👤 Carmen Orellana

Alzheimer's disease (AD) biomarkers in plasma and cerebrospinal fluid (CSF) are useful for disease diagnosis, prognosis, risk assessment and monitoring therapy response, as well as for uncovering altered disease pathways. Previously, we and others cloned a novel gene, KLK6, which encodes a serine protease of the kallikrein family. The protein (hK6) is highly expressed in the brain, spinal cord and cerebellum. To examine the correlation of hK6 concentration in CSF with various clinicopathological variables in AD, we used a quantitative ELISA system. The variables examined included patient age, sex, MMSE score, APOE status, amyloid β 1-42 (Αβ1-42), phosphorylated Tau 181 (p-Tau181), total Tau (t-Tau). Previously, using a cohort of Swedish and Norwegian patients, we established a positive correlation between CSF hK6 and age as well as the levels of core AD biomarkers in four groups of patients (cognitively normal, MCI without progression to AD, MCI with progression to AD within 2 years and AD dementia). In this investigation, our goal was to validate these previous data with a large and independent patient cohort from Spain. We found that CSF hK6 is minimally or not affected by patient age and sex, but it significantly correlates with MMSE score and CSF Aβ1-42, p-Tau1811 and t-Tau. We conclude that these correlations further support our previous findings and suggest that hK6 may be an additional biomarker for AD and may play some role in the pathogenesis of AD. Show less

The apolipoprotein E (APOE) ε4 allele represents the strongest genetic risk factor for Alzheimer's disease (AD), but its role in genetically diverse Latin American and Caribbean (LAC) populations is underexplored. We conducted a meta-analysis of 35 studies from 11 LAC countries, encompassing 3206 patients with AD and 5515 controls. The ε4 allele demonstrated significant association with increased AD risk (odds ratio [OR] = 3.25, 95% confidence interval [2.82-3.76]), while ε3 showed lower odds (0.42, [0.37-0.48]). Homozygous ε4/ε4 carriers had elevated risk (6.84, [5.09-9.19]), and heterozygous ε3/ε4 carriers showed moderate risk (2.59, [2.31-2.91]). Country-level analyses revealed variability, with Ecuador showing the highest OR for ε4/ε4 (13.29, [1.56-113.4]). These results confirm APOE ε4 as a major AD risk factor in LAC populations and highlight regional differences relevant to precision medicine. Show less

Adhering to 24-h movement guidelines protects children's health and wellbeing. We investigated adherence among a sample of children in regional and rural Victoria, Australia. Analysis was conducted using baseline data from RESPOND, a large community-based obesity prevention intervention conducted in regional and rural Victoria, Australia. Children (aged approx. 9-12 years) self-reported screen time and wore a wrist-worn accelerometer for seven days to determine the mean daily time spent on moderate to vigorous physical activity (MVPA), light physical activity (LPA), sedentary and sleeping. Multi-level linear and logistic regressions were used to estimate associations between accelerometry outcomes and individual and school level demographics overall and by gender, accounting for school level clustering. Valid accelerometry data were obtained for 1,264 students. Twenty-two percent (22%) of boys and 16% of girls met all three movement guidelines and 11% boys and 9% of girls met none of the guidelines. Boys engaged in more MVPA, and less LPA than girls. Compared to those in grade 4 (aged approx. 9-10 years), students in grade 6 (aged approx. 11-12 years) had significantly reduced MVPA minutes (- 7.8; 95%CI -12.3, - 3.4); increased sedentary minutes (31.0; 95%CI 22.7, 39.3), and reduced odds of meeting screen time guidelines (odds ratio, 0.65; 95%CI 0.50, 0.84). Stratification by gender found these results to be consistent for boys and girls. Living in a medium or large rural town was associated with having 6.4 (95%CI 0.0, 12, 8) more minutes in MVPA (boys) and greater odds of adhering to screen time guidelines (OR, 1.96 (95%CI 1.02, 3.79) (girls) compared to living in regional centers. Sleep minutes were lower for students who spoke a language other than English at home (- 21.0 95%CI - 32.5, - 9.5). Only screen-time adherence for girls was associated with socioeconomic status. This study highlights low adherence to three Australian movement behavior guidelines among this large sample of regional and rural Victorian children. Large gender-differences in duration and adherence to MVPA and screen-time guidelines and declines with increasing age (all guidelines), highlight the need for population-wide interventions. • Time spent in movement behaviors (moderate-to-vigorous physical activity, light-intensity physical activity, sedentary behavior and sleep are important for children's health. • Few studies have examined device-measured movement behaviors and adherence to 24-h movement guidelines among regional children and whether this varies by gender, rurality and socioeconomic background. • This study found 22% of boys and 16% of girls met the 24-h movement recommendations, with 11% of boys and 9% of girls meeting no guideline. • Living in a medium or large rural town was associated with more moderate to vigorous physical activity in boys, and less screen-time among girls compared to those living in regional centers. Higher socioeconomic status was associated with less screen-time among girls. Show less

Given the importance of menstrual blood in the pathogenesis of endometriosis and the multifunctional roles of menstrual mesenchymal stem cells (MenSCs) in regenerative medicine, this issue has gained prominence in the scientific community. Moreover, recent reviews highlight how robust the integrated assessment of omics data are for endometriosis. To our knowledge, no study has applied the multi-omics approaches to endometriosis MenSCs. This is a case-control study at a university-affiliated hospital. MenSCs transcriptome and proteome data were obtained by RNA-seq and UHPLC-MS/MS detection. Among the differentially expressed proteins and genes, we emphasize Show less

