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1.
Nutrients ; 13(7)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34371946

RESUMO

Nutrient sensing plays important roles in promoting satiety and maintaining good homeostatic control. Taste receptors (TAS) are located through the gastrointestinal tract, and recent studies have shown they have a relationship with metabolic disorders. The aim of this study was to analyze the jejunal expression of TAS1R2, TAS1R3, TAS2R14 and TAS2R38 in women with morbid obesity, first classified according to metabolic syndrome presence (MetS; n = 24) or absence (non-MetS; n = 45) and then classified according to hepatic histology as normal liver (n = 28) or nonalcoholic fatty liver disease (n = 41). Regarding MetS, we found decreased expression of TAS2R14 in MetS patients. However, when we subclassified patients according to liver histology, we did not find differences between groups. We found negative correlations between glucose levels, triglycerides and MetS with TAS1R3 expression. Moreover, TAS2R14 jejunal expression correlated negatively with the presence of MetS and ghrelin levels and positively with the jejunal Toll-like receptor (TLR)4, peroxisome proliferator-activated receptor (PPAR)-γ, and interleukin (IL)-10 levels. Furthermore, TAS2R38 expression correlated negatively with TLR9 jejunal expression and IL-6 levels and positively with TLR4 levels. Our findings suggest that metabolic dysfunctions such as MetS trigger downregulation of the intestinal TASs. Therefore, taste receptors modulation could be a possible therapeutic target for metabolic disorders.


Assuntos
Jejuno/metabolismo , Obesidade Mórbida/genética , Receptores Acoplados a Proteínas G/genética , Paladar , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Fígado/patologia , Síndrome Metabólica/complicações , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade Mórbida/complicações , Obesidade Mórbida/metabolismo , Obesidade Mórbida/patologia , Receptores Acoplados a Proteínas G/metabolismo
2.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34198988

RESUMO

Secreted frizzled-related protein 5 (SFRP5), an antagonist of the noncanonical WNT pathway, has a controversial role in liver disease. The aim of this study was to analyze the role of SFRP5 and the noncanonical WNT pathway in nonalcoholic fatty liver disease (NAFLD). Plasma SFRP5 levels were determined by ELISA in women with normal weight (NW; n = 20) and morbid obesity (MO; n = 69). Women with MO were subclassified according to hepatic histology into normal liver (NL; n = 28), NAFLD (n = 41) (simple steatosis (SS; n = 24), and nonalcoholic steatohepatitis (NASH; n = 17)). We used RT-qPCR to evaluate the hepatic mRNA expression of SFRP5, WNT5A, and JNK in women with MO. SFRP5 levels were lower in NW than in MO patients who underwent a very low-calorie diet before surgery. Hepatic SFRP5 mRNA expression was higher in SS than in NL or NASH; additionally, patients with hepatic inflammation or ballooning presented lower SFRP5 abundance. WNT5A and JNK expression was enhanced in NAFLD compared with NL. In conclusion, circulating SFRP5 levels depend on the diet, and hepatic SFRP5 seems to have a protective role in the first steps of NAFLD; however, SFRP5 could be deregulated in an advanced stage while WNT5A and JNK are activated, promoting liver damage.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade Mórbida/complicações , Obesidade Mórbida/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/sangue , Adipocinas/metabolismo , Biomarcadores , Índice de Massa Corporal , Suscetibilidade a Doenças , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , MAP Quinase Quinase 4/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Mensageiro/genética , Proteína Wnt-5a/metabolismo
3.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063472

RESUMO

The pathogenic mechanisms underlying nonalcoholic fatty liver disease (NAFLD) are beginning to be understood. RUNX1 is involved in angiogenesis, which is crucial in inflammation, but its role in nonalcoholic steatohepatitis (NASH) remains unclear. The aim of this study was to analyze RUNX1 mRNA hepatic and jejunal abundance in women with morbid obesity (MO) and NAFLD. RUNX1, lipid metabolism-related genes, and TLRs in women with MO and normal liver (NL, n = 28), NAFLD (n = 41) (simple steatosis (SS, n = 24), or NASH (n = 17)) were analyzed by RT-qPCR. The RUNX1 hepatic expression was higher in SS than in NL or NASH, as likewise confirmed by immunohistochemistry. An increased expression of hepatic FAS was found in NAFLD. Hepatic RUNX1 correlated positively with FAS. There were no significant differences in the jejunum RUNX1 expressions in the different groups. Jejunal FXR expression was lower in NASH than in NL, while the TLR9 expression increased as NAFLD progressed. Jejunal RUNX1 correlated positively with jejunal PPARγ, TLR4, and TLR5. In summary, the hepatic expression of RUNX1 seems to be involved in the first steps of the NAFLD process; however, in NASH, it seems to be downregulated. Our findings provide important insights into the role of RUNX1 in the context of NAFLD/NASH, suggesting a protective role.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade Mórbida/genética , Adulto , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Feminino , Humanos , Jejuno/fisiologia , Metabolismo dos Lipídeos/genética , Fígado/patologia , Fígado/fisiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade Mórbida/patologia , RNA Mensageiro , Receptor Toll-Like 9/genética , Receptores Toll-Like/genética , Transcriptoma
4.
J Pers Med ; 11(3)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809913

