Potential protective role of let-7d-5p in atherosclerosis progression reducing the inflammatory pathway regulated by NF-κB and vascular smooth muscle cells proliferation.

The prevalence of cardiovascular diseases (CVDs) is increasing in the last decades, even is the main cause of death in first world countries being atherosclerosis one of the principal triggers. Therefore, there is an urgent need to decipher the underlying mechanisms involved in atherosclerosis progression. In this respect, microRNAs dysregulation is frequently involved in the progression of multiple diseases including CVDs. Our aim was to demonstrate that let-7d-5p unbalance could contribute to the pathophysiology of atherosclerosis and serve as a potential diagnostic biomarker. We evaluated let-7d-5p levels in vascular biopsies and exosome-enriched extracellular vesicles (EVs) from patients with carotid atherosclerosis and healthy donors. Moreover, we overexpressed let-7d-5p in vitro in vascular smooth muscle cells (VSMCs) to decipher the targets and the underlying mechanisms regulated by let-7d-5p in atherosclerosis. Our results demonstrate that let-7d-5p was significantly upregulated in carotid plaques from overweight patients with carotid atherosclerosis. Moreover, in EVs isolated from plasma, we found that let-7d-5p levels were increased in carotid atherosclerosis patients compared to control subjects specially in overweight patients. Receiver Operating Characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker for atherosclerosis. In VSMCs, we demonstrated that increased let-7d-5p levels impairs cell proliferation and could serve as a protective mechanism against inflammation by impairing NF-κB pathway without affecting insulin resistance. In summary, our results highlight the role of let-7d-5p as a potential therapeutic target for atherosclerosis since its overexpression induce a decrease in inflammation and VSMCs proliferation, and also, as a novel non-invasive diagnostic biomarker for atherosclerosis in overweight patients.

Polyphenols and Triterpenes Combination in an In Vitro Model of Cardiac Damage: Protective Effects.

Olive products contain high levels of monounsaturated fatty acids as well as other minor components such as triterpenic alcohols and other pentacyclic triterpenes, which together form the main triterpenes of virgin olive oil. Olive fruits and leaves contain significant amounts of hydrophilic and lipophilic bioactives including flavones, phenolic acids and phenolic alcohols, amongst others. Several studies have shown the benefits of these substances on the cardiovascular system. Regardless, little is known about the specific combination of bioactive compounds in cardiovascular health. Thus, we aimed to test the combination of a triterpenes (TT70) and a polyphenols (HT60) olive oil bioactive extract in H9c2 cells under stress conditions: LPS and H2O2 stimulation. To evaluate the effectiveness of the combination, we measured cell viability, superoxide production and protein expression of caspase 3, eNOS, peNOS, TNF-α and Il-6. Overall, cells stimulated with LPS or H2O2 and co-incubated with the combination of triterpenes and polyphenols had increased cell survival, lower levels of superoxide anion, lower protein expression of eNOS and higher expression of peNOS, increased protein expression of SOD-1 and lower protein expression of TNF-α and Il-6. The specific combination of HT60+TT70 is of great interest for further study as a possible treatment for cardiovascular damage.

Long-term exposure to nanoplastics alters molecular and functional traits related to the carcinogenic process.

Micro/nanoplastics (MNPLs) are considered emergent pollutants widely spread over all environmental compartments. Although their potential biological effects are being intensively evaluated, many doubts remain about their potential health effects in humans. One of the most underdeveloped fields is the determination of the potential tumorigenic risk of MNPLs exposure. To shed light on this topic, we have designed a wide battery of different hallmarks of cancer applied to prone-to-transformed progress MEF cells exposed to polystyrene nanoplastics (PSNPLs) in the long term (6 months). Interestingly, most of the evaluated hallmarks of cancer are exacerbated after exposure, independently if they are associated with an early tumoral phenotype (changes in stress-related genes, or microRNA deregulation), advanced tumoral phenotype (growing independently of anchorage ability, and migration capacity), or an aggressive tumoral phenotype (invasion potential, changes in pluripotency markers, and ability to grow to form tumorspheres). This set of obtained data constitutes a relevant warning on the potential carcinogenic risk associated with long-term exposures to MNPLs, specifically that induced by the PSNPLs evaluated in this study.

CRISPR/Cas9-Directed Gene Trap Constitutes a Selection System for Corrected BCR/ABL Leukemic Cells in CML.

