Non-alcoholic fatty liver disease in patients with morbid obesity: the gut microbiota axis as a potential pathophysiology mechanism.

BACKGROUND/AIM: Alterations in gut microbiota are associated with the pathogenesis of metabolic diseases, including metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate gut microbiota composition and functionality in patients with morbid obesity with different degrees of MAFLD, as assessed by biopsy. SUBJECTS/METHODS: 110 patients with morbid obesity were evaluated by biopsy obtained during bariatric surgery for MAFLD. Stool samples were collected prior to surgery for microbiota analysis. RESULTS: Gut microbiota from patients with steatosis and non-alcoholic steatohepatitis (NASH) were characterized by an enrichment in Enterobacteriaceae (an ethanol-producing bacteria), Acidaminococcus and Megasphaera and the depletion of Eggerthellaceae and Ruminococcaceae (SCFA-producing bacteria). MAFLD was also associated with enrichment of pathways related to proteinogenic amino acid degradation, succinate production, menaquinol-7 (K2-vitamin) biosynthesis, and saccharolytic and proteolytic fermentation. Basic histological hepatic alterations (steatosis, necroinflammatory activity, or fibrosis) were associated with specific changes in microbiota patterns. Overall, the core microbiome related to basic histological alterations in MAFLD showed an increase in Enterobacteriaceae and a decrease in Ruminococcaceae. Specifically, Escherichia coli was associated with steatosis and necroinflammatory activity, whilst Escherichia-shigella was associated with fibrosis and necroinflammatory activity. CONCLUSIONS: We established a link between gut microbiota alterations and histological injury in liver diagnosis using biopsy. Harmful products such as ethanol or succinate may be involved in the pathogenesis and progression of MAFLD. Thus, these alterations in gut microbiota patterns and their possible metabolic pathways could add information to the classical predictors of MAFLD severity and suggest novel metabolic targets.

Adipose tissue as a therapeutic target for vascular damage in Alzheimer's disease.

Adipose tissue has recently been recognized as an important endocrine organ that plays a crucial role in energy metabolism and in the immune response in many metabolic tissues. With this regard, emerging evidence indicates that an important crosstalk exists between the adipose tissue and the brain. However, the contribution of adipose tissue to the development of age-related diseases, including Alzheimer's disease, remains poorly defined. New studies suggest that the adipose tissue modulates brain function through a range of endogenous biologically active factors known as adipokines, which can cross the blood-brain barrier to reach the target areas in the brain or to regulate the function of the blood-brain barrier. In this review, we discuss the effects of several adipokines on the physiology of the blood-brain barrier, their contribution to the development of Alzheimer's disease and their therapeutic potential. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

The Relationship between Depressive Symptoms, Quality of Life and miRNAs 8 Years after Bariatric Surgery.

(1) Background: There are conflicting results on whether weight loss after bariatric surgery (BS) might be associated with quality of life (QoL)/depressive symptomatology. We aim to determine whether BS outcomes are associated with QoL/depressive symptomatology in studied patients at the 8-year follow-up after BS, as well as their relationship with different serum proteins and miRNAs. (2) Methods: A total of 53 patients with class III obesity who underwent BS, and then classified into "good responders" and "non-responders" depending on the percentage of excess weight lost (%EWL) 8 years after BS (%EWL ≥ 50% and %EWL < 50%, respectively), were included. Basal serum miRNAs and different proteins were analysed, and patients completed tests to evaluate QoL/depressive symptomatology at 8 years after BS. (3) Results: The good responders group showed higher scores on SF-36 scales of physical functioning, role functioning-physical, role functioning-emotional, body pain and global general health compared with the non-responders. The expression of hsa-miR-101-3p, hsa-miR-15a-5p, hsa-miR-29c-3p, hsa-miR-144-3p and hsa-miR-19b-3p were lower in non-responders. Hsa-miR-19b-3p was the variable associated with the response to BS in a logistic regression model. (4) Conclusions: The mental health of patients after BS is limited by the success of the intervention. In addition, the expression of basal serum miRNAs related to depression/anxiety could predict the success of BS.

Rectus Femoris Cross-Sectional Area and Phase Angle asPredictors of 12-Month Mortality in Idiopathic Pulmonary Fibrosis Patients.

