Squalene: A Trove of Metabolic Actions

Squalene is present in high concentration in the liver of certain sharks and in small concentrations in olive oil. Previous studies showed that its administration decreases hepatic steatosis in male Apoe-knockout mice, but these changes might be complex. Transcriptomics, using DNA microarrays, and proteomics from mitochondrial and microsomal fractions, analyzed by 2D-DIGE and mass spectrometry, were used in these mice that received 1 g/kg/day squalene for 10 weeks. Squalene administration significantly modified the expression of genes such as lipin 1 (Lpin1) and thyroid hormone responsive (Thrsp). Changes in methionine adenosyltransferase 1 alpha (Mat1α), short-chain specific acyl-CoA dehydrogenase (Acads), and thioredoxin domain–containing protein 5 (Txndc5) expressions were consistent with their protein levels. Their mRNA levels were associated with hepatic fat content. These results suggest that squalene action involves changes in hepatic gene expression associated with its anti-steatotic properties. This approach shows new connections between nutrition and gene expression since Txndc5, a gene with unknown biological function, was upregulated by squalene administration. Overall, this nutrigenomic approach illustrates the effects of squalene and provides further support to the idea that not all monounsaturated fatty acid–containing oils behave similarly. Therefore, selection of cultivars producing olive oils enriched in this compound will be a plus

Patient-physician discrepancy in the perception of immune-mediated inflammatory diseases: rheumatoid arthritis, psoriatic arthritis and psoriasis. A qualitative systematic review of the literature

Introduction Recommendations on chronic diseases management emphasise the need to consider patient perspectives and shared decision-making. Discrepancies between patients and physicians’ perspectives on treatment objectives, disease activity, preferences and treatment have been described for immune-mediate inflammatory diseases. These differences could result on patient dissatisfaction and negatively affect outcomes. Objective To describe the degree of patient-physician discrepancy in three chronic immune-mediated inflammatory diseases (rheumatoid arthritis [RA], psoriatic arthritis [PsA] and psoriasis [Ps]), identifying the main areas of discrepancy and possible predictor factors. Methods Qualitative systematic review of the available literature on patient and physician discrepancies in the management of RA, PsA and Ps. The search was performed in international (Medline/PubMed, Cochrane Library, ISI-WOK) and Spanish electronic databases (MEDES, IBECS), including papers published from April 1, 2008 to April 1, 2018, in English or Spanish, and conducted in European or North American populations. Study quality was assessed by the Oxford Centre for Evidence-Based Medicine criteria. Results A total of 21 studies were included (13 RA; 3 PsA; 4 Ps; 1 RA, Ps, and Axial Spondyloarthritis). A significant and heterogeneous degree of discrepancy between patients and physicians was found, regarding disease activity, treatment, clinical expectations, remission concept, and patient-physician relationship. In RA and PsA, studies were mainly focused on the evaluation of disease activity, which is perceived as higher from the patient’s than the physician’s perspective, with the discrepancy determined by factors such as patient’s perception of pain and fatigue. In Ps, studies were focused on treatment satisfaction and patient-physician relationship, showing a lower degree of discrepancy in the satisfaction regarding these aspects. Conclusions There is a significant degree of patient-physician discrepancy regarding the management of RA, PA, and Ps, what can have a major impact on shared decision-making. Future research may help to show whether interventions considering discrepancy improve shared decision-making

Treatment decision-making in chronic lymphocytic leukaemia: Key factors for healthcare professionals. PRELIC study

Objective: To explore the preferences of Spanish healthcare professionals (haematologists and hospital pharmacists) for the treatment selection of active Chronic Lymphocytic Leukaemia (CLL) patients at first relapse, condition that mainly afflicts older adults. Methods: A discrete choice experiment (DCE) was conducted among haematologists and hospital pharmacists. A literature review and a focus group informed the DCE design. CLL treatment settings were defined by seven attributes: four patient/disease-related attributes (age, functional status, comorbidities, and risk of the disease) and three treatment-related attributes (efficacy [hazard ratio of progression-free survival, HR-PFS], rate of discontinuations due to adverse events and cost). A mixed-logit model was used to determine choice-based preferences. Relative importance (RI) of attributes was calculated and compared between stakeholders. Willingnessto-pay (WTP) was estimated through the DCE. Besides, nine ad-hoc questions were posed, to explore more in depth CLL treatment decision making. Results: A total of 130 participants (72 haematologists and 58 hospital pharmacists) answered the DCE. All attributes were significant predictors of preferences (p b 0.05) in the multinomial model. Higher RI was obtained for treatment-related attributes: the highest rated being ‘cost’ (23.8%) followed by ‘efficacy’ (20.9%). Regarding patient-related attributes, the highest RI was obtained for ‘age’ (18.1%). No significant differences (p N 0.05) in RI between haematologists and pharmacists were found. WTP for the treatment was higher for younger CLL patients. Ad-hoc questions showed that patient age and functional status influence treatment decisions. Conclusions: For healthcare professionals, ‘cost’ and ‘efficacy’ (treatment-related attributes) and age (patientrelated attribute) are the m

