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Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 progression that require identifying trait and state biomarkers for a more accurate diagnosis and prognosis. Moreover, the identification of potential pharmacodynamic targets and assessment of therapeutic efficacy necessitates valid biomarker profiles. The aim of this review was to identify potential trait and state biomarkers and their potential value in clinical trials. Our results show that, in SCA3, there are different fluid biomarkers involved in neurodegeneration, oxidative stress, metabolism, miRNA and novel genes. However, neurofilament light chain NfL and polyQ-ATXN3 stand out as the most prevalent in body fluids and SCA3 stages. A heterogeneity analysis of NfL revealed that it may be a valuable state biomarker, particularly when measured in plasma. Nonetheless, since it could be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy, it is more convenient to perform a biomarker profile evaluation than to rely on only one.
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Biomarcadores , Enfermedad de Machado-Joseph , Humanos , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/metabolismo , Enfermedad de Machado-Joseph/patología , Ataxina-3/genética , Ataxina-3/metabolismo , Proteínas de Neurofilamentos/metabolismo , Péptidos/metabolismo , Progresión de la Enfermedad , Estrés OxidativoRESUMEN
BACKGROUND: Breast cancer (BC) is the first cause of cancer morbidity and mortality in women. This disease has been linked to obesity; however, it is not clear how fat accumulation affects women who survive breast cancer. Although the visceral adiposity index (VAI) is a marker of cardiometabolic risk and adipose tissue dysfunction, it is not clear how it changes in breast cancer survivors. The aim of this investigation was to compare VAI in women with and without breast cancer. METHODS: A case-control cross-sectional study was conducted on women who were BC survivors and women without the history of BC (control group). Body composition was assessed using electrical bioimpedance while VAI by means of waist circumference (WC), body mass index (BMI), triacylglycerols (TG), and high-density lipoprotein cholesterol (HDL-C). RESULTS: 49 women in the BC survivor group and 50 in the control group. WC was wider in the survivor group as regards control (93.65 ± 10.48 vs. 88.52 ± 9.61 cm) (p=0.025); at once, TG and VAI were significantly higher for the survivor group (243.55 ± 199.84 vs. 159.84 ± 75.77) (p=0.007) and (11.03 ± 11.15 vs. 6.41 ± 3.66) (p < 0.005), respectively. Body composition parameters were similar in both groups. CONCLUSIONS: VAI is higher in women who are BC survivors in comparison with controls matched by age and bodyweight.
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Synthetic glucocorticoids (GCs) are widely used to treat inflammatory conditions. However, chronic use of GCs can lead to hypertension. The cause of this undesired side effect remains unclear. Previously, we developed an in vivo rat model to study the mechanisms underlying hypertension induced by the chronic administration of the potent synthetic GC, dexamethasone (DEX) and found that the catecholamine biosynthetic pathway plays an important role. In the current study, we used this model to investigate the role of the adrenal medulla, renal nerves, and other peripheral sympathetic nerves in DEX-induced hypertension. After 5 days of baseline telemetric recording of mean arterial pressure (MAP) and heart rate (HR), rats were subjected to one of the following treatments: renal denervation (RDNX), adrenal medullectomy (ADMX), 6-hydroxydopamine (6-OHDA, 20 mg/kg, i.p.) to induce chemical sympathectomy, or a combination of ADMX and 6-OHDA. On day 11, the animals received vehicle (VEH) or DEX in drinking water for 7 days, with the latter causing an increase in MAP in control animals. ADMX and RDNX by themselves exacerbated the pressor effect of DEX. In the chemical sympathectomy group, DEX still caused a rise in MAP but the response was lower (ΔMAP of 6-OHDA/DEX < VEH/DEX, p = 0.039). However, when ΔMAP was normalized to day 10, 6-OHDA + DEX did not show any difference from VEH + DEX, certainly not an increase as observed in DEX + ADMX or RDNX groups. This indicates that sympathetic nerves do not modulate the pressor effect of DEX. TH mRNA levels increased in the adrenal medulla in both VEH/DEX (p = 0.009) and 6-OHDA/DEX (p = 0.031) groups. In the 6-OHDA group, DEX also increased plasma levels of norepinephrine (NE) (p = 0.016). Our results suggest that the activation of catecholamine synthetic pathway could be involved in the pressor response to DEX in animals even under chemical sympathectomy with 6-OHDA.
