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1.
Nutrients ; 16(10)2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38794647

RESUMO

Fetal growth restriction is a hallmark of Fetal Alcohol Syndrome (FAS) and is accompanied by maternal uterine circulatory maladaptation. FAS is the most severe form of Fetal Alcohol Spectrum Disorder (FASD), a term for the range of conditions that can develop in a fetus when their pregnant mother consumes alcohol. Alcohol exerts specific direct effects on lipids that control fundamental developmental processes. We previously demonstrated that direct in vitro application of phosphatidic acid (PA, the simplest phospholipid and a direct target of alcohol exposure) to excised uterine arteries from alcohol-exposed rats improved vascular function, but it is unknown if PA can rescue end organ phenotypes in our FASD animal model. Pregnant Sprague-Dawley rats (n = 40 total dams) were gavaged daily from gestational day (GD) 5 to GD 19 with alcohol or maltose dextrin, with and without PA supplementation, for a total of four unique groups. To translate and assess the beneficial effects of PA, we hypothesized that in vivo administration of PA concomitant with chronic binge alcohol would reverse uterine artery dysfunction and fetal growth deficits in our FASD model. Mean fetal weights and placental efficiency were significantly lower in the binge alcohol group compared with those in the control (p < 0.05). However, these differences between the alcohol and the control groups were completely abolished by auxiliary in vivo PA administration with alcohol, indicating a reversal of the classic FAS growth restriction phenotype. Acetylcholine (ACh)-induced uterine artery relaxation was significantly impaired in the uterine arteries of chronic in vivo binge alcohol-administered rats compared to the controls (p < 0.05). Supplementation of PA in vivo throughout pregnancy reversed the alcohol-induced vasodilatory deficit; no differences were detected following in vivo PA administration between the pair-fed control and PA alcohol groups. Maximal ACh-induced vasodilation was significantly lower in the alcohol group compared to all the other treatments, including control, control PA, and alcohol PA groups (p < 0.05). When analyzing excitatory vasodilatory p1177-eNOS, alcohol-induced downregulation of p1177-eNOS was completely reversed following in vivo PA supplementation. In summary, these novel data utilize a specific alcohol target pathway (PA) to demonstrate a lipid-based preventive strategy and provide critical insights important for the development of translatable interventions.


Assuntos
Modelos Animais de Doenças , Etanol , Transtornos do Espectro Alcoólico Fetal , Retardo do Crescimento Fetal , Ácidos Fosfatídicos , Ratos Sprague-Dawley , Artéria Uterina , Animais , Feminino , Gravidez , Retardo do Crescimento Fetal/tratamento farmacológico , Retardo do Crescimento Fetal/fisiopatologia , Artéria Uterina/efeitos dos fármacos , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Ácidos Fosfatídicos/farmacologia , Ratos , Consumo Excessivo de Bebidas Alcoólicas/complicações , Placenta/irrigação sanguínea , Placenta/efeitos dos fármacos , Placenta/metabolismo
2.
FASEB J ; 37(5): e22897, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37000494

RESUMO

Alcohol exposure during gestation can lead to fetal alcohol spectrum disorders (FASD), an array of cognitive and physical developmental impairments. Over the past two and a half decades, Mammalian Target of Rapamycin (mTOR) has emerged at the nexus of many fields of study, and has recently been implicated in FASD etiology. mTOR plays an integral role in modulating anabolic and catabolic activities, including protein synthesis and autophagy. These processes are vital for proper development and can have long lasting effects following alcohol exposure, such as impaired hippocampal and synapse formation, reduced brain size, as well as cognitive, behavioral, and memory impairments. We highlight recent advances in the field of FASD, primarily with regard to animal model discoveries and discuss the interaction between alcohol and mTOR in the context of various tissues, including brain, placenta, bone, and muscle, with respect to developmental alcohol exposure paradigms. The current review focuses on novel FASD research within the context of the mTOR signaling and sheds light on mechanistic etiologies at various biological levels including molecular, cellular, and functional, across multiple stages of development and illuminates the dichotomy between the different mTOR complexes and their unique signaling roles.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Animais , Feminino , Transtornos do Espectro Alcoólico Fetal/etiologia , Etanol/toxicidade , Encéfalo/metabolismo , Mamíferos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Modelos Animais de Doenças , Efeitos Tardios da Exposição Pré-Natal/metabolismo
3.
Acta Biomater ; 144: 221-229, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35301146

