Crosstalk Between LXR and Caveolin-1 Signaling Supports Cholesterol Efflux and Anti-Inflammatory Pathways in Macrophages

© 2021 Ramírez, Torrecilla-Parra, Pardo-Marqués, de-Frutos, Pérez-García, Tabraue, de la Rosa, Martín-Rodriguez, Díaz-Sarmiento, Nuñez, Orizaola, Través, Camps, Boscá and Castrillo.Macrophages are immune cells that play crucial roles in host defense against pathogens by triggering their exceptional phagocytic and inflammatory functions. Macrophages that reside in healthy tissues also accomplish important tasks to preserve organ homeostasis, including lipid uptake/efflux or apoptotic-cell clearance. Both homeostatic and inflammatory functions of macrophages require the precise stability of lipid-rich microdomains located at the cell membrane for the initiation of downstream signaling cascades. Caveolin-1 (Cav-1) is the main protein responsible for the biogenesis of caveolae and plays an important role in vascular inflammation and atherosclerosis. The Liver X receptors (LXRs) are key transcription factors for cholesterol efflux and inflammatory gene responses in macrophages. Although the role of Cav-1 in cellular cholesterol homeostasis and vascular inflammation has been reported, the connection between LXR transcriptional activity and Cav-1 expression and function in macrophages has not been investigated. Here, using gain and loss of function approaches, we demonstrate that LXR-dependent transcriptional pathways modulate Cav-1 expression and compartmentation within the membrane during macrophage activation. As a result, Cav-1 participates in LXR-dependent cholesterol efflux and the control of inflammatory responses. Together, our data show modulation of the LXR-Cav-1 axis could be exploited to control exacerbated inflammation and cholesterol overload in the macrophage during the pathogenesis of lipid and immune disorders, such as atherosclerosis.We thank MINECO FPI predoctoral fellowship granted to MCO (BES-2015-075339). Experimental work was supported by grants from Ministerio de Ciencia, Investigación y Universidades, y Fondo Europeo de Desarrollo Regional (FEDER) Grant REF: PID2019-104284RB-I00/AEI/10.13039/501100011033 (to AC) and support from Networks of Excellence from MINECO (Nuclear Receptors in Cancer, Metabolism and Inflammation [NuRCaMeIn] SAF2017-90604-REDT to AC. Ministerio de Economía, Industria y Competitividad, Ministerio de Ciencia, Investigación y Universidades, and Agencia Estatal de Investigación (SAF2017-82436-R, RTC2017-6283-1), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686 and Fondo Europeo de Desarrollo Regional (to LB). Ministerio de Ciencia, Investigación y Universidades, and Agencia Estatal de Investigación Proyectos de I+D+i Retos Investigación 2018 (RTI2018-095061-B-I00); TALENTO Grant from Madrid Government, Spain (2017-T1/BMD-5333); Consejería de Ciencia, Universidades e Innovación Comunidad de Madrid, Spain (PEJD-2018-POST/BMD-8900 and PEDJ-2018-AI/BDM-9724) to CMR

POTENCIAL PROBIÓTICO DE CEPAS DE BACILLUS CON PROPIEDADES ANTIMICROBIANAS FRENTE A PATÓGENOS DE PECES

El objetivo de este trabajo ha sido aislar, identificar y caracterizar cepas bacterianas procedentes de ambiente marino, fitoplancton, zooplancton, huevos, larvas de lenguado y diferentes juveniles (branquias, intestino, piel), que pudieran tener actividad probiótica y actividad antibacteriana frente a distintos patógenos de peces. Se aislaron un total de 217 cepas bacterianas. Tras un primer cribado mediante ensayos de inhibición en placa frente a patógenos, se seleccionaron 9 cepas y se identificaron utilizando la secuenciación de su rRNA 16S. Los resultados mostraron que las mejores candidatas eran cepas del género Bacillus. Varios de estas posibles cepas candidatas se caracterizaron in vitro para determinar su potencial probiótico, mediante ensayos de inhibición en co-cultivo con V. anguillarum, resistencia a bilis de pez, y adherencia a mucus intestinal de pez. Nuestros resultados mostraron que algunas de las cepas seleccionadas pertenecientes al género Bacillus, podrían ser consideradas como potenciales probióticos frente a patógenos de peces, por lo que el beneficio de la administración de estas cepas a cultivos de peces será posteriormente estudiada

Non-motor symptom burden in patients with Parkinson's disease with impulse control disorders and compulsive behaviours: results from the COPPADIS cohort.