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INTRODUCTION: Breast cancer is the most frequently diagnosed malignancy in women, and comorbidities like hypertension and obesity diminish their quality of life and negatively affect their response to chemotherapy. Furthermore, inulin supplementation is associated with the reduction of cardiovascular diseases (CVD) risk. OBJECTIVE: To determine whether inulin supplementation prevents the elevation of blood pressure in women with breast cancer undergoing neoadjuvant therapy with cyclophosphamide and doxorubicin. METHODS: This was a randomized, double-blind placebo controlled trial which included women with early-stage breast cancer undergoing neoadjuvant therapy (n=38). Patients were randomly assigned to participate in two different groups to receive either 15 g of inulin or 15 g of placebo (maltodextrin) for 21 days. Body composition and blood pressure were evaluated before and after the supplementation period. RESULTS: Women in the inulin group showed a lower systolic blood pressure (SBP) after the supplementation (-4.21 mmHg, p<0.001). However, SBP increased in the placebo supplemented group. Diastolic blood pressure (DBP) nonsignificantly decreased in the inulin group. Inulin supplementation also increased BMI (p<0.001) but reduced BFP (p=0.288). Furthermore, confounding variables, such as BMI, baseline fasting glucose, age, menopause status, vomiting, constipation, and chronic medication did not have a statistical influence over the inulin effect on SBP. CONCLUSION: Inulin supplementation reduces SBP and prevents increases in DBP in women with breast cancer. This could be an innovative nutraceutical approach to prevent hypertension present in women with this type of cancer at an early stage and may improve the quality of life of the patients and their prognostic development through chemotherapy. TRIAL REGISTRATION NUMBER: This trial is registered with ACTRN12616001532493.
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Antihipertensivos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Hipertensión/prevención & control , Inulina/uso terapéutico , Terapia Neoadyuvante , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Comorbilidad , Ciclofosfamida/administración & dosificación , Método Doble Ciego , Doxorrubicina/administración & dosificación , Femenino , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Inulina/efectos adversos , México/epidemiología , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Estadificación de Neoplasias , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Objective: The objective of this study was to determine whether cardiovascular disease (CVD) risk factors and stress hormones are associated with cognitive performance in Mexican adolescents. Methods: This was a cross-sectional study including 139 Mexican adolescents 10-14 years old. Participants were divided into three categories: 0, 1-2, and ≥3 CVD risk factors. These factors included: high-density lipoprotein-cholesterol (HDL-C) <40 mg/dl; waist circumference (WC) ≥90th percentile for age and sex, systolic or diastolic blood pressure ≥90th percentile for age, sex, and height; and triacylglycerols (TGs) ≥110 mg/dl. Low-density lipoprotein-cholesterol (LDL-C), very low-density lipoprotein-cholesterol (VLDL-C), total cholesterol, cortisol, and plasma catecholamines were measured as well. Furthermore, attention, memory, and executive functions were evaluated using a validated test for Spanish-speaking individuals (Neuropsi). Results: Adolescents in the three risk categories did not show significant differences in Neuropsi test performance tasks; however, they presented different lipid and plasma norepinephrine concentrations. TG and VLDL-C were inversely associated with memory (r = -0.19, **p < .01). Multivariate regression analysis showed consistently that TG/HDL-C ratio was inversely related to attention-memory general score (standardized ß = -0.99, t = -2.30, p = .023), memory (standardized ß = -0.83, t = -2.08, p = .039), and attention-executive functions (standardized ß = -1.02, t = -2.42, p = .017). Plasma epinephrine levels presented an inverse and weak relation to the attention-executive functions score (standardized ß = -0.18, t = -2.19, p = .030). Conclusions: Cognitive performance is not completely dependent on the accumulation of risk factors, but instead on the combination of strong predictors of CVD like waist to height ratio, TG/HDL-C, and VLDL-C. Plasma norepinephrine and epinephrine have a stronger association with cognition and CVD risk than dopamine and cortisol.