The Search for Dietary Supplements to Elevate or Activate Circulating Paraoxonases

Low levels of paraoxonase 1 (PON1) have been associated with the development of several pathological conditions, whereas high levels have been shown to be anti-atherosclerotic in mouse models. These findings suggest that PON1 could be a good surrogate biomarker. The other members of the family, namely PON2 and PON3, the role of which has been much less studied, deserve more attention. This paper provides a systematic review of current evidence concerning dietary supplements in that regard. Preliminary studies indicate that the response to dietary supplements may have a nutrigenetic aspect that will need to be considered in large population studies or in clinical trials. A wide range of plant preparations have been found to have a positive action, with pomegranate and some of its components being the best characterized and Aronia melanocarpa one of the most active. Flavonoids are found in the composition of all active extracts, with catechins and genistein being the most promising agents for increasing PON1 activity. However, some caveats regarding the dose, length of treatment, bioavailability, and stability of these compounds in formulations still need to be addressed. Once these issues have been resolved, these compounds could be included as nutraceuticals and functional foods capable of increasing PON1 activity, thereby helping with the long-term prevention of atherosclerosis and other chronic ailments

Manejo de la fibrilación auricular no valvular desde la perspectiva del paciente en España

Resumen: Objetivo: Describir la percepción del paciente anticoagulado con fibrilación auricular no valvular (FANV) sobre el manejo de su enfermedad, según su tratamiento: antagonistas de la vitamina K (AVK) o anticoagulantes orales de acción directa (ACOD). Métodos: Estudio observacional realizado con asociaciones de pacientes españolas mediante un cuestionario específico, con: 1) variables sociodemográficas/clínicas; 2) información recibida sobre FANV y tratamiento actual; 3) preferencias por el tratamiento anticoagulante; y 4) carga del tratamiento y barreras de acceso al mismo. Resultados: Participaron 156 pacientes (35,9% ACOD, 64,1% AVK). El 73,4% deseaba participar en la decisión de su tratamiento, pero solo el 40,6% había sido involucrado (49,0% ACOD vs. 36,0% AVK; p = 0,044). Los pacientes indicaron cierto grado de desinformación sobre agentes de reversión (25,7%) y alternativas terapéuticas disponibles (19,3%).La satisfacción con su tratamiento actual era alta: 7,1/10 (DE: 2,1); (8,5 ACOD vs. 6,4 AVK; p < 0,001), siendo las características más valoradas: ausencia de interacciones farmacológicas y de analíticas frecuentes y disponibilidad de agente de reversión. La diferencia más significativa entre pacientes con ACOD y AVK fue una mayor importancia otorgada por los primeros a la dosificación fija (p = 0,009).La carga del tratamiento era baja, asociada principalmente a interacciones alimentarias (34,1%) y monitorización (31,3%). Los pacientes con ACOD percibían generalmente menor carga que aquellos con AVK (p < 0,001). Conclusiones: La implicación del paciente en las decisiones, y un tratamiento alineado con sus preferencias, pueden contribuir a mejorar el manejo de la FANV. Los tratamientos sin monitorización frecuente ni un consiguiente ajuste de dosis parecen disminuir la carga de la enfermedad y mejorar la satisfacción del paciente. Abstract: Objective: To describe the perception non-valvular atrial fibrillation (NVAF) patients treated with anticoagulants have regarding the management of their disease, according to the treatment received: vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC). Methods: Observational study conducted with Spanish patient advocacy groups, based on a specific questionnaire requesting: 1) sociodemographic/clinical variables; 2) information received on NVAF and current treatment; 3) anticoagulant treatment preferences; 4) treatment burden and access barriers. Results: 156 patients participated in the study (39.5% DOAC, 64.1% VKA). 73.4% wished to take part in their treatment decision, but only 40.6% had been involved (49.0% DOAC vs. 36.0% VKA; P = .044). Patients indicated a certain degree of misinformation regarding reversal agents (25.7%) and available therapeutic alternatives (19.3%).Satisfaction with current treatment was high: 7.1/10 (SD: 2.1), (8.5 DOAC vs. 6.4 VKA; P < .001); the most valued characteristics was: absence of pharmacological interactions, infrequent blood controls and the availability of a reversal agent. The most significant difference between patients receiving DOAC or VKA was the greater importance given by the former to fixed-dose regimens (P = .009).Treatment burden was low and mainly associated with food interactions (34.1%) and monitoring (31.3%). Patients receiving DOAC generally perceived lower burden than those with VKA treatment (p < 0.001). Conclusions: Patient involvement in decision-making and a treatment aligned with patient preferences may contribute to improve the management of NVAF. Treatments that are not frequently monitored, and therefore without a consequent dose adjustment, appear to decrease disease burden and improve patient satisfaction. Palabras clave: Fibrilación auricular no valvular, Preferencias, Tratamiento anticoagulante oral, Antagonistas de la vitamina K, Anticoagulantes orales de acción directa, Keywords: Non-valvular atrial fibrillation, Preferences, Oral anticoagulant treatment, Vitamin K antagonist, Direct oral anticoagulan

