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1.
J Cyst Fibros ; 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38688746

RESUMO

BACKGROUND: Sexual dysfunction (erectile dysfunction in males, sexual dissatisfaction, sexual interest/arousal disorders, and dyspareunia in females) has not been the subject of indepth research in people with cystic fibrosis (CF). This study aimed to determine the prevalence of sexual dysfunction in adults with CF, factors associated with sexual dysfunction, and the impact of sexual dysfunction on quality of life. METHOD: We conducted a multicentre study in adults with cystic fibrosis followed in specialist centres in Western France. We assessed erectile dysfunction and its severity using the IIEF5 self-questionnaire (International Index of Erectile Function); the FSFI (Female Sexual Function Index) was used to assess sexual function in females, and we evaluated quality of life in both sexes using the CFQ-R14+ questionnaire. RESULTS: In total, 77 males and 74 females completed the sexual function questionnaire (mean age 32+/- 10 and 25+/- 8,5 years respectively). Among them, 21 % of males and 30 % of females reported sexual dysfunction. CFQ-R14+ score was significantly lower in males with erectile dysfunction than those without (p < 0.001). Faecal incontinence was associated with more frequent sexual dysfunction in females and higher severity of erectile dysfunction in males. CONCLUSION: The prevalence of sexual disorders is relatively high in males and females with cystic fibrosis. Therefore, it seems important to train specialist teams to address the issue of sexuality without embarrassment, and to encourage them to seek out and treat faecal incontinence, which is associated with greater severity or frequency of these symptoms.

2.
J Cyst Fibros ; 2023 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-37907384

RESUMO

BACKGROUND: In cystic fibrosis (CF), coughing is associated with a risk of pelvic floor dysfunction. However, data on the prevalence of symptoms (stress urinary incontinence, bladder overactivity, dysuria, and faecal incontinence) are lacking in males and females with CF. The impact of incontinence on adherence to respiratory care has not been studied. METHODS: We conducted a multicentre study in adults with CF followed in the North-West French CF network. Urinary disorders and their severity were assessed using the Urinary Symptom Profile (USP) self-report questionnaire; the impact of urinary disorders on general quality of life was measured using the SF-Qualiveen questionnaire; faecal incontinence was assessed using the Wexner self-report questionnaire; and the CFQ-R14+ questionnaire was used to assess quality of life. A self-administered questionnaire developed for the study assessed the impact of symptoms on respiratory care. RESULTS: Of the 178 people with CF included, 34 % reported stress urinary incontinence, with a large female predominance (63.5 % of females vs. 7.5 % of males), 65 % bladder overactivity (including 16 % urge incontinence) and 50 % faecal incontinence, also with a female predominance. Neither urinary nor faecal incontinence were related to the severity of the respiratory impairment (FEV1). Quality of life was particularly affected in women. Stress urinary Incontinence symptoms affected respiratory care in both sexes. CONCLUSION: The prevalence of functional urinary and faecal disorders was high in adults with CF and impacted on quality of life and respiratory care. Therefore, multidisciplinary teams must have knowledge of symptoms, the diagnostic tools and management strategies to provide specific treatment.

3.
Orphanet J Rare Dis ; 14(1): 177, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300002

RESUMO

BACKGROUND: Although metreleptin replacement therapy was shown to improve metabolic alterations in lipodystrophic syndromes, patients' adherence and satisfaction with treatment have never been evaluated. The 20 patients with lipodystrophic syndromes participating in the French compassionate program of metreleptin therapy filled in a self-questionnaire including an Adherence Evaluation Test, the Treatment Satisfaction Questionnaire for Medication (TSQM®-vII), and items about physical appearance. RESULTS: 15 patients were women, median age was 32.5 years (IQT 25-75 (16.2;49.5), 18 had diabetes. Adherence with metreleptin (one daily subcutaneous injection) was poor in 25%, excellent in 25% and acceptable in 50% of patients. On a 0-to-100 scale, patients' satisfaction scores reached 66.7 (52.1;81.2) for effectiveness, 55.6 (44.4;66.7) for ease/comfort of use, and 83.3 (52.1;83.3) for global satisfaction with metreleptin therapy. Self-reported side effects were frequent injection site reactions 100 (79.2;100). Satisfaction scores did not differ in patients with partial (n = 10) or generalized (n = 10) lipodystrophic syndromes, did not correlate with metabolic improvement, but were significantly higher in compliant patients with fewer side effects. Morphological appearance was reported improved under metreleptin therapy in 13 among 17 patients. CONCLUSIONS: Metreleptin increases health self-perception and decreases morphotype-associated stigmatization in most patients with lipodystrophic syndromes, but poor comfort of use and local side effects weaken adherence.


