterations are related to severe diseases. Therefore, understanding the effects of aldosterone on the body is important for health maintenance in hypertensive patients. In this review, we focus on currently available evidence regarding the role of aldosterone in alterations of the cardiovascular and renal systems. We also describe the risk of cardiovascular events and renal dysfunction in hyperaldosteronism.


Assuntos
Doenças Cardiovasculares , Hiperaldosteronismo , Hipertensão , Humanos , Aldosterona/metabolismo , Doenças Cardiovasculares/metabolismo , Hipertensão/metabolismo , Hiperaldosteronismo/complicações , Hiperaldosteronismo/metabolismo , Hipertensão Essencial/complicações
12.
Plant Cell Environ ; 45(10): 3086-3099, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35751418

RESUMO

Various root-colonizing bacterial species can promote plant growth and trigger systemic resistance against aboveground leaf pathogens and herbivore insects. To date, the underlying metabolic signatures of these rhizobacteria-induced plant phenotypes are poorly understood. To identify core metabolic pathways that are targeted by growth-promoting rhizobacteria, we used combinations of three plant species and three rhizobacterial species and interrogated plant shoot chemistry by untargeted metabolomics. A substantial part (50%-64%) of the metabolites detected in plant shoot tissue was differentially affected by the rhizobacteria. Among others, the phenylpropanoid pathway was targeted by the rhizobacteria in each of the three plant species. Differential regulation of the various branches of the phenylpropanoid pathways showed an association with either plant growth promotion or growth reduction. Overall, suppression of flavonoid biosynthesis was associated with growth promotion, while growth reduction showed elevated levels of flavonoids. Subsequent assays with 12 Arabidopsis flavonoid biosynthetic mutants revealed that the proanthocyanidin branch plays an essential role in rhizobacteria-mediated growth promotion. Our study also showed that a number of pharmaceutically and nutritionally relevant metabolites in the plant shoot were significantly increased by rhizobacterial treatment, providing new avenues to use rhizobacteria to tilt plant metabolism towards the biosynthesis of valuable natural plant products.


Assuntos
Arabidopsis , Arabidopsis/genética , Flavonoides/metabolismo , Herbivoria , Desenvolvimento Vegetal , Raízes de Plantas/microbiologia , Brotos de Planta
13.
J Hum Nutr Diet ; 35(4): 713-721, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-34750902

RESUMO

BACKGROUND: The ACTN3 gene is primarily expressed in fast skeletal muscle fibres. A common nonsense polymorphism in this gene is ACTN3 R577X (rs1815739), which causes an absolute deficiency of α-actinin-3 protein and alterations in muscle metabolism. Considering metabolic alterations are influenced by nutrition and genetic factors, as well as lifestyle factors, we hypothesise a possible association of the ACTN3 R577X polymorphism with metabolic alterations. METHODS: In this cross-sectional study, 397 adults met the inclusion criteria. Body composition was measured by electrical bioimpedance. Dietary data were analysed using Nutritionist Pro™ software. Biochemical variables were determined by dry chemistry. Genomic DNA was extracted from peripheral leukocytes and genotyping of the ACTN3 R577X polymorphism was determined by allelic discrimination using TaqMan probes. The statistical analyses were performed using SPSS statistical software. p < 0.05 was considered statistically significant. RESULTS: The ACTN3 577XX genotype was associated with high glucose, triglyceride and very low density lipoprotein-cholesterol levels and a higher frequency of hypertriglyceridaemia and insulin resistance in women. In males, the genetic variant showed a trend towards significance for insulin resistance. CONCLUSIONS: The ACTN3 R577X polymorphism was associated with metabolic alterations in women and a tendency was observed in men variant carriers. Thus, this common genetic variant could be implicated in the development of chronic metabolic diseases.


Assuntos
Actinina , Resistência à Insulina , Actinina/genética , Adulto , Estudos Transversais , Feminino , Genótipo , Humanos , Resistência à Insulina/genética , Masculino , México , Polimorfismo Genético
14.
Proc Natl Acad Sci U S A ; 116(1): 52-57, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30559182

RESUMO

Characterization of tumor metabolism with spatial information contributes to our understanding of complex cancer metabolic reprogramming, facilitating the discovery of potential metabolic vulnerabilities that might be targeted for tumor therapy. However, given the metabolic variability and flexibility of tumors, it is still challenging to characterize global metabolic alterations in heterogeneous cancer. Here, we propose a spatially resolved metabolomics approach to discover tumor-associated metabolites and metabolic enzymes directly in their native state. A variety of metabolites localized in different metabolic pathways were mapped by airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) in tissues from 256 esophageal cancer patients. In combination with in situ metabolomics analysis, this method provided clues into tumor-associated metabolic pathways, including proline biosynthesis, glutamine metabolism, uridine metabolism, histidine metabolism, fatty acid biosynthesis, and polyamine biosynthesis. Six abnormally expressed metabolic enzymes that are closely associated with the altered metabolic pathways were further discovered in esophageal squamous cell carcinoma (ESCC). Notably, pyrroline-5-carboxylate reductase 2 (PYCR2) and uridine phosphorylase 1 (UPase1) were found to be altered in ESCC. The spatially resolved metabolomics reveal what occurs in cancer at the molecular level, from metabolites to enzymes, and thus provide insights into the understanding of cancer metabolic reprogramming.