The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson's disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS-2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment-related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose

Identifying comorbidities and lifestyle factors contributing to the cognitive profile of early Parkinson's disease

Background: Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. Methods: Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study. Results: Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005). Conclusions: We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD

Predictors of Loss of Functional Independence in Parkinson’s Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up and Comparison with a Control Group

COPPADIS Study Group.[Background and objective] The aim of this study was to compare the progression of independence in activities of daily living (ADL) in Parkinson’s disease (PD) patients versus a control group, as well as to identify predictors of disability progression and functional dependency (FD).[Patients and Methods] PD patients and control subjects, who were recruited from 35 centers of Spain from the COPPADIS cohort between January 2016 and November 2017 (V0), were included. Patients and subjects were then evaluated again at the 2-year follow-up (V2). Disability was assessed with the Schwab & England Activities of Daily Living Scale (S&E-ADLS) at V0 and V2. FD was defined as an S&E-ADLS score less than 80%.[Results] In the PD group, a significant decrease in the S&E-ADLS score from V0 to V2 (N = 507; from 88.58 ± 10.19 to 84.26 ± 13.38; p < 0.0001; Cohen’s effect size = −0.519) was observed but not in controls (N = 124; from 98.87 ± 6.52 to 99.52 ± 2.15; p = 0.238). When only patients considered functional independent at baseline were included, 55 out of 463 (11.9%) converted to functional dependent at V2. To be a female (OR = 2.908; p = 0.009), have longer disease duration (OR = 1.152; p = 0.002), have a non-tremoric motor phenotype at baseline (OR = 3.574; p = 0.004), have a higher score at baseline in FOGQ (OR = 1.244; p < 0.0001) and BDI-II (OR = 1.080; p = 0.008), have a lower score at baseline in PD-CRS (OR = 0.963; p = 0.008), and have a greater increase in the score from V0 to V2 in UPDRS-IV (OR = 1.168; p = 0.0.29), FOGQ (OR = 1.348; p < 0.0001) and VAFS-Mental (OR = 1.177; p = 0.013) (adjusted R-squared 0.52; Hosmer and Lemeshow test = 0.94) were all found to be independent predictors of FD at V2.[Conclusions] In conclusion, autonomy for ADL worsens in PD patients compared to controls. Cognitive impairment, gait problems, fatigue, depressive symptoms, more advanced disease, and a non-tremor phenotype are independent predictors of FD in the short-term.Fundación Curemos el Parkinson (www.curemoselparkinson.org).Peer reviewe

Staging Parkinson’s Disease Combining Motor and Nonmotor Symptoms Correlates with Disability and Quality of Life

COPPADIS Study Group.[Introduction] In a degenerative disorder such as Parkinson’s disease (PD), it is important to establish clinical stages that allow to know the course of the disease. Our aim was to analyze whether a scale combining Hoehn and Yahr’s motor stage (H&Y) and the nonmotor symptoms burden (NMSB) (assessed by the nonmotor symptoms scale (NMSS)) provides information about the disability and the patient’s quality of life (QoL) with regard to a defined clinical stage.[Materials and Methods] Cross-sectional study in which 603 PD patients from the COPPADIS cohort were classified according to H&Y (1, stage I; 2, stage II; 3, stage III; 4, stage IV/V) and NMSB (A: NMSS = 0–20; B: NMSS = 21–40; C: NMSS = 41–70; D: NMSS ≥ 71) in 16 stages (HY.NMSB, from 1A to 4D). QoL was assessed with the PDQ-39SI, PQ-10, and EUROHIS-QOL8 and disability with the Schwab&England ADL (Activities of Daily Living) scale.[Results] A worse QoL and greater disability were observed at a higher stage of H&Y and NMSB (). Combining both (HY.NMSB), patients in stages 1C and 1D and 2C and 2D had significantly worse QoL and/or less autonomy for ADL than those in stages 2A and 2B and 3A and 3B, respectively (; e.g., PDQ-39SI in 1D [n = 15] vs 2A [n = 101]: 28.6 ± 17.1 vs 7.9 ± 5.8; ).[Conclusion] The HY.NMSB scale is simple and reflects the degree of patient involvement more accurately than the H&Y. Patients with a lower H&Y stage may be more affected if they have a greater NMS burden.Peer reviewe

Diplopia is frequent and associated with motor and non-motor severity in parkinson's disease : Results from the COPPADIS cohort at 2-year follow-up

Background and objective: Diplopia is relatively common in Parkinson's disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it. Patients and Methods: PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as "with diplopia" or "without diplopia" according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls. Results: The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269-4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012-1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson's Disease Rating Scale-III (OR = 1.039; 95%CI, 1.023-1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001-1.057; p = 0.049) scores were independent factors associated with diplopia (R = 0.25; Hosmer and Lemeshow test, p = 0.716). Conclusions: Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity

Diplopia Is Frequent and Associated with Motor and Non-Motor Severity in Parkinson’s Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up

Malaltia de Parkinson; Fenotip; TremolorEnfermedad de Parkinson; Fenotipo; TemblorParkinson’s disease; Phenotype; TremorBackground and objective: Diplopia is relatively common in Parkinson’s disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it. Patients and Methods: PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as “with diplopia” or “without diplopia” according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls. Results: The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269–4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012–1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson’s Disease Rating Scale–III (OR = 1.039; 95%CI, 1.023–1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001–1.057; p = 0.049) scores were independent factors associated with diplopia (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716). Conclusions: Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity.Solano Vila B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, Bia