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Diabetic kidney disease is the leading cause of end-stage renal disease in developing and developed countries. The growing prevalence and clinical challenges of sarcopenic obesity have been associated with the frailty and disability of diabetic kidney disease. It has been reported that insulin resistance, chronic inflammation, enhanced oxidative stress and lipotoxicity contribute to the pathophysiology of muscle loss and visceral fat accumulation. Sarcopenic obesity, which is diagnosed with dual-energy X-ray absorptiometry, is associated with worse outcomes in kidney disease. Growing evidence indicates that adherence to healthy lifestyles, including low protein diet, proper carbohydrate control, vitamin D supplement, and regular physical training, has been shown to improve clinical prognosis. Based on the higher risk of sarcopenic-obesity-related renal function decline, it has led to the exploration and investigation of the pathophysiology, clinical aspects, and novel approach of these controversial issues in daily practice.
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Previously, we reported that the neurosteroid allopregnanolone (Allo) promoted neural stem cell regeneration, restored cognitive function, and reduced Alzheimer's Disease (AD) pathology in the triple transgenic Alzheimer's mouse model (3xTgAD). To investigate the underlying systems biology of Allo action in AD models in vivo, we assessed the regulation of Allo on the bioenergetic system of the brain. Outcomes of these analysis indicated that Allo significantly reversed deficits in mitochondrial respiration and biogenesis and key mitochondrial enzyme activity and reduced lipid peroxidation in the 3xTgAD mice in vivo. To explore the mechanisms by which Allo regulates the brain metabolism, we conducted targeted transcriptome analysis. These data further confirmed that Allo upregulated genes involved in glucose metabolism, mitochondrial bioenergetics, and signaling pathways while simultaneously downregulating genes involved in Alzheimer's pathology, fatty acid metabolism, and mitochondrial uncoupling and dynamics. Upstream regulatory pathway analysis predicted that Allo induced peroxisome proliferator-activated receptor gamma (PPARG) and coactivator 1-alpha (PPARGC1A) pathways while simultaneously inhibiting the presenilin 1 (PSEN 1), phosphatase and tensin homolog (PTEN), and tumor necrosis factor (TNF) pathways to reduce AD pathology. Collectively, these data indicate that Allo functions as a systems biology regulator of bioenergetics, cholesterol homeostasis, and ß-amyloid reduction in the brain. These systems are critical to neurological health, thus providing a plausible mechanistic rationale for Allo as a therapeutic to promote neural cell function and reduce the burden of AD pathology.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Pregnanolona/administração & dosagem , Animais , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacosRESUMO
Our recent developments have yielded a novel phytoestrogenic formulation, referred to as the phyto-ß-SERM formulation, which exhibits an 83-fold binding selectivity for the estrogen receptor subtype ß (ERß) over ERα. Earlier studies indicate that the phyto-ß-SERM formulation is neuroprotective and promotes estrogenic mechanisms in the brain while devoid of feminizing activity in the periphery. Further investigation in a mouse model of human menopause indicates that chronic exposure to the phyto-ß-SERM formulation at a clinically relevant dosage prevents/alleviates menopause-related climacteric symptoms. This study assessed the efficacy, in an early intervention paradigm, of the phyto-ß-SERM formulation in the regulation of early stages of physical and neurological changes associated with Alzheimer's disease (AD) in a female triple transgenic mouse model of AD. Results demonstrated that, when initiated prior to the appearance of AD pathology, a 9-month dietary supplementation with the phyto-ß-SERM formulation promoted physical health, prolonged survival, improved spatial recognition memory, and attenuated amyloid-ß deposition and plaque formation in the brains of treated AD mice. In comparison, dietary supplementation of a commercial soy extract preparation showed no effect on cognitive measures, although it appeared to have a positive impact on amyloid pathology. In overall agreement with the behavioral and histological outcomes, results from a gene expression profiling analysis offered insights on the underlying molecular mechanisms associated with the two dietary treatments. In particular, the data suggests that there may be a crosstalk between ERß and glycogen synthase kinase 3 signaling pathways that could play a role in conferring ERß-mediated neuroprotection against AD. Taken together, these results support the therapeutic potential of the phyto-ß-SERM formulation for prevention and/or early intervention of AD, and warrants further investigations in human studies.