Assuntos
Leptina/análogos & derivados , Lipodistrofia/tratamento farmacológico , Lipodistrofia/psicologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Leptina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Autoimagem , Inquéritos e Questionários , Adulto Jovem
4.
Diabetes ; 68(2): 305-317, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30455377

RESUMO

Widely used for their anti-inflammatory and immunosuppressive properties, glucocorticoids are nonetheless responsible for the development of diabetes and lipodystrophy. Despite an increasing number of studies focused on the adipocyte glucocorticoid receptor (GR), its precise role in the molecular mechanisms of these complications has not been elucidated. In keeping with this goal, we generated a conditional adipocyte-specific murine model of GR invalidation (AdipoGR knockout [KO] mice). Interestingly, when administered a corticosterone treatment to mimic hypercorticism conditions, AdipoGR-KO mice exhibited an improved glucose tolerance and insulin sensitivity. This was related to the adipose-specific activation of the insulin-signaling pathway, which contributed to fat mass expansion, as well as a shift toward an anti-inflammatory macrophage polarization in adipose tissue of AdipoGR-KO animals. Moreover, these mice were protected against ectopic lipid accumulation in the liver and displayed an improved lipid profile, contributing to their overall healthier phenotype. Altogether, our results indicate that adipocyte GR is a key factor of adipose tissue expansion and glucose and lipid metabolism control, which should be taken into account in the further design of adipocyte GR-selective modulators.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Corticosterona/farmacologia , Erros Inatos do Metabolismo/metabolismo , Receptores de Glucocorticoides/deficiência , Tecido Adiposo/efeitos dos fármacos , Animais , Células Cultivadas , Citometria de Fluxo , Teste de Tolerância a Glucose , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glucocorticoides/metabolismo
5.
Diabetes ; 68(1): 95-108, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30327384

RESUMO

Both type 1 and type 2 diabetes are characterized by deficient insulin secretion and decreased ß-cell mass. Thus, regenerative strategies to increase ß-cell mass need to be developed. To characterize mechanisms of ß-cell plasticity, we studied a model of severe insulin resistance in the adult mouse and defined how ß-cells adapt. Chronic corticosterone (CORT) treatment was given to adult mice and led to rapid insulin resistance and adaptive increased insulin secretion. Adaptive and massive increase of ß-cell mass was observed during treatment up to 8 weeks. ß-Cell mass increase was partially reversible upon treatment cessation and reinduced upon subsequent treatment. ß-Cell neogenesis was suggested by an increased number of islets, mainly close to ducts, and increased Sox9 and Ngn3 mRNA levels in islets, but lineage-tracing experiments revealed that neoformed ß-cells did not derive from Sox9- or Ngn3-expressing cells. CORT treatment after ß-cell depletion partially restored ß-cells. Finally, ß-cell neogenesis was shown to be indirectly stimulated by CORT because serum from CORT-treated mice increased ß-cell differentiation in in vitro cultures of pancreatic buds. Altogether, the results present a novel model of ß-cell neogenesis in the adult mouse and identify the presence of neogenic factors in the serum of CORT-treated mice.


Assuntos
Glucocorticoides/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Citometria de Fluxo , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição SOX9/genética
6.
Obes Surg ; 28(9): 2886-2893, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29781044

RESUMO

CONTEXT: Anti-retroviral therapy (ART) dramatically reduced AIDS development, thus enabling patients to live as long as the general population. New challenges have emerged particularly cardiometabolic diseases and weight gain, with some HIV patients seeking bariatric surgery (BS). However, BS outcomes during HIV remain poorly described, with scarce data on ART pharmacokinetic post-BS. OBJECTIVE: Describing sleeve gastrectomy (SG) results in HIV patients in terms of ART pharmacokinetic, HIV control, weight loss, and metabolic outcomes. DESIGN, SETTING, AND PATIENTS: Prospective study of HIV patients undergoing SG in a referral academic center, with at least 6 months follow-up. MAIN OUTCOME MEASURE: Clinical and biological parameters, HIV medical history, and ART pharmacokinetics were gathered before and post-SG. RESULTS: Seventeen patients (mean BMI = 44.2 ± 5.7 kg m-2) and major obesity-related diseases (47% type-2 diabetes, 64% obstructive sleep apnea, 70% hypertension) underwent SG during a mean 2 years of follow-up. They displayed an average of 20% reduction of initial BMI and improved body composition, similarly to obese non-HIV patients. SG improved metabolic status. All patients had undetectable viral load before BS. Upon HIV follow-up, 12 patients had undetectable viral load with correct ART kinetic parameters (3 and 6 months); 4 displayed detectable viral load along with significant decrease in raltegravir and atazanavir treatment exposure, leading to ART change with subsequent undetectable viral load; and 1 had persistent detectable viral load despite ART change. CONCLUSIONS: SG seems effective and safe in obese HIV patients. However, ART treatment should be monitored post-SG to control HIV infection. We suggest that some ART should be adapted before SG conjoints with infectious disease specialists.


