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1.
Clin Nutr ; 38(4): 1773-1781, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30143305

RESUMO

BACKGROUND & AIMS: Bariatric surgery has been well established and considered the treatment of choice in morbid obesity. However, some patients refuse surgery because long-term effects have not been fully elucidated, quality of life might change and lifelong supplementation with vitamins and trace elements may be required. Our aim was to exhaust non-surgical treatment modalities and to evaluate such an intensified treatment alternative. METHODS: A total of 206 patients (mean age = 46 years; BMI = 49 kg/m2) enrolled since 2013 into a non-surgical multimodality obesity treatment program covered by major health insurances were prospectively evaluated over a three year period. The 12-month treatment course comprised 57 h cognitive-behavioral therapy, 53.5 h physical exercise training, and 43.5 h nutritional therapy offered in small groups. Weight loss was induced by a formula-based, very low-calorie diet for 12 weeks in combination with a gastric balloon. The primary outcome was relative weight loss (RWL). Secondary outcome measures were waist-to-hip ratio, blood pressure, antihypertensive drug treatment, anti-diabetic medication, HbA1c, and quality of life. RESULTS: 166 Patients (81%) completed treatment. Mean (±SD) weight loss after 12 months for women and men were 28.8 kg (±14.7) and 33.7 kg (±19.5), respectively, among completers. RWL was 21.9% (±10.0) and excess weight loss (EWL) was 46.9% (±22.2), whereas intention-to-treat analysis revealed a RWL of 20.0% (±10.4) and an EWL of 42.9% (±22.9). Weight loss was accompanied by improved quality of life, lowered HbA1c values, and a significantly reduced need of antihypertensive and diabetes medications over the study period. Three year follow-up data from the first 78 patients (76% follow-up rate) revealed a RWL of 13% (±13.1) and an EWL of 27.2% (±28.8). The majority of patients (51%) maintained a RWL of 10% or more, and 44% had an EWL > 30%. CONCLUSIONS: In patients with morbid obesity, an intensified non-surgical multimodality treatment program may achieve significant and sustained weight loss accompanied by improvement of disease markers as well as quality of life for at least three years.


Assuntos
Obesidade Mórbida , Redução de Peso/fisiologia , Adolescente , Adulto , Idoso , Restrição Calórica , Feminino , Balão Gástrico , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/terapia , Cooperação do Paciente , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento , Adulto Jovem
2.
PLoS One ; 9(3): e87851, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24676346

RESUMO

The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform-mediated functions.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Tiofenos/química , Tiofenos/farmacologia , Animais , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Cricetinae , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes de Fusão , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Tiofenos/síntese química , Quinases Dyrk
3.
Chem Biol ; 18(11): 1463-73, 2011 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-22118680

RESUMO

Protein kinases are key mediators of cellular signaling, and therefore, their activities are tightly controlled. AGC kinases are regulated by phosphorylation and by N- and C-terminal regions. Here, we studied the molecular mechanism of inhibition of atypical PKCζ and found that the inhibition by the N-terminal region cannot be explained by a simple pseudosubstrate inhibitory mechanism. Notably, we found that the C1 domain allosterically inhibits PKCζ activity and verified an allosteric communication between the PIF-pocket of atypical PKCs and the binding site of the C1 domain. Finally, we developed low-molecular-weight compounds that bind to the PIF-pocket and allosterically inhibit PKCζ activity. This work establishes a central role for the PIF-pocket on the regulation of PKCζ and allows us to envisage development of drugs targeting the PIF-pocket that can either activate or inhibit AGC kinases.


Assuntos
Proteína Quinase C/química , Bibliotecas de Moléculas Pequenas/química , Regulação Alostérica/efeitos dos fármacos , Sítios de Ligação , Biocatálise , Linhagem Celular Tumoral , Humanos , NF-kappa B/metabolismo , Proteína Quinase C/metabolismo , Estrutura Terciária de Proteína , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/farmacologia
4.
J Med Chem ; 54(19): 6714-23, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-21863889

RESUMO

Protein kinase inhibitors with an allosteric mode of action are expected to reach, in many cases, higher selectivity for the target enzyme than ATP-competitive compounds. Therefore, basic research is aiming at identifying and establishing novel sites on the catalytic domain of protein kinases which might be targeted by allosteric inhibitors. We previously published the first structure-activity relationships (SARs) for allosteric activators of protein kinase PDK1. Here, we present the design, synthesis, and SAR data on a series of novel compounds, 4-benzimidazolyl-3-phenylbutanoic acids, that inhibit the atypical protein kinace C (PKC) ζ via binding to the PIF-pocket. Key positions were identified in the compounds that can be modified to increase potency and selectivity. Some congeners showed a high selectivity toward PKCζ, lacking inhibition of the most closely related isoform, PKCι, and of further AGC kinases. Furthermore, evidence is provided that these compounds are also active toward cellular PKCζ without loss of potency compared to the cell-free assay.


Assuntos
Butiratos/síntese química , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Regulação Alostérica , Sítios de Ligação , Butiratos/química , Butiratos/farmacologia , Sistema Livre de Células , Humanos , NF-kappa B/metabolismo , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Células U937
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