BACKGROUND: The value of the phase angle (PhA), measured via bioelectrical impedance analysis (BIA), could be considered a good marker of the cell mass and the cell damage of a patient; however, there are new techniques, such as muscle ultrasonography, that allow the quantity and quality of muscle to be assessed in a minimally invasive way. The aim of this study is to determine the prognostic value of morphofunctional techniques in the prognosis of mortality in patients with idiopathic pulmonary fibrosis (IPF). METHODS: This multicenter, cross-sectional study included 86 patients with idiopathic pulmonary fibrosis with a mean age of 71 years, 82.7% of whom were male. The nutritional risk of the patients was assessed by means of questionnaires, such as the Subjective Global Assessment (SGA), and non-invasive functional techniques, including BIA, nutritional ultrasound, and hand grip strength (HGS). Statistical analysis of the sample was performed using JAMOVI version 2.3.22. RESULTS: Correlations were made between the RF-CSA techniques with PhA (r = 0.48, p < 0.001), BCM (r = 0.70, p < 0.001), SMI (r = 0.64, p < 0.001), and HGS (r = 0.54, p < 0.001). The cut-off points for 12-month mortality were PhA = 4.5° (AUC = 0.722, sensitivity of 72.7% and specificity of 66.6%), BCM = 28.8 kg (AUC = 0.609, sensitivity of 32.4% and specificity of 100.0%), RF-CSA = 3.00 cm2 (AUC = 0.857, sensitivity of 64.4% and specificity of 100.0%), 6MMW = 420 m (AUC = 0.830, sensitivity of 63.27% and specificity of 100.0%), and TUG = 7.2 s (AUC = 0.771, sensitivity of 100.0% and specificity of 56.67%). In addition, a multivariate analysis was performed with RF-CSA, HR = 8.11 (1.39-47.16, p = 0.020), and PhA of 6.35 (1.29-31.15, p = 0.023), taking into account age, sex, and BMI to determine mortality. Finally, a Kaplan-Meier survival analysis was conducted with low or normal values for classical parameters (GAP and T6MM) and new parameters (PhA, BCM, RF-CSA, and TUG). CONCLUSION: RF-CSA and PhA were shown to be good prognostic markers of 12-month mortality and could, therefore, be useful screening tools to complement the nutritional assessment of IPF patients.

Downregulated Adipose Tissue Expression of Browning Genes With Increased Environmental Temperatures.

CONTEXT: Climate change and global warming have been hypothesized to influence the increased prevalence of obesity worldwide. However, the evidence is scarce. OBJECTIVE: We aimed to investigate how outside temperature might affect adipose tissue physiology and metabolic traits. METHODS: The expression of genes involved in thermogenesis/browning and adipogenesis were evaluated (through quantitative polymerase chain reaction) in the subcutaneous adipose tissue (SAT) from 1083 individuals recruited in 5 different regions of Spain (3 in the North and 2 in the South). Plasma biochemical variables and adiponectin (enzyme-linked immunosorbent assay) were collected through standardized protocols. Mean environmental outdoor temperatures were obtained from the National Agency of Meteorology. Univariate, multivariate, and artificial intelligence analyses (Boruta algorithm) were performed. RESULTS: The SAT expression of genes associated with browning (UCP1, PRDM16, and CIDEA) and ADIPOQ were significantly and negatively associated with minimum, average, and maximum temperatures. The latter temperatures were also negatively associated with the expression of genes involved in adipogenesis (FASN, SLC2A4, and PLIN1). Decreased SAT expression of UCP1 and ADIPOQ messenger RNA and circulating adiponectin were observed with increasing temperatures in all individuals as a whole and within participants with obesity in univariate, multivariate, and artificial intelligence analyses. The differences remained statistically significant in individuals without type 2 diabetes and in samples collected during winter. CONCLUSION: Decreased adipose tissue expression of genes involved in browning and adiponectin with increased environmental temperatures were observed. Given the North-South gradient of obesity prevalence in these same regions, the present observations could have implications for the relationship of the obesity pandemic with global warming.

Membrane Vesicles of Toxigenic Clostridioides difficile Affect the Metabolism of Liver HepG2 Cells.