Chronic myeloid leukaemia (CML) is a haematological neoplasm driven by the BCR/ABL fusion oncogene. The monogenic aspect of the disease and the feasibility of ex vivo therapies in haematological disorders make CML an excellent candidate for gene therapy strategies. The ability to abolish any coding sequence by CRISPR-Cas9 nucleases offers a powerful therapeutic opportunity to CML patients. However, a definitive cure can only be achieved when only CRISPR-edited cells are selected. A gene-trapping approach combined with CRISPR technology would be an ideal approach to ensure this. Here, we developed a CRISPR-Trap strategy that efficiently inserts a donor gene trap (SA-CMV-Venus) cassette into the BCR/ABL-specific fusion point in the CML K562 human cell line. The trapping cassette interrupts the oncogene coding sequence and expresses a reporter gene that enables the selection of edited cells. Quantitative mRNA expression analyses showed significantly higher level of expression of the BCR/Venus allele coupled with a drastically lower level of BCR/ABL expression in Venus+ cell fractions. Functional in vitro experiments showed cell proliferation arrest and apoptosis in selected Venus+ cells. Finally, xenograft experiments with the selected Venus+ cells showed a large reduction in tumour growth, thereby demonstrating a therapeutic benefit in vivo. This study represents proof of concept for the therapeutic potential of a CRISPR-Trap system as a novel strategy for gene elimination in haematological neoplasms.

MicroRNAs as a Suitable Biomarker to Detect the Effects of Long-Term Exposures to Nanomaterials. Studies on TiO2NP and MWCNT.

The presence of nanomaterials (NMs) in the environment may represent a serious risk to human health, especially in a scenario of chronic exposure. To evaluate the potential relationship between NM-induced epigenetic alterations and carcinogenesis, the present study analyzed a panel of 33 miRNAs related to the cell transformation process in BEAS-2B cells transformed by TiO2NP and long-term MWCNT exposure. Our battery revealed a large impact on miRNA expression profiling in cells exposed to both NMs. From this analysis, a small set of five miRNAs (miR-23a, miR-25, miR-96, miR-210, and miR-502) were identified as informative biomarkers of the transforming effects induced by NM exposures. The usefulness of this reduced miRNA battery was further validated in other previously generated transformed cell systems by long-term exposure to other NMs (CoNP, ZnONP, MSiNP, and CeO2NP). Interestingly, the five selected miRNAs were consistently overexpressed in all cell lines and NMs tested. These results confirm the suitability of the proposed set of mRNAs to identify the potential transforming ability of NMs. Particular attention should be paid to the epigenome and especially to miRNAs for hazard assessment of NMs, as wells as for the study of the underlying mechanisms of action.

¿Es adecuada la diálisis peritoneal para pacientes mayores de 65 años? Estudio multicéntrico prospectivo / Is peritoneal dialysis suitable technique CKD patients over 65 years? A prospective multicenter study

Escenario: La prevalencia de enfermedad renal crónica (ERC) aumenta en población mayor de 65años y asocia morbilidad, dependencia y fragilidad. La diálisis peritoneal (DP) se ha considerado una técnica de paciente joven y vida activa. Hipótesis: La DP puede ser adecuada en pacientes de edad avanzada. Buscamos resultados desfavorables que contravengan esta hipótesis. Objetivo: Describir el tratamiento con DP en mayores de 65años, evaluar su evolución clínica comparada con los menores de 65 e identificar áreas de mejora asistencial. Estudio: Prospectivo, observacional y multicéntrico en incidentes en DP, seguimiento hasta evento o fin del estudio (ene-2003 a ene-2018).Resultados: Se incluyen 2.435 pacientes; el 31,9% (777) eran mayores de 65 años. El tiempo medio de seguimiento fue de 2,1años para ambos grupos. El grupo de edad avanzada era 25años mayor, con más comorbilidad: diabetes (29,5% vs. 17,2%; p<0,001), evento CV previo (34,5% vs. 14,0%; p<0,001) e índice de Charlson sin edad (3,8 vs. 3,0; p<0,001). No encontramos diferencias en cumplimiento de objetivos intermedios de eficacia de DP, control de anemia o hipertensión durante el seguimiento. La tasa de peritonitis fue mayor en la cohorte mayor de 65años (0,65 vs. 0,45 episodios/paciente-año; p<0,001), aunque la distribución gérmenes, tasa de ingreso y evolución final fue similar en ambos grupos. Lógicamente, registramos mayor mortalidad en el grupo mayor de 65años (28,4% vs. 9,4%), aunque el tiempo de permanencia en DP fue similar (2,1años). La principal causa de salida fue el trasplante renal en jóvenes (48,3%), mientras que en los pacientes de mayor edad fue el paso a hemodiálisis, principalmente por cansancio de cuidador/autocuidado (20,2%) y no por fallo de la técnica (7,3%). (AU)