Assuntos
Metabolômica/métodos , Neoplasias/metabolismo , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Espectrometria de Massas , Neoplasias/enzimologia , Neoplasias/patologia , Pirrolina Carboxilato Redutases/metabolismo , Uridina Fosforilase/metabolismo
15.
Int J Neurosci ; : 1-11, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35896309

RESUMO

Glioblastoma is an aggressive type of cancer that begins in cells called astrocytes that support nerve cells that can occur in the brain or spinal cord. It can form in the brain or spinal cord. Despite the variety of modern therapies against GBM, it is still a deadly disease. Patients usually have a median survival of approximately 14 to 15 months from the diagnosis. Glioblastoma is also known as glioblastoma multiforme. The pathogenesis contributing to the proliferation and metastasis of cancer involves aberrations of multiple signalling pathways through multiple genetic mutations and altered gene expression. The coagulant factors like thrombin and tissue factor play a noteworthy role in cancer invasion. They are produced in the microenvironment of glioma through activation of protease-activated receptors (PARs) which are activated by coagulation proteases. PARs are members of family G-protein-coupled receptors (GPCRs) that are activated by coagulation proteases. These components play a key role in tumour cell angiogenesis, migration, invasion, and interactions with host vascular cells. Further, the release of neurotransmitters is also found to regulate malignancy in gliomas. Exploration of the interplay between malignant neural circuitry with the normal conditions is also decisive in finding effective therapies for these apparently invasive tumours. The present review discusses the molecular classification of gliomas, activation of PARs by coagulation protease, and its role in metastasis of gliomas. Further, the differential involvement of neurotransmitters in the pathogenesis of gliomas has also been discussed. Targeting these molecules may present a potential therapeutic approach for the treatment of gliomas.

16.
Neuroimage ; 241: 118419, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34302967

RESUMO

BACKGROUND: Metabolic disorders associated with obesity could lead to alterations in brain structure and function. Whether these changes can be reversed after weight loss is unclear. Bariatric surgery provides a unique opportunity to address these questions because it induces marked weight loss and metabolic improvements which in turn may impact the brain in a longitudinal fashion. Previous studies found widespread changes in grey matter (GM) and white matter (WM) after bariatric surgery. However, findings regarding changes in spontaneous neural activity following surgery, as assessed with the fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity of neural activity (ReHo), are scarce and heterogenous. In this study, we used a longitudinal design to examine the changes in spontaneous neural activity after bariatric surgery (comparing pre- to post-surgery), and to determine whether these changes are related to cardiometabolic variables. METHODS: The study included 57 participants with severe obesity (mean BMI=43.1 ± 4.3 kg/m2) who underwent sleeve gastrectomy (SG), biliopancreatic diversion with duodenal switch (BPD), or Roux-en-Y gastric bypass (RYGB), scanned prior to bariatric surgery and at follow-up visits of 4 months (N = 36), 12 months (N = 29), and 24 months (N = 14) after surgery. We examined fALFF and ReHo measures across 1022 cortical and subcortical regions (based on combined Schaeffer-Xiao parcellations) using a linear mixed effect model. Voxel-based morphometry (VBM) based on T1-weighted images was also used to measure GM density in the same regions. We also used an independent sample from the Human Connectome Project (HCP) to assess regional differences between individuals who had normal-weight (N = 46) or severe obesity (N = 46). RESULTS: We found a global increase in the fALFF signal with greater increase within dorsolateral prefrontal cortex, precuneus, inferior temporal gyrus, and visual cortex. This effect was more significant 4 months after surgery. The increase within dorsolateral prefrontal cortex, temporal gyrus, and visual cortex was more limited after 12 months and only present in the visual cortex after 24 months. These increases in neural activity measured by fALFF were also significantly associated with the increase in GM density following surgery. Furthermore, the increase in neural activity was significantly related to post-surgery weight loss and improvement in cardiometabolic variables, such as blood pressure. In the independent HCP sample, normal-weight participants had higher global and regional fALFF signals, mainly in dorsolateral/medial frontal cortex, precuneus and middle/inferior temporal gyrus compared to the obese participants. These BMI-related differences in fALFF were associated with the increase in fALFF 4 months post-surgery especially in regions involved in control, default mode and dorsal attention networks. CONCLUSIONS: Bariatric surgery-induced weight loss and improvement in metabolic factors are associated with widespread global and regional increases in neural activity, as measured by fALFF signal. These findings alongside the higher fALFF signal in normal-weight participants compared to participants with severe obesity in an independent dataset suggest an early recovery in the neural activity signal level after the surgery.