Clostridioides difficile infection (CDI) appears to be associated with different liver diseases. C. difficile secretes membrane vesicles (MVs), which may be involved in the development of nonalcoholic fatty liver disease (NALFD) and drug-induced liver injury (DILI). In this study, we investigated the presence of C. difficile-derived MVs in patients with and without CDI, and analyzed their effects on pathways related to NAFLD and DILI in HepG2 cells. Fecal extracellular vesicles from CDI patients showed an increase of Clostridioides MVs. C. difficile-derived MVs that were internalized by HepG2 cells. Toxigenic C. difficile-derived MVs decreased mitochondrial membrane potential and increased intracellular ROS compared to non-toxigenic C. difficile-derived MVs. In addition, toxigenic C. difficile-derived MVs upregulated the expression of genes related to mitochondrial fission (FIS1 and DRP1), antioxidant status (GPX1), apoptosis (CASP3), glycolysis (HK2, PDK1, LDHA and PKM2) and ß-oxidation (CPT1A), as well as anti- and pro-inflammatory genes (IL-6 and IL-10). However, non-toxigenic C. difficile-derived MVs did not produce changes in the expression of these genes, except for CPT1A, which was also increased. In conclusion, the metabolic and mitochondrial changes produced by MVs obtained from toxigenic C. difficile present in CDI feces are common pathophysiological features observed in the NAFLD spectrum and DILI.

Hypertension and hypercholesterolemia are predictive factors associated with type 2 diabetes persistence after metabolic surgery: A prospective study.

BACKGROUND: Metabolic surgery is the most effective therapeutic strategy for the management of type 2 diabetes (T2DM). Several preoperative clinical factors have been associated with T2DM remission after metabolic surgery. However, other potential predictors remain unexplored. AIM: To assess the role of basal (pre-surgery) clinical and biochemical parameters in T2DM remission after metabolic surgery. METHODS: A prospective study including 98 patients with T2DM undergoing metabolic surgery was performed. Clinical, anthropometric, and biochemical data were collected at baseline and 1 year following metabolic surgery. RESULTS: Patients without T2DM remission 1 year after metabolic surgery presented a longer duration of diabetes and higher glycated hemoglobin (HbA1c) levels; a higher percentage of these subjects were using insulin therapy, antihypertensive drugs, and lipid-lowering therapies before metabolic surgery, compared to those patients with T2DM remission. A lower percentage of T2DM remission after metabolic surgery was observed among patients with hypertension/hypercholesterolemia before surgery, compared to those patients without hypertension/hypercholesterolemia (51.7 % vs 86.8 %, p < 0.001, and 38.5 % vs 75 %, p < 0.001, respectively), and among patients with longer duration of diabetes (≥5 years vs <5 years; 44.4 % vs 83 %, respectively; p < 0.001). In the logistic regression model, diabetes duration, basal HbA1c, and the presence of hypertension and hypercholesterolemia before surgery were inversely related to T2DM remission following metabolic surgery, after adjusting for sex, age, waist circumference, and type of surgery. CONCLUSIONS: In a cohort of patients with obesity and T2DM, preoperative hypertension and hypercholesterolemia, together with a longer diabetes duration and higher HbA1c concentrations, were independent predictors of T2DM persistence after metabolic surgery.

Comparison of the Use of Desflurane vs. Propofol in Aortic Valve Replacement Surgery: Differences in Nephroprotection: An Explorative and Hypothesis-Generating Study.

Introduction: The cardioprotective effect of halogenated drugs in cardiac surgery has been the subject of several studies. However, there is scarcity of data on their potential nephroprotective effects. Aortic valve replacement and coronary revascularization are the most frequent cardiac surgery procedures. The objective of this explorative study was to examine the effect of desflurane vs. propofol on renal function, when administered in aortic valve replacement surgery, including the extracorporeal circulation period. Method: A quasi-experimental prospective study was performed in 60 patients, who were allocated to receive either desflurane or propofol intraoperatively during aortic valve replacement surgery. As a hypnotic, group 1 received propofol, whereas group 2 received desflurane. Markers of renal function and level of cardiac preservation were determined based on biochemical parameters (troponin I, NTProBNP). Results: In the propofol group, there were significant variations between postoperative values of urinary NGAL and creatinine and baseline values. In contrast, no variations were found in the desflurane group in terms of hemodynamic parameters and myocardial damage. Conclusions: The use of propofol vs. desflurane during aortic valve replacement surgery is associated with a decrease in renal function.

