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1.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063048

RESUMO

Pazopanib is a multikinase inhibitor with anti-tumor activity. As of now, the anti-obesity effect and mode of action of pazopanib are unknown. In this study, we investigated the effects of pazopanib on lipid accumulation, lipolysis, and expression of inflammatory cyclooxygenase (COX)-2 in differentiating and differentiated 3T3-L1 cells, a murine preadipocyte. Of note, pazopanib at 10 µM markedly decreased lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, pazopanib inhibited not only expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), and perilipin A but also phosphorylation of signal transducer and activator of transcription (STAT)-3 during 3T3-L1 preadipocyte differentiation. In addition, pazopanib treatment increased phosphorylation of cAMP-activated protein kinase (AMPK) and its downstream effector ACC during 3T3-L1 preadipocyte differentiation. However, in differentiated 3T3-L1 adipocytes, pazopanib treatment did not stimulate glycerol release and hormone-sensitive lipase (HSL) phosphorylation, hallmarks of lipolysis. Moreover, pazopanib could inhibit tumor necrosis factor (TNF)-α-induced expression of COX-2 in both 3T3-L1 preadipocytes and differentiated cells. In summary, this is the first report that pazopanib has strong anti-adipogenic and anti-inflammatory effects in 3T3-L1 cells, which are mediated through regulation of the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT-3, ACC, perilipin A, AMPK, and COX-2.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Indazóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Células 3T3-L1 , Adenilato Quinase/metabolismo , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácido Graxo Sintases/metabolismo , Glicerol/metabolismo , Leptina/metabolismo , Camundongos , PPAR gama/metabolismo , Perilipina-1/metabolismo , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resistina/metabolismo , Fator de Transcrição STAT3/metabolismo , Esterol Esterase/metabolismo , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
2.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065168

RESUMO

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aß) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aß plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1ß in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.


Assuntos
Doença de Alzheimer/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Doenças Metabólicas/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Resistina/metabolismo
3.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064456

RESUMO

Primary Sjögren's syndrome (pSS) is a complex heterogeneous disease characterized by a wide spectrum of glandular and extra-glandular manifestations. In this pilot study, a SWATH-MS approach was used to monitor extracellular vesicles-enriched saliva (EVs) sub-proteome in pSS patients, to compare it with whole saliva (WS) proteome, and assess differential expressed proteins between pSS and healthy control EVs samples. Comparison between EVs and WS led to the characterization of compartment-specific proteins with a moderate degree of overlap. A total of 290 proteins were identified and quantified in EVs from healthy and pSS patients. Among those, 121 proteins were found to be differentially expressed in pSS, 82% were found to be upregulated, and 18% downregulated in pSS samples. The most representative functional pathways associated to the protein networks were related to immune-innate response, including several members of S100 protein family, annexin A2, resistin, serpin peptidase inhibitors, azurocidin, and CD14 monocyte differentiation antigen. Our results highlight the usefulness of EVs for the discovery of novel salivary-omic biomarkers and open novel perspectives in pSS for the identification of proteins of clinical relevance that could be used not only for the disease diagnosis but also to improve patients' stratification and treatment-monitoring. Data are available via ProteomeXchange with identifier PXD025649.


Assuntos
Vesículas Extracelulares/metabolismo , Redes Reguladoras de Genes , Proteoma/genética , Saliva/metabolismo , Síndrome de Sjogren/genética , Adulto , Idoso , Anexina A2/genética , Anexina A2/metabolismo , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Biomarcadores/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Estudos de Casos e Controles , Vesículas Extracelulares/química , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Projetos Piloto , Mapeamento de Interação de Proteínas , Proteoma/classificação , Proteoma/metabolismo , Proteômica/instrumentação , Proteômica/métodos , Resistina/genética , Resistina/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , Saliva/química , Serpinas/genética , Serpinas/metabolismo , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia
4.
Eur J Pharmacol ; 900: 174062, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33798596