Assuntos
Antirretrovirais/farmacocinética , Cirurgia Bariátrica , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Absorção Intestinal , Obesidade Mórbida/complicações , Obesidade Mórbida/cirurgia , Adulto , Antirretrovirais/uso terapêutico , Cirurgia Bariátrica/efeitos adversos , Cirurgia Bariátrica/métodos , Feminino , Seguimentos , HIV/efeitos dos fármacos , Infecções por HIV/metabolismo , Infecções por HIV/cirurgia , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Síndromes de Malabsorção/etiologia , Síndromes de Malabsorção/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/metabolismo , Complicações Pós-Operatórias/metabolismo , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Redução de Peso/fisiologia
7.
J Am Geriatr Soc ; 65(12): 2713-2719, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28990160

RESUMO

OBJECTIVES: To determine whether potentially inappropriate medications (PIMs) or potentially inappropriate associations (PIAs) prescribed knowingly are associated with patient monitoring. DESIGN: Prospective observational study. SETTING: Geriatric units (n = 56) in 28 hospitals. PARTICIPANTS: Inpatients aged 75 and older (N = 1,327). MEASUREMENTS: Potentially inappropriate prescriptions (PIP) were defined as a PIM or a PIA selected by an expert board from lists of explicit criteria (Beers, Priscus, Laroche, French Health Agency) using a Delphi process. They were considered to be prescribed knowingly if they were maintained after reassessment by the geriatrician and the clinical pharmacist. Primary outcome was the rate of PIPs maintained (prescribed knowingly) and for which a geriatrician declared that specific monitoring was performed. Secondary outcomes were the parameters monitored and the rate of participants receiving knowingly a PIP. RESULTS: One thousand sixty-three PIPs were detected in 607 participants (46%). After reassessment, 826 (78%) PIPs were maintained in 490 participants (37%), the main reasons being participant's regular treatment and lack of alternative. Psychotropic (36%), cardiovascular (including antithrombotics) (29%), and laxative or antiemetic drugs (16%) were the most-frequent classes prescribed knowingly. The geriatricians declared to perform clinical or biological monitoring for 69% (n = 570) of PIMs or PIAs prescribed knowingly. Three types of specific monitoring were identified: clinical, biological, and follow-up with a specialist. CONCLUSION: Approximately three-quarters of PIMs or PIAs were prescribed knowingly, of which 69% were monitored, with wide variations in occurrence and in quality according to drug classes. This underlines the need for accurate guidelines on PIP monitoring.


Assuntos
Monitoramento de Medicamentos , Prescrição Inadequada/estatística & dados numéricos , Lista de Medicamentos Potencialmente Inapropriados/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Feminino , França , Hospitalização , Humanos , Masculino , Estudos Prospectivos
8.
Diabetes ; 65(9): 2502-15, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27284105

RESUMO

Identification of new adipokines that potentially link obesity to insulin resistance represents a major challenge. We recently showed that NOV/CCN3, a multifunctional matricellular protein, is synthesized and secreted by adipose tissue, with plasma levels highly correlated with BMI. NOV involvement in tissue repair, fibrotic and inflammatory diseases, and cancer has been previously reported. However, its role in energy homeostasis remains unknown. We investigated the metabolic phenotype of NOV(-/-) mice fed a standard or high-fat diet (HFD). Strikingly, the weight of NOV(-/-) mice was markedly lower than that of wild-type mice but only on an HFD. This was related to a significant decrease in fat mass associated with an increased proportion of smaller adipocytes and to a higher expression of genes involved in energy expenditure. NOV(-/-) mice fed an HFD displayed improved glucose tolerance and insulin sensitivity. Interestingly, the absence of NOV was associated with a change in macrophages profile (M1-like to M2-like), in a marked decrease in adipose tissue expression of several proinflammatory cytokines and chemokines, and in enhanced insulin signaling. Conversely, NOV treatment of adipocytes increased chemokine expression. Altogether, these results show that NOV is a new adipocytokine that could be involved in obesity-associated insulin-resistance.