Evaluation of Adipose Tissue Zinc-Alpha 2-Glycoprotein Gene Expression and Its Relationship with Metabolic Status and Bariatric Surgery Outcomes in Patients with Class III Obesity.

Zinc-α2 glycoprotein (ZAG) is an adipokine involved in adipocyte metabolism with potential implications in the pathogenesis of metabolic disorders. Our aim was to evaluate the relationship between visceral (VAT) and subcutaneous adipose tissue (SAT) ZAG expression and metabolic parameters in patients with class III obesity, along with the impact of basal ZAG expression on short- and medium-term outcomes related to bariatric surgery. 41 patients with class III obesity who underwent bariatric surgery were included in this study. ZAG gene expression was quantified in SAT and VAT. Patients were classified into two groups according to SAT and VAT ZAG percentile. Anthropometric and biochemical variables were obtained before and 15 days, 45 days, and 1 year after surgery. The lower basal SAT ZAG expression percentile was associated with higher weight and waist circumference, while the lower basal VAT ZAG expression percentile was associated with higher weight, waist circumference, insulin, insulin resistance, and the presence of metabolic syndrome. Basal SAT ZAG expression was inversely related to weight loss at 45 days after surgery, whereas no associations were found between basal VAT ZAG expression and weight loss after surgery. Additionally, a negative association was observed between basal SAT and VAT ZAG expression and the decrease of gamma-glutamyl transferase after bariatric surgery. Therefore, lower SAT and VAT ZAG expression levels were associated with an adverse metabolic profile. However, this fact did not seem to confer worse bariatric surgery-related outcomes. Further research is needed to assess the clinical significance of the role of ZAG expression levels in the dynamics of hepatic enzymes after bariatric surgery.

Synergic effect of metabolic syndrome and lipodystrophy on oxidative stress and inflammation process in treated HIV-patients.

The aim of this study was to assess the effect of lipodystrophy (LD) associated to metabolic syndrome (MS) on oxidative stress and inflammation in a cohort of 243 HIV-infected patients with MS, all of them under three different antiretroviral regimens. We collected immunovirological, biochemical and metabolic data, as well as anthropometric measurements. In addition, cardiovascular risk was also assessed by means of Atherogenic Index of Plasma (API) and Framingham Risk Score. The MS-LD patient set was characterized by a lower initial lymphocyte CD4 count and CD4/CD8 ratio and a higher initial viral load than the group without LD. We also found worse lipidic and glycaemic profiles (with lower HDL-cholesterol and higher triglyceride and glucose levels) in the MS-LD group. BMI, systolic blood pressure and Framingham score were significantly increased compared to MS-Non LD. In addition, patients with MS and LD had significantly higher levels of carbonylated proteins, lipid peroxidation, IL-6 and IL-8, as well as a significant decrease in the levels of leptin, adiponectin and antioxidant activities of catalase, super oxide dismutase and glutathione associated enzymes. In MS-LD HIV-1 patients, a significant negative correlation was found between Framingham Risk Score and the antioxidant biomarkers, however a positive association was found between API and protein-C reactive and carbonylated proteins. Segregating by ART, the above-mentioned conditions were worse within the MS-LD group whose treatment contained protease inhibitors, such as lopinavir. In conclusion, HIV-1 infected patients treated for at least six months, especially with regimens including PIs, showed a worsening of inflammatory process and oxidative stress.

Synergic effect of metabolic syndrome and lipodystrophy on oxidative stress and inflammation process in treated HIV-patients / Efecto sinérgico del síndrome metabólico y la lipodistrofia en el estrés oxidativo y el proceso de inflamación en pacientes con VIH que reciben tratamiento