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Enfermedades Cardiovasculares/sangre , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/fisiopatología , Lípidos/sangre , Norepinefrina/sangre , Adolescente , Presión Sanguínea/fisiología , Niño , Trastornos del Conocimiento/diagnóstico , Estudios Transversales , Femenino , Humanos , Masculino , Pruebas de Estado Mental y Demencia , México , Factores de Riesgo , Circunferencia de la Cintura/fisiologíaRESUMEN
Our objective was to study hypertension induced by chronic administration of synthetic glucocorticoid, dexamethasone (DEX), under nonstressful conditions and examine the role of catecholamine biosynthesis. To achieve this, we did the following: 1) used radiotelemetry to record mean arterial pressure (MAP) and heart rate (HR) in freely moving rats, and 2) administered different doses of DEX in drinking water. To evaluate the involvement of tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, we treated rats with the TH inhibitor, α-methyl-para-tyrosine (α-MPT), for 3 days prior to administration of DEX and assessed TH mRNA and protein expression by quantitative real-time polymerase chain reaction and Western blot in the adrenal medulla. We observed a dose-dependent elevation in blood pressure with a DEX dose of 0.3 mg/kg administered for 10 days, significantly increasing MAP by +15.0 ± 1.1 mm Hg, while concomitantly reducing HR. Although this DEX treatment also significantly decreased body weight, pair-fed animals that showed similar decreases in body weight due to lowered food intake were not hypertensive, suggesting that body weight changes may not account for DEX-induced hypertension. Chronic DEX treatment significantly increased the TH mRNA and protein levels in the adrenal medulla, and α-MPT administration not only reduced DEX pressor effects, but also inhibited TH (serine(40)) phosphorylation. Our study thus validates a novel model to study hypertension induced by chronic intake of DEX in freely moving rats not subject to the confounding factors of previous models and establishes its dependence on concomitant activation of peripheral catecholamine biosynthesis.
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Dexametasona/farmacología , Modelos Animales de Enfermedad , Hipertensión/inducido químicamente , Hipertensión/enzimología , Tirosina 3-Monooxigenasa/metabolismo , Médula Suprarrenal/efectos de los fármacos , Médula Suprarrenal/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Fosforilación/efectos de los fármacos , Ratas , Serina/metabolismo , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , Tirosina 3-Monooxigenasa/química , Tirosina 3-Monooxigenasa/genética , alfa-Metiltirosina/farmacologíaRESUMEN
RATIONALE: Chronic stress perturbs modulatory brain neurotransmitter systems, including serotonin (5-HT), and is a risk factor for psychiatric disorders such as depression. Deficits in cognitive flexibility, reflecting prefrontal cortical dysfunction, are prominent in such disorders. Orbitofrontal cortex (OFC) has been implicated specifically in reversal learning, a form of cognitive flexibility modulated by 5-HT. OBJECTIVES: The objectives of the study were (1) to assess the effects of chronic intermittent cold (CIC) stress, a potent metabolic stressor, on performance of rats in an attentional set-shifting test (AST), and (2) to assess a possible role for serotonin in CIC-induced deficits and test the effects of acute serotonin reuptake blockade. MATERIALS AND METHODS: Male Sprague-Dawley rats were exposed to CIC stress (14 days x 6 h/day at 4 degrees C) before testing on the AST. In subsequent experiments, brain 5-HT was depleted in naïve rats with para-chlorophenylalanine or 5-HT release was increased acutely in CIC-stressed rats with citalopram (5 mg/kg, s.c.) given 30 min prior to the first reversal task. Microdialysis was used to assess CIC-induced changes in 5-HT release in OFC during testing. RESULTS: CIC-stressed rats exhibited a selective impairment on the first reversal task in the AST. 5-HT depletion induced a similarly selective deficit in reversal learning. The CIC-induced impairment in reversal learning was attenuated by acute 5-HT reuptake blockade. 5-HT release was reduced in OFC of CIC-stressed rats during behavioral testing. CONCLUSIONS: The CIC stress-induced impairment of cognitive flexibility may involve dysregulation of 5-HT modulatory function in OFC. Such deficits may thus model relevant symptoms of neuropsychiatric disorders that respond positively to SSRI treatment.