Background: Chronic kidney disease (CKD) is increasing in patients older than 65years and is related to morbidity, frailty, and dependence. Peritoneal dialysis (PD) has classically been associated with young patients with an active life. Hypothesis: PD should be offered to patients over 65years. We search for any unfavorable results that may advice not to recommend PD therapy for this group. Objective: To describe PD treatment and outcomes in patients >65years, to compare their results with patients <65years and to identify areas with room for improvement in a real-life study. Study: Prospective, observational, and multicenter study performed in incident PD patients, from January 2003 until January 2018. Results: We included 2,435 PD patients, 31.9% were older than 65years; there was a difference of 25years between both groups. Median follow up was 2.1years. Older than 65years group had more comorbidity: Diabetes (29.5% vs 17.2%; p<0.001), previous CV events 34.5% vs 14.0%; p<0.001), Charlson index (3.8 vs 3.0; p<0.001). We did not find differences in efficacy and PD adequacy objectives fulfillment, anaemia management or blood pressure during follow-up. Peritonitis rate was higher in older 65years group (0.65 vs 0.45 episodes/patient/year; p<0.001), but there was not differences in germs, admission rate and follow up. Mortality was higher in older 65years group (28.4% vs 9.4%) as expected. PD permanence probability was similar (2.1years). The main cause of PD withdrawal was transplant in group <65years (48.3%) and transfer to HD in group >65years. The main reason was caregiver or patient fatigue (20.2%), and not technique failure (7.3%). (AU)

Proanthocyanidins Maintain Cardiac Ionic Homeostasis in Aldosterone-Induced Hypertension and Heart Failure.

Excess aldosterone promotes pathological remodeling of the heart and imbalance in cardiac ion homeostasis of sodium, potassium and calcium. Novel treatment with proanthocyanidins in aldosterone-treated rats has resulted in downregulation of cardiac SGK1, the main genomic aldosterone-induced intracellular mediator of ion handling. It therefore follows that proanthocyanidins could be modulating cardiac ion homeostasis in aldosterone-treated rats. Male Wistar rats received aldosterone (1 mg kg-1 day-1) +1% NaCl for three weeks. Half of the animals in each group were simultaneously treated with the proanthocyanidins-rich extract (80% w/w) (PRO80, 5 mg kg-1 day-1). PRO80 prevented cardiac hypertrophy and decreased calcium content. Expression of ion channels (ROMK, NHE1, NKA and NCX1) and calcium transient mediators (CAV1.2, pCaMKII and oxCaMKII) were reduced by PRO80 treatment in aldosterone-treated rats. To conclude, our data indicate that PRO80 may offer an alternative treatment to conventional MR-blockade in the prevention of aldosterone-induced cardiac pathology.

Ex vivo exposure to different types of graphene-based nanomaterials consistently alters human blood secretome.

The biomedical applications of graphene-based nanomaterials (GBN) have significantly grown in the last years. Many of these applications suppose their intravenous exposure and, in this way, GBN could encounter blood cells triggering an immunological response of unknown effects. Consequently, understanding the relationships between GBN and the immune system response should be a prerequisite for its adequate use in biomedicine. In the present study, we have conducted a little explored ex vivo exposure method in order to study the complexity of the secretome given by the interactions between GBN and blood cells. Blood samples from different healthy donors were exposed to three different types of GBN widely used in the biomedical field. In this sense, graphene oxide (GO), graphene nanoplatelets (GNPs), graphene nanoribbons (GNRs) and a panel of 105 proteins representatives of the blood secretome were evaluated. The results show broad changes in both the cytokines number and the expression levels, with important changes in inflammatory response markers. Furthermore, the indirect soft-agar assay was used as a tool to unravel the global functional impact of the found secretome changes. Our results indicate that the GBN-induced altered secretome can modify the natural anchorage-independent growth capacity of HeLa cells, used as a model. As a conclusion, this study describes an innovative approach to study the potential harmful effects of GBN, providing relevant data to be considered in the biomedical context when GBN are planned to be used in patients.