The aim of this study was to assess the effect of lipodystrophy (LD) associated to metabolic syndrome (MS) on oxidative stress and inflammation in a cohort of 243 HIV-infected patients with MS, all of them under three different antiretroviral regimens. We collected immunovirological, biochemical and metabolic data, as well as anthropometric measurements. In addition, cardiovascular risk was also assessed by means of Atherogenic Index of Plasma (API) and Framingham Risk Score. The MS-LD patient set was characterized by a lower initial lymphocyte CD4 count and CD4/CD8 ratio and a higher initial viral load than the group without LD. We also found worse lipidic and glycaemic profiles (with lower HDL-cholesterol and higher triglyceride and glucose levels) in the MS-LD group. BMI, systolic blood pressure and Framingham score were significantly increased compared to MS-Non LD. In addition, patients with MS and LD had significantly higher levels of carbonylated proteins, lipid peroxidation, IL-6 and IL-8, as well as a significant decrease in the levels of leptin, adiponectin and antioxidant activities of catalase, super oxide dismutase and glutathione associated enzymes. In MS-LD HIV-1 patients, a significant negative correlation was found between Framingham Risk Score and the antioxidant biomarkers, however a positive association was found between API and protein-C reactive and carbonylated proteins. Segregating by ART, the above-mentioned conditions were worse within the MS-LD group whose treatment contained protease inhibitors, such as lopinavir. In conclusion, HIV-1 infected patients treated for at least six months, especially with regimens including PIs, showed a worsening of inflammatory process and oxidative stress.(AU)

El objetivo de este estudio fue evaluar el efecto de la lipodistrofia (LD) asociada al síndrome metabólico (SM) en el estrés oxidativo y la inflamación en una cohorte de 243 pacientes con VIH y SM, todos en tratamiento con pautas antirretrovirales diferentes. Recopilamos datos inmunovirológicos, bioquímicos y metabólicos, así como medidas antropométricas. Además, el riesgo cardiovascular también se evaluó mediante el índice de plasma aterogénico (API) y la puntuación de riesgo de Framingham. El grupo de pacientes con SM-LD se caracterizó por un recuento inicial de linfocitos CD4 y una relación CD4/CD8 inferiores y una carga vírica inicial más alta que el grupo sin LD. También observamos peores perfiles lipídicos y glucémicos (con menor colesterol HDL y niveles más altos de triglicéridos y glucosa) en el grupo de SM-LD. El IMC, la presión arterial sistólica y la puntuación de Framingham aumentaron significativamente en comparación con el grupo de SM-sin LD. Además, los pacientes con SM y LD tenían niveles significativamente más altos de proteínas carboniladas, peroxidación lipídica, IL-6 e IL-8, así como una disminución significativa de los niveles de leptina, adiponectina y actividades antioxidantes de la catalasa, superóxido dismutasa y enzimas asociadas al glutatión. En los pacientes con SM-LD VIH-1, se observó una correlación negativa significativa entre la puntuación de riesgo de Framingham y los biomarcadores antioxidantes, sin embargo, se observó una asociación positiva entre el API y la proteína C reactiva y las proteínas carboniladas. Al segregarse por ART, las condiciones mencionadas anteriormente fueron peores en el grupo de SM-LD, cuyo tratamiento incluía inhibidores de la proteasa, como el lopinavir. En conclusión, los pacientes con VIH-1 tratados durante al menos seis meses, especialmente con pautas que incluían IP, mostraron un empeoramiento del proceso inflamatorio y el estrés oxidativo.(AU)

EVOO Promotes a Less Atherogenic Profile Than Sunflower Oil in Smooth Muscle Cells Through the Extracellular Vesicles Secreted by Endothelial Cells.

Background: Little is known about the effect of extra virgin olive (EVOO) and sunflower oil (SO) on the composition of extracellular vesicles (EVs) secreted by endothelial cells and the effects of these EVs on smooth muscle cells (SMCs). These cells play an important role in the development of atherosclerosis. Methods: We evaluated the effects of endothelial cells-derived EVs incubated with triglyceride-rich lipoproteins obtained after a high-fat meal with EVOO (EVOO-EVs) and SO (SO-EVs), on the transcriptomic profile of SMCs. Results: We found 41 upregulated and 19 downregulated differentially expressed (DE)-miRNAs in EVOO-EVs. Afterwards, SMCs were incubated with EVOO-EVs and SO-EVs. SMCs incubated with SO-EVs showed a greater number of DE-mRNA involved in pathways related to cancer, focal adhesion, regulation of actin cytoskeleton, and MAPK, toll-like receptor, chemokine and Wnt signaling pathways than in SMCs incubated with EVOO-EVs. These DE-mRNAs were involved in biological processes related to the response to endogenous stimulus, cell motility, regulation of intracellular signal transduction and cell population proliferation. Conclusion: EVOO and SO can differently modify the miRNA composition of HUVEC-derived EVs. These EVs can regulate the SMCs transcriptomic profile, with SO-EVs promoting a profile more closely linked to the development of atherosclerosis than EVOO-EVs.