RESUMO

Polycystic ovary syndrome is a common endocrine disorder worldwide. Recently, quercetin has been extensively investigated as a therapeutic option in patients with PCOS. Therefore, this study aimed to investigate the mechanisms underlying quercetin's positive effects by modulating key components of energy homeostasis and adipose tissue hormones in rats with letrozole-induced PCOS. Eighteen female Wistar rats were divided into three groups including control group (received carboxy methylcellulose (CMC 0.5%)), letrozole-induced PCOS ± quercetin group (received 1 mg/kg letrozole in CMC 0.5%), and letrozole-induced PCOS +/+ quercetin group (received same dose of letrozole + 100 mg/kg quercetin in CMC 0.5%). The estrous cycle, biochemical and hormonal parameters, as well as insulin resistance (IR) were evaluated in all groups. Western blotting was used to assess the expression levels of sirtuin-1 (SIRT-1), 5' AMP-activated protein kinase (AMPK), and adiponectin in target tissues of rats. The expression levels of visfatin and resistin were also evaluated through Real-time polymerase chain reaction (PCR). Treatment with quercetin improved the PCOS related disturbances in estrous cycle, lipid profile, serum levels of testosterone, estradiol and progesterone, and IR. Besides, the expression levels of AMPK and SIRT-1 in ovarian tissue were upregulated in the rats which received quercetin. Quercetin also reversed the PCOS-induced alteration in adipose tissue levels of adiponectin, visfatin, and resistin. Modulation of energy homeostasis through key components involved in this axis, as well as regulation of hormones releasing from adipose tissue may be the main underlying mechanisms for positive effects of quercetin in PCOS.


Assuntos
Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Quercetina/uso terapêutico , Sirtuína 1/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônios/sangue , Resistência à Insulina , Letrozol , Metabolismo dos Lipídeos/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Ratos , Ratos Wistar , Resistina/metabolismo
5.
Biochem Biophys Res Commun ; 534: 707-713, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33261886

RESUMO

In the current work we have investigated the cellular and molecular regulation of resistin secretion in cultured and primary mouse adipocytes. Resistin is an adipose tissue hormone proposed to contribute to metabolic disease. In rodents, resistin is secreted from white adipocytes whereas it is in humans synthesised and released from other cell types within white adipose tissue. The metabolic importance of resistin has been studied in both mouse and man, but the regulation of its release remains poorly investigated. Here we define that, in mouse adipocytes, resistin secretion is triggered by an intracellular elevation of cAMP and/or Ca2+. Resistin release is stimulated via activation of beta 3 adrenergic receptors (ß3ARs) and the downstream signalling protein exchange protein activated by cAMP (Epac). The secretion of resistin is markedly abrogated in adipocytes isolated from obese and diabetic mice. Immunocytochemical staining demonstrates a significant overlap between signals for resistin and the adipocyte hormone adiponectin. Our data propose that resistin and adiponectin are contained within the same vesicles in mouse adipocytes and that the two hormones are co-secreted in response to the same exocytosis-triggering signals.


Assuntos
Adipócitos Brancos/metabolismo , Adiponectina/metabolismo , Resistina/metabolismo , Células 3T3-L1 , Adipócitos Brancos/efeitos dos fármacos , Animais , Cálcio/metabolismo , AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Insulina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Vesículas Secretórias/metabolismo
6.
Cancer Lett ; 498: 229-239, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152400

RESUMO

Obesity is one of the major modifiable risk factors in breast cancer, with obese adipose tissue showing a pathological role in breast cancer development and malignancy via the release of secretory factors, such as proinflammatory cytokines and adipocytokines. The current article focuses on visfatin and resistin, two such adipocytokines that have emerged over the last two decades as leading breast cancer promoting factors in obesity. The clinical association of circulating visfatin and resistin with breast cancer and their biological mechanisms are reviewed, in addition to their role in the context of tumor-stromal interactions in the breast cancer microenvironment. Recent findings have unraveled several mediators of visfatin and resistin that are involved in the crosstalk between breast cancer cells and adipose tissue in the breast tumor microenvironment, including growth differentiation factor 15 (GDF15), interleukin 6 (IL-6), and toll-like receptor 4 (TLR4). Finally, current therapeutics targeting visfatin and resistin and their respective pathways are discussed, including future therapeutic strategies such as new drug design or neutralizing peptides that target extracellular visfatin or resistin. These hold promise in the development of novel breast cancer therapies and are of increasing relevance as the prevalence of obesity-related breast cancer increases worldwide.