Nanoceria, alone or in combination with cigarette-smoke condensate, induce transforming and epigenetic cancer-like features in vitro.

Aim: To detect cell transformation effects of nanoceria after long-term exposure (up to 6 weeks) and to determine their potential interactions with cigarette smoke condensate, as a model of environmental carcinogenic pollutant. Materials & methods: Human bronchial epithelial BEAS-2 cells were used to determine transformation effects (invasion and tumorspheres induction), as well as changes in the expression of a battery of miRNAs related to the carcinogenesis process. Results: Nanoceria- and co-exposed cells exhibit cell transforming potential, with significantly increased invasion and tumorsphere formation abilities. Likewise, these exposures produced a high impact on the battery of miRNAs used. Conclusion: Nanoceria exposure induces cell-transformation and shows a positive interaction with the cell-transforming effects of cigarette smoke condensate. Besides, cerium dioxide nanoparticles and the co-exposure produced potential toxicity at the transcriptome level, which is related to tumorigenesis.

Is peritoneal dialysis suitable technique CKD patients over 65 years? A prospective multicenter study.

BACKGROUND: Chronic kidney disease (CKD) is increasing in patients older than 65 years and is related to morbidity, frailty, and dependence. Peritoneal dialysis (PD) has classically been associated with young patients with an active life. HYPOTHESIS: PD should be offered to patients over 65 years. We search for any unfavorable results that may advice not to recommend PD therapy for this group. OBJECTIVE: To describe PD treatment and outcomes in patients > 65 years, to compare their results with patients < 65 years and to identify areas with room for improvement in a real-life study. STUDY: Prospective, observational, and multicenter study performed in incident PD patients, from January 2003 until January 2018. RESULTS: We included 2,435 PD patients, 31.9% were older than 65 years; there was a difference of 25 years between both groups. Median follow up was 2.1 years. Older than 65 years group had more comorbidity: Diabetes (29.5% vs 17.2%; p < 0.001), previous CV events 34.5% vs 14.0%; p < 0.001), Charlson index (3.8 vs 3.0; p < 0.001). We did not find differences in efficacy and PD adequacy objectives fulfillment, anaemia management or blood pressure during follow-up. Peritonitis rate was higher in older 65 years group (0.65 vs 0.45 episodes/patient/year; p < 0.001), but there was not differences in germs, admission rate and follow up. Mortality was higher in older 65 years group (28.4% vs 9.4%) as expected. PD permanence probability was similar (2.1 years). The main cause of PD withdrawal was transplant in group < 65 years (48.3%) and transfer to HD in group > 65 years. The main reason was caregiver or patient fatigue (20.2%), and not technique failure (7.3%). Multivariate Cox regression analysis showed a relation (HR [95%CI]) between mortality and age > 65 years 2.4 [1.9-3.0]; DM 1.6 [1.3-2.1]; CV events 2.1 [1.7-2.7]. Multivariate Cox regression analysis identify a relation between technique failure and age > 65 years 1.5 [1.3-1.9]; DM 1.6 [1.3-1.9] and previous transplant 1.5 [1.2-2.0]. CONCLUSION: Patients older than 65 years fulfilled PD adequacy criteria during the follow up. We believe PD is a valid option for patients older 65 years. It is necessary to try to prevent infections and patient/caregiver fatigue, to avoid HD transfer for reasons not related to technique failure.

Clinical relevance of marginal factors on ultrafiltration in peritoneal dialysis.

BACKGROUND: Ultrafiltration (UF) in peritoneal dialysis (PD) is mainly driven by the osmotic gradient and peritoneal permeability, but other factors-such as intraperitoneal pressure (IPP)-also have an influence. METHODS: To assess the clinical relevance of these marginal factors, we studied 41 unselected PD patients undergoing two consecutive 2 h, 2.27% glucose exchanges, first with 2.5 L and then with 1.5 L. RESULTS: IPP, higher in the 2.5 L exchange, had a wide interpatient range, was higher in obese and polycystic patients and their increase with infusion volume was higher for women regardless of body size. UF with 2.5 L correlated inversely with IPP and was higher for patients with polycystosis or hernias, while for 1.5 L we found no significant correlations. The effluent had higher glucose and osmolarity in the 2.5 L exchange than in the 1.5 L one, similar for both sexes. In spite of this stronger osmotic gradient, only 21 patients had more UF in the 2.5 L exchange, with differences up to 240 mL. The other 20 patients had more UF in the 1.5 L exchange, with stronger differences (up to 800 mL, and more than 240 mL for 9 patients). The second group, with similar effluent osmolarity and peritoneal equilibration test (PET) parameters than the first, has higher IPP and preponderance of men. The sex influence is so intense that men decreased average UF with 2.5 L with respect to 1.5 L, while women increased it. CONCLUSIONS: With 2.27% glucose, sex and IPP-modulated by obesity, polycystosis, hernias, and intraperitoneal volume-significantly affect UF in clinical settings and might be useful for its management.