Assuntos
Cirurgia Bariátrica/tendências , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Imageamento por Ressonância Magnética/tendências , Obesidade/diagnóstico por imagem , Descanso/fisiologia , Adulto , Cirurgia Bariátrica/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Obesidade/cirurgia , Cuidados Pós-Operatórios/métodos , Cuidados Pré-Operatórios/métodos
17.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361064

RESUMO

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs' critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.


Assuntos
Hepatopatias/tratamento farmacológico , Hepatopatias/patologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Preparações Farmacêuticas/administração & dosagem , Animais , Humanos , Hepatopatias/metabolismo , Terapia de Alvo Molecular
18.
Plant Foods Hum Nutr ; 76(3): 297-303, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34218401

RESUMO

Time-restricted feeding and food enriched in polyphenols are strategies to prevent or reduce metabolic disorders. Bean leaves (Phaseolus vulgaris L.) are a recognized source of polyphenolic compounds, whose effects on metabolic pathways are not well studied. We evaluated the combined effects of dietary supplementation with Phaseolus vulgaris leaves (10% w/w) (BL) and a 7-h daytime-restricted feeding protocol (RF) under a hypercaloric diet (high fat + high fructose) (HFFD) on the metabolic parameters related to glucose and lipid handling. Adult male Wistar rats were treated for 8 weeks with standard and HFFD diets with or without BL. The results showed that RF improved metabolic alterations induced by HFFD (e.g., hepatic steatosis, increased triacylglycerols, and serum lipoproteins). Supplementation with BL significantly enhanced this effect and downregulated the mRNA expression of carbohydrate and lipid metabolism genes in the liver. These results indicate that dietary supplementation with BL enhances the benefits elicited by RF.


Assuntos
Frutose , Phaseolus , Animais , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Fígado , Folhas de Planta , Ratos , Ratos Wistar
19.
Semin Cancer Biol ; 59: 187-207, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31362075

RESUMO

Cutaneous melanoma (CM) represents one of the most metastasizing and drug resistant solid tumors. CM is characterized by a remarkable metabolic plasticity and an important connection between oncogenic activation and energetic metabolism. In fact, melanoma cells can use both cytosolic and mitochondrial compartments to produce adenosine triphosphate (ATP) during cancer progression. However, the CM energetic demand mainly depends on glycolysis, whose upregulation is strictly linked to constitutive activation of BRAF/MAPK pathway affected by BRAFV600E kinase mutant. Furthermore, the impressive metabolic plasticity of melanoma allows the development of resistance mechanisms to BRAF/MEK inhibitors (BRAFi/MEKi) and the adaptation to microenvironmental changes. The metabolic interaction between melanoma cells and tumor microenvironment affects the immune response and CM growth. In this review article, we describe the regulation of melanoma metabolic alterations and the metabolic interactions between cancer cells and microenvironment that influence melanoma progression and immune response. Finally, we summarize the hallmarks of melanoma therapies and we report BRAF/MEK pathway targeted therapy and mechanisms of metabolic resistance.


Assuntos
Metabolismo Energético , Melanoma/metabolismo , Animais , Progressão da Doença , Suscetibilidade a Doenças , Metabolismo Energético/efeitos dos fármacos , Glicólise , Humanos , Melanoma/tratamento farmacológico , Melanoma/etiologia , Melanoma/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Terapia de Alvo Molecular , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
20.
Metabolomics ; 16(9): 94, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894362

RESUMO

INTRODUCTION: Rice leaves and stems, which can be used as rice straw for livestock feed, accumulate soluble oxalate. The oxalate content often reaches 5% of the dry weight leaves. Excess uptake of oxalate-rich plants causes mineral deficiencies in vertebrates, so it is important to reduce the oxalate content in rice leaves to produce high-quality rice straw. However, the mechanism of oxalate accumulation in rice has remained unknown. OBJECTIVES: To understand metabolic networks relating oxalate accumulation in rice. METHODS: In this study, we performed metabolome analysis of rice M2 population generated by ion-beam irradiation using CE-MS. RESULTS: The result showed wide variation of oxalate contents in M2 plants compared with those of control plants. Multivariate analyses of metabolome dataset revealed that oxalate accumulation was strongly related with anionic compounds such as 2OG and succinate. For low-oxalate plants, four patterns of metabolic alterations affected oxalate contents in the M2 leaves were observed. In M3 plants, we found putative low-oxalate line obtained from low-oxalate M2 mutant. CONCLUSIONS: These findings would lead to produce the low-oxalate rice and to understand the oxalate synthesis in plants.These findings would lead to produce the low-oxalate rice and to understand the oxalate synthesis in plants.


Assuntos
Metaboloma , Oryza/metabolismo , Oxalatos/metabolismo , Folhas de Planta/metabolismo , Regulação da Expressão Gênica de Plantas , Redes e Vias Metabólicas , Nitrogênio , Oryza/genética
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