Assuntos
Tecido Adiposo/metabolismo , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , Obesidade/metabolismo , Células 3T3-L1 , Tecido Adiposo/fisiopatologia , Animais , Composição Corporal/genética , Composição Corporal/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Feminino , Intolerância à Glucose/metabolismo , Intolerância à Glucose/fisiopatologia , Inflamação/metabolismo , Inflamação/patologia , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Fígado/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Sobre-Expressa em Nefroblastoma/genética , Obesidade/fisiopatologia , Pâncreas/metabolismo , RNA Interferente Pequeno/genética
9.
Obes Surg ; 24(11): 1896-903, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24947346

RESUMO

BACKGROUND: This study aims to determine the influence of Roux-en-Y gastric bypass (RYGB) on medication-related costs. METHODS: The study analyzed the types, dosages, and costs of drugs and medical devices prescribed before and after surgery (1, 3, 6, and 12 months and yearly thereafter) in patients who underwent RYGB between June 2004 and May 2010 and had an outpatient visit between December 2009 and May 2010 at Pitié-Salpêtrière University Hospital, Paris, France. RESULTS: The cohort included 143 patients (78 % female; mean age, 42.9 years; mean BMI, 48.6 kg/m(2)). Total prescription costs were significantly lower (-32 %, p < 0.001) 1 year after RYGB compared with preoperative costs. However, the cost for medications to prevent RYGB side effects (in particular nutritional deficiencies) displayed a 36-fold increase in the first month postsurgery, but then decreased progressively over time. Importantly, the cost related to the treatment of the two most frequent obesity-related diseases significantly decreased 1 year after surgery. Indeed, prescription costs for treatment of type 2 diabetes (T2D) and obstructive sleep apnea (OSA) (namely CPAP therapy considered as the gold standard treatment) were reduced 1 year after surgery by 85 and by 63 % (both p < 0.001), respectively. We also observed a trend toward a decrease in the prescription costs of other obesity-related diseases, although it did not reach significance in our cohort. CONCLUSIONS: Considering medication to treat both obesity-related diseases and prevention of secondary effects of bariatric surgery, we observed that overall postoperative medication costs were significantly reduced one year after surgery, especially for T2D and OSA.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Derivação Gástrica/métodos , Obesidade Mórbida/cirurgia , Adulto , Análise Custo-Benefício , Diabetes Mellitus Tipo 2/economia , Feminino , Seguimentos , Derivação Gástrica/economia , Humanos , Masculino , Obesidade Mórbida/economia , Paris , Estudos Retrospectivos , Resultado do Tratamento
10.
Am J Physiol Endocrinol Metab ; 306(6): E668-80, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24425764

RESUMO

The oligopeptide transporter peptide cotransporter-1 Slc15a1 (PEPT1) plays a major role in the regulation of nitrogen supply, since it is responsible for 70% of the dietary nitrogen absorption. Previous studies demonstrated that PEPT1 expression and function in jejunum are reduced in diabetes and obesity, suggesting a nitrogen malabsorption from the diet. Surprisingly, we reported here a decrease in gut nitrogen excretion in high-fat diet (HFD)-fed mice and further investigated the mechanisms that could explain this apparent contradiction. Upon HFD, mice exhibited an increased concentration of free amino acids (AAs) in the portal vein (60%) along with a selective increase in the expression of two AA transporters (Slc6a20a, Slc36a1), pointing to a specific and adaptive absorption of some AAs. A delayed transit time (+40%) and an increased intestinal permeability (+80%) also contribute to the increase in nitrogen absorption. Besides, HFD mice exhibited a 2.2-fold decrease in fecal DNA resulting from a reduction in nitrogen catabolism from cell desquamation and/or in the intestinal microbiota. Indeed, major quantitative (2.5-fold reduction) and qualitative alterations of intestinal microbiota were observed in feces of HFD mice. Collectively, our results strongly suggest that both increased AA transporters, intestinal permeability and transit time, and changes in gut microbiota are involved in the increased circulating AA levels. Modifications in nitrogen homeostasis provide a new insight in HFD-induced obesity and glucose intolerance; however, whether these modifications are beneficial or detrimental for the HFD-associated metabolic complications remains an open issue.