Morbid Obesity in Women Is Associated with an Altered Intestinal Expression of Genes Related to Cancer Risk and Immune, Defensive, and Antimicrobial Response.

BACKGROUND: Little is known about the relation between morbid obesity and duodenal transcriptomic changes. We aimed to identify intestinal genes that may be associated with the development of obesity regardless of the degree of insulin resistance (IR) of patients. MATERIAL AND METHODS: Duodenal samples were assessed by microarray in three groups of women: non-obese women and women with morbid obesity with low and high IR. RESULTS: We identified differentially expressed genes (DEGs) associated with morbid obesity, regardless of IR degree, related to digestion and lipid metabolism, defense response and inflammatory processes, maintenance of the gastrointestinal epithelium, wound healing and homeostasis, and the development of gastrointestinal cancer. However, other DEGs depended on the IR degree. We mainly found an upregulation of genes involved in the response to external organisms, hypoxia, and wound healing functions in women with morbid obesity and low IR. CONCLUSIONS: Regardless of the degree of IR, morbid obesity is associated with an altered expression of genes related to intestinal defenses, antimicrobial and immune responses, and gastrointestinal cancer. Our data also suggest a deficient duodenal immune and antimicrobial response in women with high IR.

Predictive Role of Gut Microbiota in Weight Loss Achievement after Bariatric Surgery.

BACKGROUND: Bariatric surgery induces changes in gut microbiota that have been suggested to contribute to weight loss and metabolic improvement. However, whether preoperative gut microbiota composition could predict response to bariatric surgery has not yet been elucidated. STUDY DESIGN: Seventy-six patients who underwent sleeve gastrectomy were classified according to the percentage of excess weight loss (%EWL) 1 year after surgery in the responder group: >50%EWL (n=50) and the nonresponder group: <50%EWL (n=26). Patients were evaluated before surgery, and 3 months and 1 year after surgery. Gut microbiota composition was analyzed before surgery (n=76) and 3 months after bariatric surgery (n=40). RESULTS: Diversity analysis did not show differences between groups before surgery or 3 months after surgery. Before surgery, there were differences in the abundance of members belonging to Bacteroidetes and Firmicutes phyla (nonresponder group: enriched in Bacteroidaceae, Bacteroides, Bacteroides uniformis, Alistipes finegoldii, Alistipes alistipes, Dorea formicigenerans, and Ruminococcus gnavus. Responder group: enriched in Peptostreptococcaceae, Gemmiger, Gemiger formicilis, Barnesiella, Prevotellaceae, and Prevotella; linear discriminant analysis >2; p < 0.05). Prevotella-to-Bacteroides ratio was significantly lower in the nonresponder group compared to the responder group (p = 0.048). After surgery, the responder group showed an enrichment in taxa that have been shown to have beneficial effects on host metabolism. Before surgery, PICRUSt analysis showed an enrichment in pathways involved in the biosynthesis components of the O-antigen polysaccharideunits in lipopolysaccharides in the nonresponder group. CONCLUSIONS: Preoperative gut microbiota could have an impact on bariatric surgery outcomes. Prevotella-to-Bacteroides ratio could be used as a predictive tool for weight loss trajectory. Early after surgery, patients who experienced successful weight loss showed an enrichment in taxa related to beneficial effects on host metabolism.

Oxidized LDL Increase the Proinflammatory Profile of Human Visceral Adipocytes Produced by Hypoxia.