Assuntos
Adipocinas/metabolismo , Neoplasias da Mama/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Resistina/metabolismo , Tecido Adiposo/metabolismo , Animais , Citocinas/metabolismo , Feminino , Humanos , Microambiente Tumoral/fisiologia
7.
Mol Biol Rep ; 47(12): 9489-9497, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33269434

RESUMO

Insulin resistance may become the most powerful predictor of future development of type 2 diabetes mellitus (T2DM) and a therapeutic target for the treatment of the same. Both Resistin, an adipose derived peptide hormone and Urotensin II a potent vasoconstrictor, are reported to be involved in the development of insulin resistance and T2DM but the results remain contradictory. Therefore, investigations were carried out to study the association of T2DM and single nucleotide polymorphism (SNP) in Resistin (RETN) gene at rs3745367 (+ 299 G > A) and Urotensin II (UTS2) gene at rs228648 (+ 143 G > A) and rs2890565 (+ 3836 C > T) in a North Indian population. Method: The present case-control study, conducted from August 2017 to July 2020, involved 168 T2DM patients and 102 healthy controls. SNPs rs3745367, rs228648 and rs2890565 were amplified from genomic DNA in the studied samples by polymerase chain reaction (PCR) using specific primers. The amplified products were genotyped by restriction fragment length polymorphism (RFLP) using particular restriction endonucleases. Clinical parameters viz. glycosylated haemoglobin (HbA1c), fasting blood glucose (FBG), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol (CHL) and fasting insulin were determined by enzymatic methods. Result and conclusion: A statistically significant association between T2DM and RETN gene at SNP rs3745367 (p = 0.001) and UTS2 gene at SNP rs2890565 (p = 0.001) was observed. In RETN gene SNP rs3745367, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were found to be higher in GA + AA combined genotype than in GG genotype for T2DM subjects. Regression analysis revealed that SNP rs2890565 and HOMA-IR were independently associated with the risk of development of T2DM when three SNPs were taken as independent variable adjusted for clinical variables. Among four haplotypes, A/T was found associated with increased risk of T2DM as determined for rs228648 and rs2890565 of UTS2 gene. It can be concluded from these results that polymorphism at rs3745367 of RETN gene and at rs2890565 of UTS2 gene are associated with risk of T2DM in North Indian population.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Resistência à Insulina/genética , Polimorfismo de Fragmento de Restrição , Resistina/genética , Urotensinas/genética , Fatores Etários , Idoso , Glicemia/metabolismo , Peso Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Feminino , Expressão Gênica , Haplótipos , Humanos , Índia , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Resistina/metabolismo , Risco , Fatores Sexuais , Urotensinas/metabolismo
8.
Proc Natl Acad Sci U S A ; 117(52): 33295-33304, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318171

RESUMO

Adipocytes have been implicated in breast tumor growth and stemness maintenance through secreted factors. However, the mechanisms by which these cytokines are regulated during diet-induced obesity and contribute to breast tumorigenesis remain largely unknown. Here we show that transcription cofactor TAZ in adipocytes is directly up-regulated by the free fatty acid/PPARγ axis upon dietary fat stimulation. TAZ knockdown alters the expression profile of a series of secreted proteins and attenuates the tumor-supporting function of adipocytes. Moreover, we identify Resistin, an adipose-derived hormone, as a functional downstream target of TAZ, which facilitates tumorigenesis, and its expression correlated with adipocyitc TAZ in triple-negative breast cancer samples. Further, Adiponectin-cre-mediated TAZ knockout in adipocytes mitigates breast tumor growth. Taken together, our findings highlight how diet-induced TAZ expression in adipocytes promotes tumorigenesis, suggesting promising cancer therapeutic targets.


Assuntos
Adipócitos/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinogênese/patologia , Resistina/metabolismo , Transativadores/metabolismo , Adipócitos/metabolismo , Adiposidade , Animais , Neoplasias da Mama/genética , Carcinogênese/metabolismo , Proliferação de Células , Dieta , Ácidos Graxos/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos C57BL , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Obesidade/patologia , PPAR gama/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
9.
Molecules ; 25(21)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182462

RESUMO

Obesity as an independent risk factor for cardiovascular diseases (CVDs) leads to an increase in morbidity, mortality, and a shortening of life span. The changes in heart structure and function as well as metabolic profile are caused by obese people, including those free of metabolic disorders. Obesity alters heart function structure and affects lipid and glucose metabolism, blood pressure, and increase inflammatory cytokines. Adipokines, specific cytokines of adipocytes, are involved in the progression of obesity and the associated co-morbidities. In the current study, we review the scientific evidence on the effects of obesity on CVDs, focusing on the changes in adipokines. Several adipokines have anti-inflammatory and cardioprotective effects comprising omentin, apelin, adiponectin, and secreted frizzled-related protein (Sfrp-5). Other adipokines have pro-inflammatory impacts on the cardiovascular system and obesity including leptin, tumor necrosis factor (TNF), retinol-binding protein4 (RBP-4), visfatin, resistin, and osteopontin. We found that obesity is associated with multiple CVDs, but can only occur in unhealthy metabolic patients. However, more studies should be designed to clarify the association between obesity, adipokine changes, and the occurrence of CVDs.