Assuntos
Sistemas de Transporte de Aminoácidos/biossíntese , Aminoácidos/metabolismo , Modelos Animais de Doenças , Intolerância à Glucose/metabolismo , Absorção Intestinal , Mucosa Intestinal/metabolismo , Obesidade/metabolismo , Simportadores/biossíntese , Alostase , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos/sangue , Animais , DNA/análise , Dieta Hiperlipídica/efeitos adversos , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Fezes/química , Fezes/microbiologia , Regulação da Expressão Gênica , Intolerância à Glucose/etiologia , Intolerância à Glucose/microbiologia , Intolerância à Glucose/patologia , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/crescimento & desenvolvimento , Bactérias Gram-Positivas/isolamento & purificação , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Intestinos/microbiologia , Intestinos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrogênio/análise , Nitrogênio/metabolismo , Obesidade/etiologia , Obesidade/microbiologia , Obesidade/patologia , Transportador 1 de Peptídeos , Simportadores/genética , Simportadores/metabolismo
12.
J Alzheimers Dis ; 30(1): 155-66, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22391220

RESUMO

The accumulation of amyloid-ß peptide (Aß) in the brain is a critical hallmark of Alzheimer's disease. This high cerebral Aß concentration may be partly caused by impaired clearance of Aß across the blood-brain barrier (BBB). The low-density lipoprotein receptor-related protein-1 (LRP-1) and the ATP-binding cassette (ABC) protein ABCB1 (P-glycoprotein) are involved in the efflux of Aß across the BBB. We hypothesized that other ABC proteins, such as members of the G subfamily, are also involved in the BBB clearance of Aß. We therefore investigated the roles of ABCG2 (BCRP) and ABCG4 in the efflux of [3H] Aß1-40 from HEK293 cells stably transfected with human ABCG2 or mouse abcg4. We showed that ABCG2 and Abcg4 mediate the cellular efflux of [3H] Aß1-40. In addition, probucol fully inhibited the efflux of [3H] Aß1-40 from HEK293-abcg4 cells. Using the in situ brain perfusion technique, we showed that GF120918 (dual inhibitor of Abcb1 and Abcg2) strongly enhanced the uptake (Clup, µl/g/s) of [3H] Aß1-40 by the brains of Abcb1-deficient mice, but not by the brains of Abcb1/Abcg2-deficient mice, suggesting that Abcg2 is involved in the transport of Aß at the mouse BBB. Perfusing the brains of Abcb1/Abcg2- and Abca1-deficient mice with [3H] Aß1-40 plus probucol significantly increased the Clup of Aß. This suggests that a probucol-sensitive transporter that is different from Abca1, Abcb1, and Abcg2 is involved in the brain efflux of Aß. We suggest that this probucol-sensitive transporter is Abcg4. We conclude that Abcg4 acts in concert with Abcg2 to efflux Aß from the brain across the BBB.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Proteínas de Neoplasias/metabolismo , Fragmentos de Peptídeos/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Acridinas/farmacologia , Análise de Variância , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Isótopos de Carbono/metabolismo , Linhagem Celular Transformada , Glucose/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Perfusão , Tetra-Hidroisoquinolinas/farmacologia , Fatores de Tempo , Transfecção , Trítio/metabolismo
13.
Mol Pharmacol ; 81(3): 319-27, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22108913

RESUMO

The intestinal H(+)/peptide cotransporter 1 (PepT1) plays a major role in nitrogen supply to the body by mediating intestinal absorption of di- and tripeptides. Previous studies have reported that in animal models of type 2 diabetes/obesity, PepT1 activity and expression were markedly reduced. This prompted us to investigate the effects of two antidiabetic drugs, rosiglitazone and metformin, on PepT1 activity/expression in a murine diet-induced obesity model. C57BL/6J male mice were fed a high-fat diet (HFD) or a standard chow for 6 weeks and then were treated for 7 days with metformin (250 mg/kg/day) and/or rosiglitazone (8 mg/kg/day). For in vitro studies, Caco-2 enterocyte-like cells were treated for 7 days with metformin (10 mM) and/or rosiglitazone (10 µM). A 7-day rosiglitazone treatment increased PepT1 activity and prevented the 2-fold HFD-induced reduction in PepT1 transport. Metformin alone did not modify PepT1 activity but counteracted rosiglitazone-induced PepT1-mediated transport. As with the in vivo studies, rosiglitazone treatment up-regulated PepT1 transport activity with concomitant induction of S6 ribosomal protein activation in vitro. Furthermore, metformin decreased PepT1 expression (mRNA and protein) and its transport activity. The effect of metformin was linked to a reduction of phosphorylated S6 ribosomal protein (active form) and of phosphorylated 4E-BP1 (inactive form), a translation repressor. These data demonstrate that two antidiabetic drugs exert opposite effects on the PepT1 transport function probably through direct action on enterocytes. In our type 2 diabetes/obesity model, rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist compensated for the HFD-induced PepT1 down-regulation, whereas metformin reversed rosiglitazone activity at the translational level.