RESUMO

In SARS-CoV-2-infected patients, obesity, hypertension, and diabetes are dangerous factors that may result in death. Priority in detection and specific therapies for these patients are necessary. We wanted to investigate the impact of obesity and metabolic syndrome (MS) on the clinical course of COVID-19 and whether prognostic biomarkers described are useful to predict the evolution of COVID-19 in patients with obesity or MS. This prospective cohort study included 303 patients hospitalized for COVID-19. Participants were first classified according to the presence of obesity; then, they were classified according to the presence of MS. Clinical, radiologic, and analytical parameters were collected. We reported that patients with obesity presented moderate COVID-19 symptoms and pneumonia, bilateral pulmonary infiltrates, and needed tocilizumab more frequently. Meanwhile, patients with MS presented severe pneumonia and respiratory failure more frequently, they have a higher mortality rate, and they also showed higher creatinine and troponin levels. The main findings of this study are that IL-6 is a potential predictor of COVID-19 severity in patients with obesity, while troponin and LDH can be used as predictive biomarkers of COVID-19 severity in MS patients. Therefore, treatment for COVID-19 in patients with obesity or MS should probably be intensified and personalized.

5.
N Engl J Med ; 384(5): 417-427, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33289973

RESUMO

BACKGROUND: Current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking. METHODS: We conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)-confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days. RESULTS: The analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported. CONCLUSIONS: Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.).


Assuntos
Anti-Infecciosos/uso terapêutico , COVID-19/prevenção & controle , Hidroxicloroquina/uso terapêutico , SARS-CoV-2 , Adulto , Anti-Infecciosos/efeitos adversos , COVID-19/transmissão , COVID-19/virologia , Transmissão de Doença Infecciosa/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Falha de Tratamento , Carga Viral
6.
Life (Basel) ; 10(10)2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33081272

RESUMO

Non-alcoholic fatty liver disease (NAFLD) extends from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH). Peripheral serotonin (5-HT) has become as an important regulator of different metabolic pathways. 5-HT has been related to obesity and lipid accumulation in the liver. The objective of this study was to assess the relationship between the 5-HT signaling pathway and the degree of NAFLD, as well as to investigate whether peripheral 5-HT levels are related to the hepatic and jejunal mRNA abundance of serotonin receptors (HTR) in a cohort of women with morbid obesity (MO) and NAFLD. ELISA was used to quantify the serum 5-HT from normal-weight subjects (n = 26) and patients with MO (n = 58). We used RTq-PCR analysis to evaluate the relative expression of HTR in women with MO with normal liver (n = 22), SS (n = 21), and NASH (n = 15). The 5-HT was diminished in women with MO under a hypocaloric diet, regardless of the presence of NAFLD. Additionally, we report a negative correlation of 5-HT levels with metabolic syndrome criteria, suggesting that serotonin may have a protective role in obesity. Additionally, the hepatic expression of HTR2A and HTR2B were decreased in women with MO and NAFLD, but no significant differences in the HTR jejunal expression according to the presence of NAFLD were found.

