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1.
Biol Reprod ; 106(1): 118-131, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34726240

RESUMO

A population of cows with excess androstenedione (A4; High A4) in follicular fluid, with follicular arrest, granulosa cell dysfunction, and a 17% reduction in calving rate was previously identified. We hypothesized that excess A4 in the ovarian microenvironment caused the follicular arrest in High A4 cows and that vascular endothelial growth factor A would rescue the High A4 phenotype. In trial 1, prior to culture, High A4 ovarian cortex (n = 9) had greater numbers of early stage follicles (primordial) and fewer later-stage follicles compared to controls (n = 11). Culture for 7 days did not relieve this follicular arrest; instead, High A4 ovarian cortex had increased indicators of inflammation, anti-Mullerian hormone, and A4 secretion compared to controls. In trial 2, we tested if vascular endothelial growth factor A isoforms could rescue the High A4 phenotype. High A4 (n = 5) and control (n = 5) ovarian cortex was cultured with (1) PBS, (2) VEGFA165 (50 ng/mL), (3) VEGFA165B (50 ng/mL), or (4) VEGFA165 + VEGFA165B (50 ng/mL each) for 7 days. Follicular progression increased with VEGFA165 in High A4 cows with greater early primary, primary, and secondary follicles than controls. Similar to trial 1, High A4 ovarian cortex secreted greater concentrations of A4 and other steroids and had greater indicators of inflammation compared to controls. However, VEGFA165 rescued steroidogenesis, oxidative stress, and fibrosis. The VEGFA165 and VEGFA165b both reduced IL-13, INFα, and INFß secretion in High A4 cows to control levels. Thus, VEGFA165 may be a potential therapeutic to restore the ovarian steroidogenic microenvironment and may promote folliculogenesis.


Assuntos
Androstenodiona/análise , Anovulação/veterinária , Doenças dos Bovinos/tratamento farmacológico , Inflamação/tratamento farmacológico , Folículo Ovariano/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Androstenodiona/metabolismo , Animais , Anovulação/tratamento farmacológico , Anovulação/fisiopatologia , Hormônio Antimülleriano/metabolismo , Bovinos , Citocinas/metabolismo , Feminino , Fibrose , Líquido Folicular/química , Folículo Ovariano/fisiopatologia , Ovário/metabolismo , Ovário/patologia , Estresse Oxidativo/efeitos dos fármacos , Isoformas de Proteínas/administração & dosagem , Técnicas de Cultura de Tecidos/veterinária
2.
Pain Pract ; 19(4): 440-442, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30554461

RESUMO

Loin pain hematuria syndrome (LPHS) is a rare condition characterized by cryptogenic debilitating flank pain and microscopic or macroscopic hematuria. The pathophysiology of LPHS remains poorly understood, and diagnosis is made largely by exclusion of alternate pathology. Management strategies can vary widely and include chronic opioid medication and a variety of invasive procedures, including regional nerve blocks, transcutaneous electrical nerve stimulation, local capsaicin infusion, and surgical renal denervation. Neuromodulation may provide a new paradigm of treatment for LPHS, potentially sparing patients from long-term complications of opiate therapy and invasive surgery. This report demonstrates the first case of successful symptomatic management of LPHS using spinal cord stimulation.


Assuntos
Dor no Flanco/terapia , Hematúria/terapia , Estimulação da Medula Espinal/métodos , Feminino , Humanos , Síndrome , Adulto Jovem
3.
Bioorg Med Chem Lett ; 17(20): 5671-6, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17804233

RESUMO

Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.


Assuntos
Benzoxazinas/química , Benzoxazinas/farmacologia , Desenho de Fármacos , Cinesinas/antagonistas & inibidores , Cinesinas/metabolismo , Mitose/efeitos dos fármacos , Pirazóis/química , Animais , Benzoxazinas/síntese química , Benzoxazinas/farmacocinética , Linhagem Celular , Cães , Humanos , Hidrogênio/química , Estrutura Molecular , Relação Estrutura-Atividade
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