Effect of Pectin on the Expression of Proteins Associated with Mitochondrial Biogenesis and Cell Senescence in HT29-Human Colorectal Adenocarcinoma Cells.

Mitochondria dynamic is regulated by different proteins, maintaining a balance between fission and fusion. An imbalance towards mitochondrial fission has been associated with tumor cell proliferation. The aim of this study was to analyze whether pectin modifies the viability of human colon cancer cells and the expression of proteins involved in mitochondrial fusion and fission. The human colon carcinoma cell line HT29 cells was growth in 10% fetal bovine serum in the absence and presence of pectin. Pectin reduced HT29 cell viability in a concentration-dependent manner, reaching a plateau at 150~300 µmol/L pectin. The presence of 200 µmol/L pectin reduced the expression of dynamin-related protein-1 and increased expression of the mitochondrial fusion-associated proteins mitofusin-1 and 2. Expression of cyclin B1, a protein involved in G2/M transition, was found decreased in pectin-incubated HT29 cells. Moreover, expression of p53 protein, the amount of p53 in the nucleous and ß-galactosidase activity, which are all biomarkers for cellular senescence, were significantly higher in pectin-incubated HT29 cells than in HT29 cells incubated without pectin. Expression of the protein B-cell lymphoma 2 (Bcl-2) homologous antagonist/killer was increased in response to incubation with pectin. However, incubation with pectin did not affect expression of Bcl-2-associated X protein or Bcl-2, or the caspase-3 activity. Overall, we concluded that pectin reduces the viability of human HT29 colon cancer cells, which is accompanied with a shift in the expression of proteins associated with mitochondrial dynamics towards mitochondrial fusion. Moreover, incubation with pectin favors cellular senescence over apoptosis in HT29 cells.

Supplementation with an insoluble fiber obtained from carob pod (Ceratonia siliqua L.) rich in polyphenols prevents dyslipidemia in rabbits through SIRT1/PGC-1α pathway.

PURPOSE: To investigate the mechanism implicated in the effect of an insoluble fiber (obtained from carob pod) rich in polyphenols (IFCP) in lipid metabolism in the liver. METHODS: Male New Zealand rabbits were fed with the following diets for 8 weeks: control diet (CT group), dyslipidemic diet supplemented with 0.5% cholesterol + 14% coconut oil (DL group) and dyslipidemic diet containing 0.5% cholesterol + 14% coconut oil plus 3% IFCP (DL + IFCP group). RESULTS: Dyslipidemic diet with IFCP was able to reduce development of mixed dyslipidemia, liver relative weight and collagen I protein expression compared to DL rabbits. Analyses of the main enzymes implicated in cholesterol and triglycerides metabolism revealed that IFCP increased hepatic concentration of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and cytochrome P450, family 7, subfamily a, polypeptide 1C (CYP7A1) (82.34, 114.42%, respectively) as well as protein expression of LDL receptor (42.48%) in DL rabbits. Importantly, IFCP also increased hepatic lipase (HL) levels (91.43%) and decreased glycerol phosphate acyltransferase (GPAT) and sterol regulatory element-binding protein 1C (SREBP1c) liver expression levels (20.38 and 41.20%, respectively). Finally, sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) hepatic expression increased in DL + IFCP group compared with DL (159.81 and 48.00%, respectively). CONCLUSIONS: These findings show that IFCP is able to abrogate the deleterious effects of hepatic dyslipidemia by modulating SIRT1 and PGC-1α pathways.

Low Phytanic Acid-Concentrated DHA Prevents Cognitive Deficit and Regulates Alzheimer Disease Mediators in an ApoE-/- Mice Experimental Model.