Assuntos
Hipoglicemiantes/farmacologia , Absorção Intestinal/efeitos dos fármacos , Metformina/farmacologia , Oligopeptídeos/metabolismo , Simportadores/metabolismo , Tiazolidinedionas/farmacologia , Adenilato Quinase/metabolismo , Animais , Sequência de Bases , Células CACO-2 , Primers do DNA , Ativação Enzimática , Ensaio de Imunoadsorção Enzimática , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transportador 1 de Peptídeos , Prótons , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosiglitazona
14.
Am J Pathol ; 179(3): 1230-42, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21741932

RESUMO

Treatment options for inflammatory bowel disease (IBD) are incompletely helpful, and surgery is often needed. One promising class of future therapeutic agents for IBD is melanocortin-related peptides, which exhibit potent immunomodulatory effects. We investigated KdPT, a tripeptide derivative of the C-terminus of α-melanocyte-stimulating hormone, as an anti-inflammatory small molecule in vivo and in vitro. Intestinal inflammation was studied after oral administration of dextran sodium sulfate and in IL-10 gene-deficient mice. The effects of KdPT on key colonic epithelial cell functions were studied in vitro and in vivo by evaluating proliferation, wound healing, transepithelial resistance, and expression of tight junction proteins. Melanin assays were performed to determine the melanotropic effects of KdPT. KdPT-treated animals showed markedly reduced severity of inflammation in both colitis models. In colonic epithelial cells, KdPT increased proliferation, accelerated closure of wounds, and improved transepithelial electrical resistance after stimulation with interferon-γ/tumor necrosis factor-α. Moreover, treatment with KdPT also prevented the loss of tight junction protein expression and improved barrier function in vivo. KdPT acted independently of IL-1 receptor type I in vivo and did not affect melanogenesis in vitro. KdPT is capable of attenuating the course of experimental colitis in different models and maintains epithelial cell function. Furthermore, KdPT does not induce pigmentation, emphasizing the potential of this small molecule for the future treatment of IBD.


Assuntos
Colite/prevenção & controle , Oligopeptídeos/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Células Cultivadas , Colite/metabolismo , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Células Epiteliais , Imunofluorescência , Interleucina-10/deficiência , Interleucina-1beta/metabolismo , Mucosa Intestinal/metabolismo , Antígeno Ki-67/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Cicatrização/efeitos dos fármacos
15.
Eur J Pharmacol ; 636(1-3): 189-97, 2010 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-20361960

RESUMO

Failed medical therapy is a common problem in inflammatory bowel disease. P-glycoprotein (P-gp), an efflux pump encoded by MDR1 (ABCB1) gene can actively pump drugs out of cells conferring the phenotype of multidrug resistance. Various studies evoked that cyclooxygenase (COX) system may be involved in the regulation of P-gp activity. Since COX-2 isoform is overexpressed in colic inflammatory states, we examined the inhibitory effect of COX-2-inhibitors on P-gp expression and function under COX-2 stimulated conditions mediated by trinitrobenzene sulfonic acid (TNBS) in vitro, in Caco-2 cells, and in TNBS-induced colitis in mice. COX-2 and P-gp expressions were evaluated by real-time PCR and western blot. The activity of P-gp was measured by intracellular accumulation of rhodamine123 (Rho123) in Caco-2 cells and by Rho123 efflux using the intestinal everted loop method in mice. We showed that COX-2 stimulation in Caco-2 cells by 0.1mM TNBS exposure for 24h induced P-gp protein expression and activity. This activation was reversed by simultaneous COX-2-inhibitor treatment. Moreover, this effect was reproduced in vivo, in mice, where an increased P-gp expression and activity were observed 24h post intra-rectal TNBS administration. Induced P-gp expression and activity could be blocked by the oral pre-treatment with indomethacin heptyl ester (IHE) (20mg/kg). Administration of indomethacin heptyl ester had also a protective effect in TNBS-induced colitis. Our observations suggest that the inhibition of P-gp by COX-2-inhibitors could contribute to the improvement of medical response and this finding may have relevance to medical treatment of inflammatory bowel disease patients.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ácido Trinitrobenzenossulfônico/farmacologia , Regulação para Cima/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Células CACO-2 , Colite/tratamento farmacológico , Colite/genética , Colite/metabolismo , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dinoprostona/farmacologia , Indução Enzimática/efeitos dos fármacos , Humanos , Indometacina/farmacologia , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos
16.
Neurosci Lett ; 472(3): 166-70, 2010 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-20138122