Assuntos
Adipocinas/metabolismo , Adiponectina/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Leptina/metabolismo , Resistina/metabolismo , Animais , Biomarcadores/metabolismo , Genoma , Humanos , Inflamação , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Fatores de Risco
10.
Niger J Clin Pract ; 23(10): 1345-1355, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33047690

RESUMO

Background: Several studies have demonstrated an association between obesity, periodontitis, and exercise. Aims: This study aimed to investigate the effects of regular exercise on obese women with periodontal disease, using serum, saliva, and gingival crevicular fluid (GCF) samples. A before-after study design was adopted to evaluate the effects of 12 weeks of regular exercise on obese women grouped according to periodontal status, without a control group (no exercise). The study sample comprised of 15 patients without periodontitis (NP group) and 10 patients with chronic periodontitis (CP group), from whom periodontal parameters were measured and serum, saliva, and GCF samples were collected. Body mass index (BMI), anthropometric measurements, somatotype-motoric tests, and maximal oxygen consumption (VO2max) were recorded at baseline and after exercise. Subjects and Methods: Med Calc was used for statistical analysis. Results: After exercise, a significant decrease in BMI and a significant increase in VO2max were observed in both groups. A significant decrease in probing depth and clinical attachment loss, serum leptin, GCF tumor necrosis factor-α(TNF-α) and leptin, and a significant increase in GCF resistin were observed in the CP group. A significant decrease in serum TNF-α and leptin levels and a significant increase in serum resistin and GCF TNF-α, leptin, resistin, and adiponectin levels were observed in the NP group. Significant correlations between bleeding on probing and levels of interleukin-1ß and leptin in GCF were observed in the CP group. Conclusions: This study showed that regular exercise exerts different impacts with respect to clinical and biochemical aspects of periodontal and systemic conditions in obese women.


Assuntos
Adipocinas/metabolismo , Periodontite Crônica/complicações , Periodontite Crônica/metabolismo , Exercício Físico/fisiologia , Líquido do Sulco Gengival/química , Obesidade/complicações , Saliva/química , Adipocinas/sangue , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Periodontite Crônica/sangue , Feminino , Humanos , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/metabolismo , Bolsa Periodontal/metabolismo , Resistina/sangue , Resistina/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
11.
Sci Rep ; 10(1): 18166, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097799

RESUMO

Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). In response to injury, the neuroendocrine system increases secretion of counterregulatory hormones that promote rapid mobilization of nutrient stores, impair insulin action, and ultimately cause hyperglycemia, a condition known to impair recovery from injury in the clinical setting. We investigated the contributions of adipocyte lipolysis to the metabolic response to acute stress. Both surgical injury with HS and counterregulatory hormone (epinephrine) infusion profoundly stimulated adipocyte lipolysis and simultaneously triggered insulin resistance and hyperglycemia. When lipolysis was inhibited, the stress-induced insulin resistance and hyperglycemia were largely abolished demonstrating an essential requirement for adipocyte lipolysis in promoting stress-induced insulin resistance. Interestingly, circulating non-esterified fatty acid levels did not increase with lipolysis or correlate with insulin resistance during acute stress. Instead, we show that impaired insulin sensitivity correlated with circulating levels of the adipokine resistin in a lipolysis-dependent manner. Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury. This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes.