BACKGROUND: Little is known about the effects of hypoxia on scavenger receptors (SRs) levels in adipocytes. We analyzed the effect of morbid obesity and hypoxia on SRs and inflammation markers in human visceral adipocytes and whether ox-LDL modify the inflammatory profile produced by hypoxia. METHODS: We studied in 17 non-obese and 20 subjects with morbid obesity (MO) the mRNA expression of HIF-1α, SRs (LOX-1, MSR1, CL-P1 and CXCL16), IL6 and TNFα in visceral adipocytes and the effect of hypoxia with or without ox-LDL on visceral in vitro-differentiated adipocytes (VDA). RESULTS: HIF-1α, TNFα, IL6, LOX-1, MSR1 and CXCL16 expression in adipocytes was increased in MO when compared with those in non-obese subjects (p < 0.05). The expression of most of the inflammatory markers and SRs gene correlated with HIF-1α. In VDA, hypoxia increased TNFα, IL6, MSR1, CXCL16 and CL-P1 (p < 0.05) in non-obese subjects, and TNFα, IL6, MSR1 and CXCL16 (p < 0.05) in MO. Silencing HIF-1α prevented the increase of TNFα, IL6, LOX-1, MSR1, CL-P1 and CXCL16 expression (p < 0.05). The combination of hypoxia and ox-LDL produced higher TNFα expression (p = 0.041). CONCLUSIONS: Morbid obesity and hypoxia increased SRs and inflammatory markers in visceral adipocytes. In a hypoxic state, ox-LDL increased the proinflammatory response of visceral adipocytes to hypoxia.

Different Weight Loss Intervention Approaches Reveal a Lack of a Common Pattern of Gut Microbiota Changes.

Options for treatment of obesity include dietary approaches and bariatric surgery. Previous studies have shown that weight loss interventions have an impact on gut microbiota. However, a pattern of gut microbiota changes associated with weight loss independently of the type of intervention has not been described yet. This study includes 61 individuals who followed different weight loss strategies in three different trials: 21 followed a hypocaloric Mediterranean diet (MedDiet), 18 followed a very-low-calorie ketogenic diet (VLCKD) and 22 patients underwent sleeve gastrectomy bariatric surgery (BS). Gut microbiota profile was assessed by next-generation sequencing. A common taxon that had significantly changed within the three weight loss interventions could not be find. At the family level, Clostiridiaceae significantly increased its abundance with MedDiet and VLCKD, whilst Porphyromonadacean and Rikenellaceae significantly increased with VLCKD and BS. At genus level, in VLCKD and BS, Parabacteroides and Alistipes significantly increased their abundance whilst Lactobacillus decreased. At the species level, BS and VLCKD produced an increase in Parabacteroidesdistasonis and a decrease in Eubactieriumventriosum and Lactobacillusrogosae, whilst Orodibactersplanchnicus increased its abundance after the BS and MedDiet. Predicted metagenome analysis suggested that most of the changes after VLCKD were focused on pathways related to biosynthesis and degradation/utilization/assimilation, while BS seems to decrease most of the biosynthesis pathways. MedDiet was enriched in several pathways related to fermentation to short-chain fatty acids. Our results show that weight loss is not associated with a specific pattern of gut microbiota changes independently of the strategy used. Indeed, gut microbiota changes according to type of weight loss intervention.

Synergic effect of metabolic syndrome and lipodystrophy on oxidative stress and inflammation process in treated HIV-patients.

The aim of this study was to assess the effect of lipodystrophy (LD) associated to metabolic syndrome (MS) on oxidative stress and inflammation in a cohort of 243 HIV-infected patients with MS, all of them under three different antiretroviral regimens. We collected immunovirological, biochemical and metabolic data, as well as anthropometric measurements. In addition, cardiovascular risk was also assessed by means of Atherogenic Index of Plasma (API) and Framingham Risk Score. The MS-LD patient set was characterized by a lower initial lymphocyte CD4 count and CD4/CD8 ratio and a higher initial viral load than the group without LD. We also found worse lipidic and glycaemic profiles (with lower HDL-cholesterol and higher triglyceride and glucose levels) in the MS-LD group. BMI, systolic blood pressure and Framingham score were significantly increased compared to MS-Non LD. In addition, patients with MS and LD had significantly higher levels of carbonylated proteins, lipid peroxidation, IL-6 and IL-8, as well as a significant decrease in the levels of leptin, adiponectin and antioxidant activities of catalase, super oxide dismutase and glutathione associated enzymes. In MS-LD HIV-1 patients, a significant negative correlation was found between Framingham Risk Score and the antioxidant biomarkers, however a positive association was found between API and protein-C reactive and carbonylated proteins. Segregating by ART, the above-mentioned conditions were worse within the MS-LD group whose treatment contained protease inhibitors, such as lopinavir. In conclusion, HIV-1 infected patients treated for at least six months, especially with regimens including PIs, showed a worsening of inflammatory process and oxidative stress.

Influence of Obesity in the miRNome: miR-4454, a Key Regulator of Insulin Response Via Splicing Modulation in Prostate.