Alzheimer's disease (AD) is the main cause of dementia and cognitive impairment. It has been associated with a significant diminution of omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) levels in the brain. Clinical trials with DHA as a treatment in neurological diseases have shown inconsistent results. Previously, we reported that the presence of phytanic acid (PhA) in standard DHA compositions could be blunting DHA's beneficial effects. Therefore, we aimed to analyze the effects of a low PhA-concentrated DHA and a standard PhA-concentrated DHA in Apolipoprotein E knockout (ApoE-/-) mice. Behavioral tests and protein expression of pro-inflammatory, pro-oxidant, antioxidant factors, and AD-related mediators were evaluated. Low PhA-concentrated DHA decreased Aß, ß-amyloid precursor protein (APP), p-tau, Ca2+/calmodulin-dependent protein kinase II (CAMKII), caspase 3, and catalase, and increased brain derived neurotrophic factor (BDNF) when compared to standard PhA-concentrated DHA. Low PhA-concentrated DHA decreased interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) protein expression in ApoE-/- mice when compared to standard PhA-concentrated DHA. No significant differences were found in p22phox, inducible nitric oxide synthase (iNOS), glutathione peroxidase (GPx), superoxide dismutase 1 (SOD-1), and tau protein expression. The positive actions of a low PhA-concentrated DHA were functionally reflected by improving the cognitive deficit in the AD experimental model. Therefore, reduction of PhA content in DHA compositions could highlight a novel pathway for the neurodegeneration processes related to AD.

Chronic Exercise Improves Mitochondrial Function and Insulin Sensitivity in Brown Adipose Tissue.

The aim of the present work was to study the consequences of chronic exercise training on factors involved in the regulation of mitochondrial remodeling and biogenesis, as well as the ability to produce energy and improve insulin sensitivity and glucose uptake in rat brown adipose tissue (BAT). Male Wistar rats were divided into two groups: (1) control group (C; n = 10) and (2) exercise-trained rats (ET; n = 10) for 8 weeks on a motor treadmill (five times per week for 50 min). Exercise training reduced body weight, plasma insulin, and oxidized LDL concentrations. Protein expression of ATP-independent metalloprotease (OMA1), short optic atrophy 1 (S-OPA1), and dynamin-related protein 1 (DRP1) in BAT increased in trained rats, and long optic atrophy 1 (L-OPA1) and mitofusin 1 (MFN1) expression decreased. BAT expression of nuclear respiratory factor type 1 (NRF1) and mitochondrial transcription factor A (TFAM), the main factors involved in mitochondrial biogenesis, was higher in trained rats compared to controls. Exercise training increased protein expression of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and AMP-activated protein kinase (pAMPK/AMPK ratio) in BAT. In addition, training increased carnitine palmitoyltransferase II (CPT II), mitochondrial F1 ATP synthase α-chain, mitochondrial malate dehydrogenase 2 (mMDH) and uncoupling protein (UCP) 1,2,3 expression in BAT. Moreover, exercise increased insulin receptor (IR) ratio (IRA/IRB ratio), IRA-insulin-like growth factor 1 receptor (IGF-1R) hybrids and p42/44 activation, and decreased IGF-1R expression and IR substrate 1 (p-IRS-1) (S307) indicating higher insulin sensitivity and favoring glucose uptake in BAT in response to chronic exercise training. In summary, the present study indicates that chronic exercise is able to improve the energetic profile of BAT in terms of increased mitochondrial function and insulin sensitivity.

Effects of Low Phytanic Acid-Concentrated DHA on Activated Microglial Cells: Comparison with a Standard Phytanic Acid-Concentrated DHA.