Assuntos
Adipócitos/metabolismo , Hiperglicemia/metabolismo , Lipólise/fisiologia , Choque Hemorrágico/complicações , Ferida Cirúrgica/complicações , Animais , Modelos Animais de Doenças , Epinefrina/administração & dosagem , Epinefrina/metabolismo , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/etiologia , Hiperglicemia/fisiopatologia , Insulina/metabolismo , Resistência à Insulina/fisiologia , Lipase/genética , Lipase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Resistina/sangue , Resistina/metabolismo , Choque Hemorrágico/sangue , Choque Hemorrágico/metabolismo , Choque Hemorrágico/fisiopatologia , Ferida Cirúrgica/sangue , Ferida Cirúrgica/metabolismo , Ferida Cirúrgica/fisiopatologia
12.
Biomolecules ; 10(9)2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32899418

RESUMO

An imbalance between hepatic fatty acid uptake and removal results in ectopic fat accumulation, which leads to non-alcoholic fatty liver disease (NAFLD). The amount and type of accumulated triglycerides seem to play roles in NAFLD progression; however, a complete understanding of how triglycerides contribute to NAFLD evolution is lacking. Our aim was to evaluate triglyceride accumulation in NAFLD in a murine model and its associations with molecular mechanisms involved in liver damage and adipose tissue-liver cross talk by employing lipidomic and molecular imaging techniques. C57BL/6J mice fed a high-fat diet (HFD) for 12 weeks were used as a NAFLD model. Standard-diet (STD)-fed animals were used as controls. Standard liver pathology was assessed using conventional techniques. The liver lipidome was analyzed by liquid chromatography-mass spectrometry (LC-MS) and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging. Liver triglycerides were identified by MS/MS. The transcriptome of genes involved in intracellular lipid metabolism and inflammation was assessed by RT-PCR. Plasma leptin, resistin, adiponectin, and FABP4 levels were determined using commercial kits. HFD-fed mice displayed increased liver lipid content. LC-MS analyses identified 14 triglyceride types that were upregulated in livers from HFD-fed animals. Among these 14 types, 10 were identified in liver cross sections by LDI-MS tissue imaging. The accumulation of these triglycerides was associated with the upregulation of lipogenesis and inflammatory genes and the downregulation of ß-oxidation genes. Interestingly, the levels of plasma FABP4, but not of other adipokines, were positively associated with 8 of these triglycerides in HFD-fed mice but not in STD-fed mice. Our findings suggest a putative role of FABP4 in the liver-adipose tissue cross talk in NAFLD.


Assuntos
Fígado/química , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Adipocinas/sangue , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Animais , Cromatografia Líquida , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Leptina/metabolismo , Metabolismo dos Lipídeos/genética , Lipidômica/métodos , Masculino , Camundongos Endogâmicos C57BL , Imagem Molecular , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Resistina/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem , Triglicerídeos/metabolismo
13.
Biochim Biophys Acta Rev Cancer ; 1874(2): 188419, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32822824

RESUMO

Systemic and organ-confined inflammation has been associated with cancer development and progression. Resistin, initially described as an adipocyte-derived cytokine in mice, is mostly expressed by the macrophages in humans. It has potent pro-inflammatory properties, and its elevated serum levels are detected in cancer patients. Aberrant expression of resistin receptors is also reported in several malignancies and associated with aggressive clinicopathological features. Several lines of evidence demonstrate that resistin, acting through its different receptors, promotes tumor growth, metastasis, and chemoresistance by influencing a variety of cellular phenotypes as well as by modulating the tumor microenvironment. Racially disparate expression of resistin has also attracted much interest, considering prevalent cancer health disparities. This review discusses the aberrant expression of resistin and its receptors, its diverse downstream signaling and impact on tumor growth, metastasis, angiogenesis, and therapy resistance to support its clinical exploitation in biomarker and therapeutic development.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias/imunologia , Resistina/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/sangue , Resistina/sangue , Resistina/química , Transdução de Sinais , Microambiente Tumoral
14.
Am J Pathol ; 190(11): 2226-2236, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32798443

RESUMO

In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokine levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of STAT3. In HepG2 cells, leptin and resistin up-regulated PCSK9 gene and protein expression, as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knockdown of STAT3 did not affect the expression of leptin and resistin receptors or that of PCSK9. The analysis of the human PCSK9 promoter region showed that the two adipokines raised PCSK9 promoter activity via the involvement of a sterol regulatory element motif. In healthy males, a positive association between circulating leptin and PCSK9 levels was found only when the body mass index was <25 kg/m2. In conclusion, this study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.