RESUMO

Radiation cystitis, a long-term bladder defect due to pelvic radiation therapy, results in lower urinary tract symptoms, such as urinary frequency and nocturia, suggestive of compromised bladder compliance. The goal of this study was to identify alterations to the mechanical behavior of the urinary bladder extracellular matrix of a murine model of radiation cystitis, at 3 and 6 months after radiation exposure. The results of this study demonstrated that the extracellular matrix of irradiated bladders was significantly less distensible when compared to age matching controls. These findings coincided with functional bladder changes, including increased number of voids and decreased voided volume. Both mechanical and functional changes were apparent at 3 months post-irradiation and were statistically significant at 6 months, demonstrating the progressive nature of radiation cystitis. Overall, the results of this study indicate that irradiation exposure changes both the mechanical and physiological properties of the bladder. STATEMENT OF SIGNIFICANCE: In humans, radiation cystitis results in lower urinary tract symptoms, such as urinary frequency and nocturia, suggestive of compromised bladder compliance. This pathology can significantly affect recovery and quality of life for cancer survivors. Gaining knowledge about how alterations to the mechanical behavior of the urinary bladder extracellular matrix can affect urinary function will have a significant impact on this population. The results of this study demonstrated that the extracellular matrix of irradiated bladders was significantly less distensible when compared to age matching controls, in a mouse model of radiation cystitis. These findings were accompanied by functional voiding changes, including increased number of voids and decreased voided volume. The results of this study uncovered that irradiation exposure changes the mechanical and physiological properties of the bladder.


Assuntos
Cistite , Noctúria , Animais , Cistite/etiologia , Cistite/patologia , Modelos Animais de Doenças , Matriz Extracelular/patologia , Feminino , Humanos , Masculino , Camundongos , Noctúria/patologia , Qualidade de Vida , Bexiga Urinária
4.
Sci Rep ; 11(1): 19277, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588475

RESUMO

Long term-side effects from cancer therapies are a growing health care concern as life expectancy among cancer survivors increases. Damage to the bladder is common in patients treated with radiation therapy for pelvic cancers and can result in radiation (hemorrhagic) cystitis (RC). The disease progression of RC consists of an acute and chronic phase, separated by a symptom-free period. Gaining insight in tissue changes associated with these phases is necessary to develop appropriate interventions. Using a mouse preclinical model, we have previously shown that fibrosis and vascular damage are the predominant pathological features of chronic RC. The goal of this study was to determine the pathological changes during acute RC. We identified that radiation treatment results in a temporary increase in micturition frequency and decrease in void volume 4-8 weeks after irradiation. Histologically, the micturition defect is associated with thinning of the urothelium, loss of urothelial cell-cell adhesion and tight junction proteins and decrease in uroplakin III expression. By 12 weeks, the urothelium had regenerated and micturition patterns were similar to littermate controls. No inflammation or fibrosis were detected in bladder tissues after irradiation. We conclude that functional bladder defects during acute RC are driven primarily by a urothelial defect.


Assuntos
Cistite/fisiopatologia , Lesões Experimentais por Radiação/fisiopatologia , Bexiga Urinária/patologia , Micção/efeitos da radiação , Animais , Caderinas/análise , Caderinas/metabolismo , Cistite/etiologia , Cistite/patologia , Feminino , Humanos , Camundongos , Neoplasias Pélvicas/radioterapia , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/patologia , Bexiga Urinária/fisiopatologia , Bexiga Urinária/efeitos da radiação , Micção/fisiologia , Uroplaquina III/análise , Uroplaquina III/metabolismo , Urotélio/patologia , Urotélio/efeitos da radiação , Proteína da Zônula de Oclusão-1/análise , Proteína da Zônula de Oclusão-1/metabolismo
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