Assuntos
Doença de Alzheimer , Receptor beta de Estrogênio/agonistas , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Fitoestrógenos/uso terapêutico , Reconhecimento Psicológico/efeitos dos fármacos , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/mortalidade , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Feminino , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Mutação/genética , Ovariectomia , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/patologia , Placa Amiloide/ultraestrutura , Presenilina-1/genética , Proteínas tau/genéticaRESUMO
Previously we developed an estrogen receptor ß-selective phytoestrogenic (phytoSERM) combination, which contains a mixture of genistein, daidzein, and racemic R/S-equol. The phytoSERM combination was found neuroprotective and non-feminizing both in vitro and in vivo. Further, it prevented or alleviated physical and neurological changes associated with human menopause and Alzheimer's disease. In the current study, we conducted translational analyses to compare the effects of racemic R/S-equol-containing with S-equol-containing phytoSERM therapeutic combinations on mitochondrial markers in rat hippocampal neuronal cultures and in a female mouse ovariectomy (OVX) model. Data revealed that both the S-equol and R/S-equol phytoSERM treatments regulated mitochondrial function, with S-equol phytoSERM combination eliciting greater response in mitochondrial potentiation. Both phytoSERM combination treatments increased expression of key proteins and enzymes involved in energy production, restored the OVX-induced decrease in activity of key bioenergetic enzymes, and reduced OVX-induced increase in lipid peroxidation. Comparative analyses on gene expression profile revealed similar regulation between S-equol phytoSERM and R/S-equol phytoSERM treatments with minimal differences. Both combinations regulated genes involved in essential bioenergetic pathways, including glucose metabolism and energy sensing, lipid metabolism, cholesterol trafficking, redox homeostasis and ß-amyloid production and clearance. Further, no uterotrophic response was induced by either of the phytoSERM combinations. These findings indicate translational validity for development of an ER ß selective S-equol phytoSERM combination as a nutraceutical to prevent menopause-associated symptoms and to promote brain metabolic activity. This article is part of a Special Issue entitled Hormone Therapy.
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Encéfalo/citologia , Equol/farmacologia , Receptor beta de Estrogênio/metabolismo , Mitocôndrias/efeitos dos fármacos , Neurônios/ultraestrutura , Fitoestrógenos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Células Cultivadas , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Embrião de Mamíferos , Metabolismo Energético/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Ovariectomia , Gravidez , Complexo Piruvato Desidrogenase/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Previously, we demonstrated that reproductive senescence was associated with mitochondrial deficits comparable to those of female triple-transgenic Alzheimer's mice (3xTgAD). Herein, we investigated the impact of chronic ovarian hormone deprivation and 17ß-estradiol (E2) replacement on mitochondrial function in nontransgenic (nonTg) and 3xTgAD female mouse brain. Depletion of ovarian hormones by ovariectomy (OVX) in nontransgenic mice significantly decreased brain bioenergetics, and induced mitochondrial dysfunction and oxidative stress. In 3xTgAD mice, OVX significantly exacerbated mitochondrial dysfunction and induced mitochondrial ß-amyloid and ß-amyloid (Aß)-binding-alcohol-dehydrogenase (ABAD) expression. Treatment with E2 at OVX prevented OVX-induced mitochondrial deficits, sustained mitochondrial bioenergetic function, decreased oxidative stress, and prevented mitochondrial ß-amyloid and ABAD accumulation. In vitro, E2 increased maximal mitochondrial respiration in neurons and basal and maximal respiration in glia. Collectively, these data demonstrate that ovarian hormone loss induced a mitochondrial phenotype comparable to a transgenic female model of Alzheimer's disease (AD), which was prevented by E2. These findings provide a plausible mechanism for increased risk of Alzheimer's disease in premenopausally oophorectomized women while also suggesting a therapeutic strategy for prevention.