The key relationship between Sampson's theory and the presence of mesenchymal stem cells in the menstrual flow (MenSCs), as well as the changes in post-transcriptional regulatory processes as actors in the etiopathogenesis of endometriosis, are poorly understood. No study to date has investigated the imbalance of miRNAs in MenSCs related to the disease. Thus, through literature and in silico analyses, we selected four predicted miRNAs as regulators of EGR1, SNAI1, NR4A1, NR4A2, ID1, LAMC3, and FOSB involved in pathways of apoptosis, angiogenesis, response to steroid hormones, migration, differentiation, and cell proliferation. These genes are frequently overexpressed in the endometriosis condition in our group studies. They were the trigger for the miRNAs search. Therefore, a case-control study was conducted with MenSCs of women with and without endometriosis (ten samples per group). Crossing information obtained from the STRING, PubMed, miRPathDB, miRWalk, and DIANA TOOLS databases, we chose to explore the expression of miR-21-5p, miR-100-5p, miR-143-3p, and miR-200b-3p by RT-qPCR. We found an upregulation of the miR-200b-3p in endometriosis MenSCs (P = 0.0207), with a 7.93-fold change (ratio of geometric means) compared to control. Overexpression of miR-200b has been associated with increased cell proliferation, stemness, and accentuated mesenchymal-epithelial transition process in eutopic endometrium of endometriosis. We believe that dysregulated miR-200b-3p may establish primary changes in the MenSCs, thus favoring tissue implantation at the ectopic site. Show less

High ethanol intake induces a neuroinflammatory response resulting in the subsequent maintenance of chronic alcohol consumption. The melanocortin system plays a pivotal role in the modulation of alcohol consumption. Interestingly, it has been shown that the activation of melanocortin-4 receptor (MC4R) in the brain decreases the neuroinflammatory response in models of brain damage other than alcohol consumption, such as LPS-induced neuroinflammation, cerebral ischemia, glutamate excitotoxicity, and spinal cord injury. In this work, we aimed to study whether MC4R activation by a synthetic MC4R-agonist peptide prevents ethanol-induced neuroinflammation, and if alcohol consumption produces changes in MC4R expression in the hippocampus and hypothalamus. Ethanol-preferring Sprague Dawley rats were selected offering access to 20% ethanol on alternate days for 4 weeks (intermittent access protocol). After this time, animals were i.p. administered an MC4R agonist peptide in the last 2 days of the protocol. Then, the expression of the proinflammatory cytokines interleukin 6 (IL-6), interleukin 1-beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) were measured in the hippocampus, hypothalamus and prefrontal cortex. It was also evaluated if ethanol intake produces alterations in the expression of MC4R in the hippocampus and the hypothalamus. Alcohol consumption increased the expression of MC4R in the hippocampus and the hypothalamus. The administration of the MC4R agonist reduced IL-6, IL-1β and TNF-α levels in hippocampus, hypothalamus and prefrontal cortex, to those observed in control rats that did not drink alcohol. High ethanol consumption produces an increase in the expression of MC4R in the hippocampus and hypothalamus. The administration of a synthetic MC4R-agonist peptide prevents neuroinflammation induced by alcohol consumption in the hippocampus, hypothalamus, and prefrontal cortex. These results could explain the effect of α-MSH and other synthetic MC4R agonists in decreasing alcohol intake through the reduction of the ethanol-induced inflammatory response in the brain. Show less

Liver X receptors (LXRs) α and β are nuclear hormone receptors that are widely expressed in the kidney. They promote cholesterol efflux from cells and inhibit inflammatory responses by regulating gene transcription. Here, we hypothesised (1) that LXR deficiency would promote renal decline in a mouse model of diabetes by accelerating intraglomerular cholesterol accumulation and, conversely, (2) that LXR agonism would attenuate renal decline in diabetes. Diabetes was induced with streptozotocin (STZ) and maintained for 14 weeks in Lxrα/β (+/+) (Lxrα, also known as Nr1h3; Lxrβ, also known as Nr1h2) and Lxrα/β (-/-) mice. In addition, STZ-injected DBA/2J mice were treated with vehicle or the LXR agonist N,N-dimethyl-hydroxycholenamide (DMHCA) (80 mg/kg daily) for 10 weeks. To determine the role of cholesterol in diabetic nephropathy (DN), mice were placed on a Western diet after hyperglycaemia developed. Even in the absence of diabetes, Lxrα/β (-/-) mice exhibited a tenfold increase in the albumin:creatinine ratio and a 40-fold increase in glomerular lipid accumulation compared with Lxrα/β (+/+) mice. When challenged with diabetes, Lxrα/β (-/-) mice showed accelerated mesangial matrix expansion and glomerular lipid accumulation, with upregulation of inflammatory and oxidative stress markers. In the DN-sensitive STZ DBA/2J mouse model, DMHCA treatment significantly decreased albumin and nephrin excretion (by 50% each), glomerular lipids and plasma triacylglycerol (by 70%) and cholesterol (by 48%); it also decreased kidney inflammatory and oxidative stress markers compared with vehicle-treated mice. These data support the idea that LXR plays an important role in the normal and diabetic kidney, while showing that LXR, through its inhibitory effect on inflammation and cholesterol accumulation in glomeruli, could also be a novel therapeutic target for DN. Show less