Assuntos
Regulação Enzimológica da Expressão Gênica , Leptina/metabolismo , Pró-Proteína Convertase 9/biossíntese , Resistina/metabolismo , Fator de Transcrição STAT3/metabolismo , Regulação para Cima , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Hep G2 , Humanos , Leptina/genética , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Pró-Proteína Convertase 9/genética , Resistina/genética , Elementos de Resposta , Fator de Transcrição STAT3/genética
15.
FASEB J ; 34(10): 13671-13684, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32790946

RESUMO

Resistin is a cysteine-rich adipokine that promotes the release of inflammatory cytokines, particularly interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α), which are critical pro-inflammatory mediators in osteoarthritis (OA) pathogenesis. We describe evidence of significantly higher levels of resistin, IL-1ß, and TNF-α expression in OA knee synovial tissue compared with that from non-OA knees. Resistin-induced enhancement of IL-1ß and TNF-α expression in human OA synovial fibroblasts (OASFs) were attenuated by MEK and ERK inhibitors, as well as their respective siRNAs. Our data reveal that resistin enhances the expression of TNF-α and IL-1ß in OASFs by inhibiting miR-149 expression via MEK and ERK signaling. Our findings elucidate the inter-relationships between resistin and pro-inflammatory mediators during OA pathogenesis and could help to facilitate the development of synovium-targeted therapy in OA.


Assuntos
Fibroblastos/metabolismo , Interleucina-1beta/metabolismo , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Resistina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células Cultivadas , Humanos , Interleucina-1beta/genética , Sistema de Sinalização das MAP Quinases , Masculino , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , Resistina/genética , Líquido Sinovial/citologia , Fator de Necrose Tumoral alfa/genética
16.
Am J Physiol Lung Cell Mol Physiol ; 319(3): L422-L434, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32692581

RESUMO

The family of resistin-like molecules (RELMs) consists of four members in rodents (RELMα/FIZZ1/HIMF, RELMß/FIZZ2, Resistin/FIZZ3, and RELMγ/FIZZ4) and two members in humans (Resistin and RELMß), all of which exhibit inflammation-regulating, chemokine, and growth factor properties. The importance of these cytokines in many aspects of physiology and pathophysiology, especially in cardiothoracic diseases, is rapidly evolving in the literature. In this review article, we attempt to summarize the contribution of RELM signaling to the initiation and progression of lung diseases, such as pulmonary hypertension, asthma/allergic airway inflammation, chronic obstructive pulmonary disease, fibrosis, cancers, infection, and other acute lung injuries. The potential of RELMs to be used as biomarkers or risk predictors of these diseases also will be discussed. Better understanding of RELM signaling in the pathogenesis of pulmonary diseases may offer novel targets or approaches for the development of therapeutics to treat or prevent a variety of inflammation, tissue remodeling, and fibrosis-related disorders in respiratory, cardiovascular, and other systems.


Assuntos
Hipertensão Pulmonar/metabolismo , Resistina/metabolismo , Animais , Humanos , Inflamação/metabolismo , Transdução de Sinais/fisiologia
17.
PLoS One ; 15(7): e0235546, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609743

RESUMO

Resistin and resistin-like molecules are pleiotropic cytokines that are involved in inflammatory diseases. Our previous work suggested that resistin has the potential to be used as a biomarker and therapeutic target for human pulmonary arterial hypertension. However, data are limited on the distribution of resistin in healthy human organs. In this study, we used our newly developed anti-human resistin (hResistin) antibody to immunohistochemically detect the expression, localization, and intracellular/extracellular compartmentalization of hResistin in a full human tissue panel from healthy individuals. The potential cross reactivity of this monoclonal anti-hResistin IgG1 with normal human tissues also was verified. Results showed that hResistin is broadly distributed and principally localized in the cytoplasmic granules of macrophages scattered in the interstitium of most human tissues. Bone marrow hematopoietic precursor cells also exhibited hResistin signals in their cytoplasmic granules. Additionally, hResistin labeling was observed in the cytoplasm of nervous system cells. Notably, the cytokine activity of hResistin was illustrated by positively stained extracellular material in most human tissues. These data indicate that our generated antibody binds to the secreted hResistin and support its potential use for immunotherapy to reduce circulating hResistin levels in human disease. Our findings comprehensively document the basal expression patterns of hResistin protein in normal human tissues, suggest a critical role of this cytokine in normal and pathophysiologic inflammatory processes, and offer key insights for using our antibody in future pharmacokinetic studies and immunotherapeutic strategies.