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3-Hidroxiacil-CoA Desidrogenases/metabolismo , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Estradiol/deficiência , Mitocôndrias/metabolismo , Animais , Feminino , Camundongos , Camundongos Knockout , Estresse OxidativoRESUMO
To address controversies of estrogen therapy, in vitro models of perimenopause and prevention vs. treatment modes of 17beta-estradiol (E(2)) exposure were developed and used to assess the neuroprotective efficacy of E(2) against beta-amyloid-1-42 (Abeta(1-42))-induced neurodegeneration in rat primary hippocampal neurons. Low E(2) (10 ng/ml) exposure exerted neuroprotection in each of the perimenopausal temporal patterns, acute, continuous, and intermittent. In contrast, high E(2) (200 ng/ml) was ineffective at inducing neuroprotection regardless of temporal pattern of exposure. Although high E(2) alone was not toxic, neurons treated with high-dose E(2) resulted in greater Abeta(1-42)-induced neurodegeneration. In prevention vs. treatment simulations, E(2) was most effective when present before and during Abeta(1-42) insult. In contrast, E(2) treatment after Abeta(1-42) exposure was ineffective in reversing Abeta-induced degeneration, and exacerbated Abeta(1-42)-induced cell death when administered after Abeta(1-42) insult. We sought to determine the mechanism by which high E(2) exacerbated Abeta(1-42)-induced neurodegeneration by investigating the impact of low vs. high E(2) on Abeta(1-42)-induced dysregulation of calcium homeostasis. Results of these analyses indicated that low E(2) significantly prevented Abeta(1-42)-induced rise in intracellular calcium, whereas high E(2) significantly increased intracellular calcium and did not prevent Abeta(1-42)-induced calcium dysregulation. Therapeutic benefit resulted only from low-dose E(2) exposure before, but not after, Abeta(1-42)-induced neurodegeneration. These data are relevant to impact of perimenopausal E(2) exposure on protection against neurodegenerative insults and the use of estrogen therapy to prevent vs. treat Alzheimer's disease. Furthermore, these data are consistent with a healthy cell bias of estrogen benefit.
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Doença de Alzheimer/tratamento farmacológico , Estradiol/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/toxicidade , Animais , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Homeostase/efeitos dos fármacos , Humanos , Acetato de Medroxiprogesterona/farmacologia , Fragmentos de Peptídeos/toxicidade , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Epidemiological data from retrospective and case-control studies have indicated that estrogen replacement therapy can decrease the risk of developing Alzheimer's disease. In addition, estrogen replacement therapy has been found to promote neuronal survival both in vivo and in vitro. We have shown that conjugated equine estrogens (CEE), containing 238 different molecules composed of estrogens, progestins, and androgens, exerted neurotrophic and neuroprotective effects in cultured neurons. In the current study, we sought to determine whether a steroidal formulation of nine synthetic conjugated estrogens (SCE) chemically derived from soybean and yam extracts is as effective as the complex multisteroidal formulation of CEE. Analyses of the neuroprotective efficacy indicate that SCE exhibited significant neuroprotection against beta amyloid, hydrogen peroxide, and glutamate-induced toxicity in cultured hippocampal neurons. Indices of neuroprotection included an increase in neuronal survival, a decrease in neurotoxin-induced lactate dehydrogenase release, and a reduction in neurotoxin-induced apoptotic cell death. Furthermore, SCE was found to attenuate excitotoxic glutamate-induced [Ca2+]i rise. Quantitative analyses indicate that the neuroprotective efficacy of SCE was comparable to that of the multisteroidal CEE formulation. Data derived from these investigations predict that SCE could exert neuroprotective effects comparable to CEE in vivo and therefore could reduce the risk of Alzheimer's disease in postmenopausal women.