Dietary oleanolic acid mediates circadian clock gene expression in liver independently of diet and animal model but requires apolipoprotein A1

Oleanolic acid is a triterpene widely distributed throughout the plant kingdom and present in virgin olive oil at a concentration of 57 mg/kg. To test the hypotheses that its long-term administration could modify hepatic gene expression in several animal models and that this could be influenced by the presence of APOA1-containing high-density lipoproteins (HDLs), diets including 0.01% oleanolic acid were provided to Apoe- and Apoa1-deficient mice and F344 rats. Hepatic transcriptome was analyzed in Apoe-deficient mice fed long-term semipurified Western diets differing in the oleanolic acid content. Gene expression changes, confirmed by reverse transcriptase quantitative polymerase chain reaction, were sought for their implication in hepatic steatosis. To establish the effect of oleanolic acid independently of diet and animal model, male rats were fed chow diet with or without oleanolic acid, and to test the influence of HDL, Apoa1-deficient mice consuming the latter diet were used. In Apoe-deficient mice, oleanolic acid intake increased hepatic area occupied by lipid droplets with no change in oxidative stress. Bmal1 and the other core component of the circadian clock, Clock, together with Elovl3, Tubb2a and Cldn1 expressions, were significantly increased, while Amy2a5, Usp2, Per3 and Thrsp were significantly decreased in mice receiving the compound. Bmal1 and Cldn1 expressions were positively associated with lipid droplets. Increased Clock and Bmal1 expressions were also observed in rats, but not in Apoa1-deficient mice. The core liver clock components Clock-Bmal1 are a target of oleanolic acid in two animal models independently of the diets provided, and this compound requires APOA1-HDL for its hepatic action

Effect of squalene on lipoproteins from the three experimental models.

<p>Plasma was obtained following 11 weeks of consuming control or squalene- enriched semipurified diets and after a four-hour fast. Two independent pools of all mice per experimental group were prepared, except for <i>Apoe</i>-deficient mice, where three plasma pools were utilized. Lipoproteins were separated by FPLC, and collected fractions analyzed for total cholesterol (A, G, L), esterified cholesterol (B, H, M), phosphatidylcholine (C, I, N), sphingomyelin (D, J, O), APOA1 (E, P) and APOA4 (F, K, Q). Representative profiles are shown from WT mice, left panels (control and squalene pools consisting of plasma from 6 and 7 mice, respectively), <i>Apoa1</i>-deficient mice, middle panels (n = 7 for control and n = 7 for squalene plasma pool) and Apoe-deficient mice, right panels (n = 13 for control, n = 13 for 0.25 g/kg and n = 14 for 1 g/kg squalene plasma pool). Fraction numbers 1–6 corresponded to VLDL/chylomicron remnants, 7–13 to low density lipoproteins, 14–21 to cholesterol-rich HDL and 22–27 to cholesterol-poor HDL (pHDL).</p

Effect of the experimental diets on somatic variables in male mice of the three experimental models.

<p>Results are shown as mean values with their standard deviations. Statistical analysis was carried out using Mann Whitney U test.</p><p>* p<0.05 <i>vs</i> control.</p

Relationship between hepatic gene expression and plasma cholesterol in wild type mice.

<p>Direct correlations among <i>Pcyox1</i> and <i>Pon2</i> gene expression (A), or plasma cholesterol (B), and <i>Lcat</i> and <i>Pon1</i> gene expression (C). Association analyses were carried out using Spearman's test for non- parametric distributions.</p

Effect of squalene on antioxidative parameters from the three experimental models.

<p>ROS levels in lipoprotein fractions from control and squalene treated mice expressed as arbitrary fluorescence units after incubation of lipoprotein fractions during 24 h with 2′,7′-dichlorofluorescein diacetate A) 0.8 µg LDL or VLDL, and 60 ng HDL from WT mice; B) 0.8 µg LDL and 60 ng HDL from <i>Apoa1</i>-deficient mice; C) 1.5 µg LDL or VLDL, and 60 ng HDL from <i>Apoe</i>-deficient mice. Each pool was assayed in triplicate. Individual plasma malondialdehyde levels from WT (D), <i>Apoa1</i>-(E) and <i>Apoe</i>-deficient mice (F). HDL-PON1 levels from WT (G), <i>Apoa1</i>-(H) and <i>Apoe</i>-deficient mice (I) with their representative Western blots. Each pool was assayed in triplicate. Results are shown as means ± SD. *p<0.05, **p<0.01 according to corrected unpaired t Welch's test.</p