RESUMO

The efflux pumps located at the blood-brain barrier (BBB) prevent drugs entering the brain. As such, efflux pumps are a major obstacle to drug brain distribution. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with little therapeutics available: riluzole is the only drug approved in its treatment. The lack of response to treatment in ALS may be, at least in part, due to increased activities of efflux pumps in relation to disease, leading to subtherapeutic brain concentrations of drugs. In the present study, we used a transgenic mouse model of ALS (G86R mSOD1 mice) to test this hypothesis. Expression and functionality of P-glycoprotein (ABCB1, P-gp) and Breast Cancer Resistance Protein (ABCG2, BCRP), two major efflux pumps, were studied. We observed an increased P-gp expression (1.5-fold) in presymptomatic mSOD1 mice compared to wild-type controls. Consistent with this, P-gp function was also increased by 1.5-fold and riluzole brain disposition was decreased by 1.7-fold in mSOD1 mice. Contrasting with this, BCRP expression and function were unaltered by the pathology. These results demonstrate that BBB transport proteins are modified in G86R mSOD1 mice ALS model. Such findings underline potential problems in extrapolating the results of animal studies to humans and developing clinical trials, especially for drugs transported by P-gp.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Esclerose Lateral Amiotrófica/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Mutação , Fármacos Neuroprotetores/metabolismo , Riluzol/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase-1
17.
J Biol Chem ; 284(11): 6801-8, 2009 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-19144638

RESUMO

Leptin is a major determinant of energy homeostasis, acting both centrally and in the gastrointestinal tract. We previously reported that acute leptin treatment enhances the absorption of di- and tripeptides via the proton-dependent PepT1 transporter. In this study, we investigated the long term effect of leptin on PepT1 levels and activity in Caco2 cell monolayers in vitro. We then assessed the significance of the regulation of PepT1 in vivo in a model of diet-induced obesity. We demonstrated that 1) leptin regulated PepT1 at the transcriptional level, via the MAPK pathway, and at the translational level, via ribosomal protein S6 activation, in Caco2 cells and 2) this activation was systematically followed by a time- and concentration-dependent loss of leptin action reflecting desensitization. Deciphering this desensitization, we demonstrated that leptin induced a down-regulation of its own receptor protein and mRNA expression. More importantly, we showed, in mice with diet-induced obesity, that a 4-week hypercaloric diet resulted in a 46% decrease in PepT1-specific transport, because of a 30% decrease in PepT1 protein and a 50% decrease in PepT1 mRNA levels. As shown in Caco2 cells, these changes in PepT1 were supported by a parallel 2-fold decrease in leptin receptor expression in mice. Taken together, these results indicate that during induction of obesity, leptin resistance may also occur peripherally in the gastrointestinal tract, disrupting the absorption of oligopeptides and peptidomimetic drugs.


Assuntos
Dieta/efeitos adversos , Dipeptídeos/metabolismo , Absorção Intestinal , Obesidade/metabolismo , Receptores para Leptina/biossíntese , Simportadores/biossíntese , Animais , Transporte Biológico , Células CACO-2 , Modelos Animais de Doenças , Regulação para Baixo , Trato Gastrointestinal/metabolismo , Humanos , Leptina/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Obesidade/etiologia , Transportador 1 de Peptídeos , RNA Mensageiro/biossíntese , Fatores de Tempo
18.
Obesity (Silver Spring) ; 17(3): 431-8, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19131941