Docosahexaenoic acid (DHA, 22:6 n-3) is an essential omega-3 (ω-3) long chain polyunsaturated fatty acid of neuronal membranes involved in normal growth, development, and function. DHA has been proposed to reduce deleterious effects in neurodegenerative processes. Even though, some inconsistencies in findings from clinical and pre-clinical studies with DHA could be attributed to the presence of phytanic acid (PhA) in standard DHA treatments. Thus, the aim of our study was to analyze and compare the effects of a low PhA-concentrated DHA with a standard PhA-concentrated DHA under different neurotoxic conditions in BV-2 activated microglial cells. To this end, mouse microglial BV-2 cells were stimulated with either lipopolysaccharide (LPS) or hydrogen peroxide (H2O2) and co-incubated with DHA 50 ppm of PhA (DHA (PhA:50)) or DHA 500 ppm of PhA (DHA (PhA:500)). Cell viability, superoxide anion (O2-) production, Interleukin 6 (L-6), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), glutathione peroxidase (GtPx), glutathione reductase (GtRd), Caspase-3, and the brain-derived neurotrophic factor (BDNF) protein expression were explored. Low PhA-concentrated DHA protected against LPS or H2O2-induced cell viability reduction in BV-2 activated cells and O2- production reduction compared to DHA (PhA:500). Low PhA-concentrated DHA also decreased COX-2, IL-6, iNOS, GtPx, GtRd, and SOD-1 protein expression when compared to DHA (PhA:500). Furthermore, low PhA-concentrated DHA increased BDNF protein expression in comparison to DHA (PhA:500). The study provides data supporting the beneficial effect of low PhA-concentrated DHA in neurotoxic injury when compared to a standard PhA-concentrated DHA in activated microglia.

La presión intraperitoneal en diálisis peritoneal / Intraperitoneal pressure in peritoneal dialysis

La medida de la presión intraperitoneal en diálisis peritoneal es muy sencilla y aporta claros beneficios terapéuticos. Sin embargo, su monitorización todavía no se ha generalizado en las unidades de diálisis peritoneal de adultos. Esta revisión pretende divulgar su conocimiento y la utilidad de su medida. Se realiza en decúbito antes de iniciar el drenaje de un intercambio manual con bolsa en Y, elevando la bolsa de drenaje y midiendo la altura que alcanza la columna de líquido desde la línea medio-axilar. Los valores habituales son 10 a 16 cmH2O y nunca debe superar los 18 cmH2O. Aumenta de 1 a 3 cmH2O por litro de volumen intraperitoneal sobre valores basales que dependen del índice de masa corporal y varía con la postura y la actividad física. Su aumento provoca malestar, alteraciones del sueño y de la respiración, y se ha relacionado con la aparición de fugas de líquido, hernias, hidrotórax, reflujo gastroesofágico y peritonitis por gérmenes intestinales. Menos conocida y valorada es su capacidad para disminuir la eficacia de la diálisis contrarrestando, sobre todo, la ultrafiltración y, en menor grado, el aclaramiento de solutos. Por su facilidad de medida y potencial utilidad, debería ser uno de los factores que investigar en los fallos de ultrafiltración, pues su elevación podría contribuir a ellos en algunos pacientes. Aunque todavía no se menciona en las guías de actuación en diálisis peritoneal, sus claros beneficios justifican su inclusión entre las mediciones periódicas que considerar para la prescripción y seguimiento de la diálisis peritoneal (AU)

The measure of intraperitoneal pressure in peritoneal dialysis is easy and provides clear therapeutic benefits. However it is measured only rarely in adult peritoneal dialysis units. This review aims to disseminate the usefulness of measuring intraperitoneal pressure. This measurement is performed in supine before initiating the drain of a manual exchange with 'Y' system, by raising the drain bag and measuring from the mid-axillary line the height of the liquid column that rises from the patient. With typical values of 10-16 cmH2O, intraperitoneal pressure should never exceed 18 cmH2O. With basal values that depend on body mass index, it increases 1-3 cmH2O/L of intraperitoneal volume, and varies with posture and physical activity. Its increase causes discomfort, sleep and breathing disturbances, and has been linked to the occurrence of leaks, hernias, hydrothorax, gastro-esophageal reflux and enteric peritonitis. Less known and valued is its ability to decrease the effectiveness of dialysis significantly counteracting ultrafiltration and decreasing solute clearance to a smaller degree. Because of its easy measurement and potential utility, should be monitored in case of ultrafiltration failure to rule out its eventual contribution in some patients. Although not yet mentioned in the clinical practice guidelines for PD, its clear benefits justify its inclusion among the periodic measurements to consider for prescribing and monitoring peritoneal dialysis (AU)

Intraperitoneal pressure in peritoneal dialysis. / La presión intraperitoneal en diálisis peritoneal.