7.
Clin Infect Dis ; 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32674126

RESUMO

BACKGROUND: No therapeutics have yet been proven effective for the treatment of mild-illness caused by SARS-CoV-2. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be more efficacious than no-treatment for outpatients with mild Covid-19. METHODS: We conducted a multicenter, open label, randomized controlled trial in Catalonia (Spain) between March 17, and May 26, 2020. Eligible Covid-19 cases were non-hospitalized adult patients with recently confirmed SARS-CoV-2 infection and less than five days of symptoms. Patients were assigned to receive HCQ (800 mg on day 1, followed by 400 mg once daily for 6 days) or no antiviral treatment (not-placebo controlled). Study outcomes were the reduction of viral RNA load in nasopharyngeal swabs up to 7 days after treatment start, patient disease progression using the WHO scale up to 28 days, and time to complete resolution of symptoms. Adverse events were assessed up to 28 days. RESULTS: A total of 293 patients were eligible for intention-to-treat analysis: 157 in the control arm and 136 in the intervention arm. The mean age was 41.6 years (SD 12.6), mean viral load at baseline was 7.90 (SD 1.82) Log10 copies/mL, and median time from symptom onset to randomization was 3 days. No significant differences were found in the mean reduction of viral load at day 3 (-1.41 vs. -1.41 Log10 copies/mL in the control and intervention arm, respectively; difference 0.01 [95% CI -0.28;0.29]) or at day 7 (-3.37 vs. -3.44; d -0.07 [-0.44;0.29]). This treatment regimen did not reduce risk of hospitalization (7.1%, control vs. 5.9%, intervention; RR 0.75 [0.32;1.77]) nor shortened the time to complete resolution of symptoms (12 days, control vs. 10 days, intervention; p = 0.38). No relevant treatment-related AEs were reported. CONCLUSIONS: In patients with mild Covid-19, no benefit was observed with HCQ beyond the usual care.

8.
Obesity (Silver Spring) ; 28(8): 1487-1493, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32657010

RESUMO

OBJECTIVE: This cohort study aimed to explore the relationship between the Notch signaling pathway and the degree of nonalcoholic fatty liver disease (NAFLD). Moreover, this study intended to investigate whether this pathway is related to hepatic lipid metabolism and Toll-like receptors (TLRs). METHODS: This study used real-time polymerase chain reaction analysis to evaluate the hepatic expression level of all genes studied (Notch receptors NOTCH1, NOTCH2, NOTCH3, and NOTCH4, transcription factors HES1 and HES5, and Hes-related repressor proteins HEY1 and HEY2) in hepatic tissue from two cohorts: women with severe obesity (n = 57) and normal liver structure (n = 20) or NAFLD (n = 37). RESULTS: In women with severe obesity and NAFLD, this study found downregulation of hepatic HES5 expression. This expression correlated positively with the hepatic expression of HES1, HEY1, and NOTCH3. This study also found a positive correlation between HES5 expression and sterol regulatory element-binding protein 1c (SREBP1c) and between NOTCH3 and several genes related to hepatic lipid metabolism (encoding liver X nuclear receptor α variant 1, farnesoid X nuclear receptor, SREBP1c, acetyl-CoA carboxylase 1, fatty acid synthase, peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1, carnitine O-octanoyltransferase, ATP-binding cassette subfamily A member 1, and ATP-binding cassette subfamily G member 1). Finally, this study found a positive correlation between NOTCH2 and TLR2, TLR4, and TLR9 and a positive relationship between NOTCH1 and TLR9. CONCLUSIONS: Taken together, these findings suggest that hepatic expression of Notch proteins and ligands in relation to lipid metabolism pathways in the liver could have a role in NAFLD pathogenesis.


Assuntos
Hepatócitos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/genética , Receptores Notch/metabolismo , Animais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Transdução de Sinais
9.
Int J Mol Sci ; 21(11)2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32545403

RESUMO

The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is linked to systemic inflammation. Currently, two of the aspects that need further investigation are diagnosis and treatment of NASH. In this sense, the aim of this study was to assess the relationship between circulating levels of cytokines, hepatic expression of toll-like receptors (TLRs), and degrees of NAFLD, and to investigate whether these levels could serve as noninvasive biomarkers of NASH. The present study assessed plasma levels of cytokines in 29 normal-weight women and 82 women with morbid obesity (MO) (subclassified: normal liver (n = 29), simple steatosis (n = 32), and NASH (n = 21)). We used enzyme-linked immunosorbent assays (ELISAs) to quantify cytokine and TLR4 levels and RTqPCR to assess TLRs hepatic expression. IL-1ß, IL-8, IL-10, TNF-α, tPAI-1, and MCP-1 levels were increased, and adiponectin levels were decreased in women with MO. IL-8 was significantly higher in MO with NASH than in NL. To sum up, high levels of IL-8 were associated with the diagnosis of NASH in a cohort of women with morbid obesity. Moreover, a positive correlation between TLR2 hepatic expression and IL-8 circulating levels was found.


Assuntos
Interleucina-8/sangue , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/sangue , Obesidade Mórbida/sangue , Receptor 2 Toll-Like/metabolismo , Adipocinas/sangue , Adulto , Cirurgia Bariátrica , Estudos de Casos e Controles , Feminino , Humanos , Fígado/metabolismo , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade Mórbida/cirurgia , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
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