Assuntos
Anticorpos Monoclonais/imunologia , Regulação da Expressão Gênica , Resistina/imunologia , Resistina/metabolismo , Espaço Extracelular/metabolismo , Células HEK293 , Humanos , Imuno-Histoquímica , Espaço Intracelular/metabolismo , Especificidade de Órgãos , Transporte Proteico
18.
Cells ; 9(6)2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32492888

RESUMO

The development of osteoarthritis (OA) is characterized by synovial inflammation and the upregulation of vascular cell adhesion molecule type 1 (VCAM-1) in human osteoarthritis synovial fibroblasts (OASFs). This increase in VCAM-1 expression promotes monocyte adhesion to OASFs. The adipokine resistin is known to promote the release of inflammatory cytokines during OA progression. In this study, we identified significantly higher levels of resistin and CD68 (a monocyte surface marker) expression in human OA tissue compared with in healthy control tissue. We also found that resistin enhances VCAM-1 expression in human OASFs and facilitates the adhesion of monocytes to OASFs. These effects were attenuated by inhibitors of PKCα, p38, and JNK; their respective siRNAs; and by a microRNA-381 (miR-381) mimic. In our anterior cruciate ligament transection (ACLT) rat model of OA, the inhibition of resistin activity prevented ACLT-induced damage to the OA rat cartilage and pathological changes in resistin and monocyte expression. We also found that resistin affects VCAM-1 expression and monocyte adhesion in human OASFs by inhibiting miR-381 synthesis via the PKCα, p38, and JNK signaling pathways. Our clarification of the crucial role played by resistin in the pathogenesis of OA may lead to more effective therapy that reduces OA inflammation.


Assuntos
Fibroblastos/patologia , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , Monócitos/patologia , Osteoartrite/patologia , Resistina/metabolismo , Sinoviócitos/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Sequência de Bases , Adesão Celular , Fibroblastos/metabolismo , Humanos , Masculino , MicroRNAs/genética , Modelos Biológicos , Proteína Quinase C/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Índice de Gravidade de Doença
20.
Vet Surg ; 49(6): 1164-1173, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32472596

RESUMO

OBJECTIVE: To compare synovial fluid (SF) resistin concentrations in healthy dogs to dogs with osteoarthritis (OA) secondary to cranial cruciate ligament (CrCL) injury and to correlate resistin concentrations with body condition score (BCS) and evaluate resistin release from peripheral blood mononuclear cells (PBMC) and adipocytes. STUDY DESIGN: Controlled, prospective, clinical study ANIMALS: Thirty-nine client-owned dogs, 13 healthy and 26 with secondary OA, were enrolled. Blood was collected from six healthy purpose-bred dogs for PBMC culture. An additional six mixed-breed dogs were used for adipocyte collection and culture. METHODS: Resistin concentrations were measured with a canine-specific enzyme-linked immunoabsorbent assay. Resistin was compared between healthy SF and OA SF with Student's t test. Correlation of resistin concentrations to BCS was performed. Peripheral blood mononuclear cells and adipocytes were cultured under three conditions: negative control, lipopolysaccharide, and concanavalin A (Con A). A linear mixed model was used to determine differences in resistin concentrations among treatments. RESULTS: Resistin concentrations in OA SF were comparable to healthy SF. Neither serum nor SF resistin was correlated with BCS. Cultured PBMC stimulated with Con A released resistin, while adipocytes did not. CONCLUSION: Neither serum nor SF resistin were altered in dogs with OA secondary to CrCL insufficiency. In addition, resistin was not correlated with canine body fat and did not appear to function as adipocytokine in the dog. CLINICAL SIGNIFICANCE: Resistin may not be involved in the pathogenesis of OA. However, resistin may be important in inflammation because it is released from inflammatory cells.


Assuntos
Lesões do Ligamento Cruzado Anterior/veterinária , Ligamento Cruzado Anterior/metabolismo , Doenças do Cão/metabolismo , Cães/metabolismo , Osteoartrite/veterinária , Resistina/metabolismo , Animais , Ligamento Cruzado Anterior/patologia , Lesões do Ligamento Cruzado Anterior/metabolismo , Lesões do Ligamento Cruzado Anterior/patologia , Feminino , Leucócitos Mononucleares/metabolismo , Masculino , Osteoartrite/complicações , Estudos Prospectivos , Resistina/sangue , Soro/química , Joelho de Quadrúpedes , Líquido Sinovial/química
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