RESUMO

Obesity leads to the appearance of an inflammatory process, which can be initiated even with a moderate weight gain. Palmitoylethanolamide (PEA) is an endogenous lipid, secreted by human adipocytes, that possesses numerous anti-inflammatory properties. The main purpose of this study was to investigate the anti-inflammatory effect of PEA on human adipocytes, as well as in a murine model. The production of tumor necrosis factor-alpha (TNF-alpha) by lipopolysaccharide (LPS)-treated human subcutaneous adipocytes in primary culture and CF-1 mice was investigated by enzyme-linked immunosorbent assay. The effects of PEA on adipocyte TNF-alpha secretion were explored as well as some suspected PEA anti-inflammatory pathways: nuclear factor-kappaB (NF-kappaB) pathway, peroxisome proliferator-activated receptor-alpha (PPAR-alpha) gene expression, and TNF-alpha-converting enzyme (TACE) activity. The effects of PEA on the TNF-alpha serum concentration in intraperitoneally LPS-treated mice were also studied. We demonstrate that the LPS induced secretion of TNF-alpha by human adipocytes is inhibited by PEA. This action is neither linked to a reduction in TNF-alpha gene transcription nor to the inhibition of TACE activity. Moreover, PPAR-alpha is not implicated in this anti-inflammatory activity. Lastly, PEA exhibits a wide-reaching anti-inflammatory action as the molecule is able to completely inhibit the strong increase in TNF-alpha levels in the serum of mice treated with high doses of LPS. In view of its virtual lack of toxicity, PEA might become a potentially interesting candidate molecule in the prevention of obesity-associated insulin resistance.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Palmíticos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas ADAM/metabolismo , Proteína ADAM17 , Adulto , Amidas , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Endocanabinoides , Etanolaminas , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , Modelos Animais , NF-kappa B/metabolismo , PPAR alfa/metabolismo
19.
Neurosci Lett ; 442(1): 19-23, 2008 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-18598736

RESUMO

Parkinson's disease is a neurodegenerative disorder that requires treatment by dopaminergic agonists, which may be responsible for central side effects. We hypothesized that the efflux transporter ABCB1/P-glycoprotein played a role in brain disposition of antiparkinsonian drugs and could control central toxicity. We aimed to evaluate antiparkinsonian drugs as ABCB1 substrates and/or inhibitors in rat brain endothelial cells GPNT, in order to predict potential clinical drug-drug interactions. Among the antiparkinsonian drugs tested, levodopa, bromocriptine, pergolide and pramipexole were ABCB1 substrates. However, only bromocriptine could inhibit ABCB1 functionality with an IC(50) of 6.71 microM on Rhodamine 123 uptake and an IC(50) of 1.71 microM on digoxine uptake. Thus, bromocriptine at 100 microM is responsible for an increase of levodopa intracellular transport of about 2.05-fold versus control. Therefore, we can conclude that bromocriptine is a potent drug for medicinal interactions in vitro. Hence, in patients with Parkinson's disease, these results may be considered to optimise treatments individually.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Antiparkinsonianos/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antiparkinsonianos/farmacologia , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Linhagem Celular , Ratos
20.
Pharm Res ; 25(9): 1991-2001, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18581209

RESUMO

PURPOSE: Elevated expression of the ABC transporters P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) seems to correlate with multidrug resistance of cancer cells. In this study we investigated the effect of COX inhibitors in modulating P-gp and BCRP expression and P-gp activity in Caco-2 cells. METHODS: mRNA and protein expression of MDR1 and BCRP were evaluated by real time PCR and western blot respectively. The activity of P-gp was measured by intracellular accumulation of rhodamine123 or 3H-Digoxin. RESULTS: The chronic exposure of Caco-2 to indomethacin heptyl ester (indo HE) (0.4 muM) or nimesulide (10 muM) (selective COX-2 inhibitors) and naproxen (6 muM) (non selective inhibitor COX-1/COX-2) significantly decreased the expression and activity of P-gp. In contrast, the acute treatment by nimesulide and naproxen did not modify these parameters while indo HE treatment (48-72 h) caused a protein decrease and a functional inhibition of P-gp. Unexpectedly, the short-term treatment with naproxen induced an important increase of BCRP expression, but this induction was lost after long-term treatment. No modification of BCRP expression was observed after indo HE or nimesulide treatment. CONCLUSION: Our observations suggest a possible down regulation of P-gp by COX inhibitors, which may enhance the accumulation of chemotherapy agents.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Células CACO-2 , Celecoxib , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Indometacina/análogos & derivados , Indometacina/farmacologia , Naproxeno/farmacologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Pirazóis/farmacologia , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Sulfonamidas/farmacologia , Fatores de Tempo
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