The measure of intraperitoneal pressure in peritoneal dialysis is easy and provides clear therapeutic benefits. However it is measured only rarely in adult peritoneal dialysis units. This review aims to disseminate the usefulness of measuring intraperitoneal pressure. This measurement is performed in supine before initiating the drain of a manual exchange with "Y" system, by raising the drain bag and measuring from the mid-axillary line the height of the liquid column that rises from the patient. With typical values of 10-16 cmH2O, intraperitoneal pressure should never exceed 18 cmH2O. With basal values that depend on body mass index, it increases 1-3 cmH2O/L of intraperitoneal volume, and varies with posture and physical activity. Its increase causes discomfort, sleep and breathing disturbances, and has been linked to the occurrence of leaks, hernias, hydrothorax, gastro-esophageal reflux and enteric peritonitis. Less known and valued is its ability to decrease the effectiveness of dialysis significantly counteracting ultrafiltration and decreasing solute clearance to a smaller degree. Because of its easy measurement and potential utility, should be monitored in case of ultrafiltration failure to rule out its eventual contribution in some patients. Although not yet mentioned in the clinical practice guidelines for PD, its clear benefits justify its inclusion among the periodic measurements to consider for prescribing and monitoring peritoneal dialysis.

Molecular factors involved in the hypolipidemic- and insulin-sensitizing effects of a ginger (Zingiber officinale Roscoe) extract in rats fed a high-fat diet.

Hypolipidemic and hypoglycemic properties of ginger in animal models have been reported. However, information related to the mechanisms and factors involved in the metabolic effects of ginger at a hepatic level are limited. The aim of the present study was to investigate molecular factors involved in the hypoglycemic and hypolipidemic effects of a hydroethanolic ginger extract (GE) in the liver of rats fed a high-fat diet (HFD). The study was conducted in male Wistar rats divided into the following 3 groups: (i) Rats fed a standard diet (3.5% fat), the control group; (ii) rats fed an HFD (33.5% fat); and (iii) rats fed an HFD treated with GE (250 mg·kg-1·day-1) for 5 weeks (HFD+GE). Plasma levels of glucose, insulin, lipid profile, leptin, and adiponectin were measured. Liver expression of glycerol phosphate acyltransferase (GPAT), cholesterol 7 alpha-hydroxylase, peroxisome proliferator-activated receptors (PPAR), PPARα and PPARγ, glucose transporter 2 (GLUT-2), liver X receptor, sterol regulatory element-binding protein (SREBP1c), connective tissue growth factor (CTGF), and collagen I was measured. Data were analyzed using a 1-way ANOVA, followed by a Newman-Keuls test if differences were noted. The study showed that GE improved lipid profile and attenuated the increase of plasma levels of glucose, insulin, and leptin in HFD rats. This effect was associated with a higher liver expression of PPARα, PPARγ, and GLUT-2 and an enhancement of plasma adiponectin levels. Furthermore, GE reduced liver expression of GPAT, SREBP1c, CTGF, and collagen I. The results suggest that GE might be considered as an alternative therapeutic strategy in the management of overweight and hepatic and metabolic-related alterations.

Proanthocyanidins block aldosterone-dependent up-regulation of cardiac gamma ENaC and Nedd4-2 inactivation via SGK1.

Aldosterone plays a central role in the development of cardiac pathological states involving ion transport imbalances, especially sodium transport. We have previously demonstrated a cardioprotective effect of proanthocyanidins in aldosterone-treated rats. Our objective was to investigate for the first time the effect of proanthocyanidins on serum and glucocorticoid-regulated kinase 1 (SGK1), epithelial Na+ channel (γ-ENaC), neuronal precursor cells expressed developmentally down-regulated 4-2 (Nedd4-2) and phosphoNedd4-2 protein expression in the hearts of aldosterone-treated rats. Male Wistar rats received aldosterone (1mg kg-1day-1)+1% NaCl for 3weeks. Half of the animals in each group were simultaneously treated with the proanthocyanidins-rich extract (80% w/w) (PRO80, 5mg kg-1day-1). Hypertension and diastolic dysfunction induced by aldosterone were abolished by treatment with PRO80. Expression of fibrotic, inflammatory and oxidative mediators were increased by aldosterone-salt administration and blunted by PRO80. Antioxidant capacity was improved by PRO80. The up-regulated aldosterone mediator SGK1, ENaC and p-Nedd4-2/total Nedd4-2 ratio were blocked by PRO80. PRO80 blunted aldosterone-mineralocorticoid-mediated up-regulation of ENaC provides new mechanistic insight of the beneficial effect of proanthocyanidins preventing the cardiac alterations induced by aldosterone excess.