CONTEXT: Obesity is a major health problem associated with severe comorbidities, including type 2 diabetes and cancer, wherein microRNAs (miRNAs) might be useful as diagnostic/prognostic tools or therapeutic targets. OBJECTIVE: To explore the differential expression pattern of miRNAs in obesity and their putative role in obesity-related comorbidities such as insulin resistance. METHODS: An Affymetrix-miRNA array was performed in plasma samples from normoweight (n = 4/body mass index < 25) and obese subjects (n = 4/body mass index > 30). The main changes were validated in 2 independent cohorts (n = 221/n = 18). Additionally, in silico approaches were performed and in vitro assays applied in tissue samples and prostate (RWPE-1) and liver (HepG2) cell-lines. RESULTS: A total of 26 microRNAs were altered (P < 0.01) in plasma of obese subjects compared to controls using the Affymetrix-miRNA array. Validation in ampler cohorts revealed that miR-4454 levels were consistently higher in obesity, associated with insulin-resistance (Homeostatic Model Assessment of Insulin Resistance/insulin) and modulated by medical (metformin/statins) and surgical (bariatric surgery) strategies. miR-4454 was highly expressed in prostate and liver tissues and its expression was increased in prostate and liver cells by insulin. In vitro, overexpression of miR-4454 in prostate cells resulted in decreased expression levels of INSR, GLUT4, and phosphorylation of AMPK/AKT/ERK, as well as in altered expression of key spliceosome components (ESRP1/ESRP2/RBM45/RNU2) and insulin-receptor splicing variants. CONCLUSIONS: Obesity was associated to an alteration of the plasmatic miRNA landscape, wherein miR-4454 levels were higher, associated with insulin-resistance and modulated by obesity-controlling interventions. Insulin regulated miR-4454, which, in turn may impair the cellular response to insulin, in a cell type-dependent manner (i.e., prostate gland), by modulating the splicing process.

NGS of microRNAs Involved in Cardioprotection Induced by Sevoflurane Compared to Propofol in Myocardial Revascularization Surgery: The ACDHUVV-16 Clinical Trial.

BACKGROUND: Numerous studies have demonstrated that halogenated agents elicit myocardial conditioning effects when administered perioperatively in cardiac surgery. Recent evidence has been published on the benefits of maintaining exposure to halogenated agents during the early postoperative period. The enzymatic mechanisms by which this beneficial effect is exerted were explained recently. OBJECTIVES: Our study was performed to investigate whether this phenomenon is mediated by either the activation or suppression of miRNAs targeted by halogenated anesthetics. METHODS: A double-blind, two-stage trial was conducted. The results of the first stage of the trial are presented in this paper. The sample was composed of patients undergoing off-pump myocardial revascularization surgery. Patients were randomized to receive either sevoflurane [S] or propofol [P] during the intraoperative and early postoperative period (during the first six hours after the intervention). Hemodynamics (heart rate, blood pressure, central venous pressure, cardiac index, systolic volume index, LVEF) and myocardial enzymes (troponin I) were monitored at six hour intervals during the first 48 hours. In the first stage of the trial, blood was drawn for gene sequencing from eight patients (four per group) at baseline and at 24 h. In the second stage of the study, a qPCR analysis was performed of the miRNAs identified as significant by gene sequencing. Levels of cardioprotective enzymes (serine/threonine protein kinase (Akt), tumor necrosis factor alpha (TNFα), extracellular regulated protein kinase (ERK 1/2), and caspase 3) were measured to assess their role in myocardial conditioning pathways. The purpose was to identify the miRNAs that play a major role in myocardial conditioning induced by halogenated agents. Concentrations of cardioprotective enzymes were higher in patients who received sevoflurane than the patients who were administered propofol. RESULTS: NGS differences were observed between baseline and 24-h values in the two study groups. In group P, miRNA 197-3p was overexpressed, whereas miRNAs 4443 and 1294, 708-3p were underexpressed. In group S, miRNAs 615-3p, 4466, 29, 937-3p, 636, 197-3P, 184, 4685, 296-3p, 147b, 3199, 6815, 1294 and 3176 were underexpressed; whereas 708-3p was overexpressed. qPCR showed significant variations in miRNAs 197-3p, 4443, 708-3p and 1294 in the P group, and in miRNAs 937-3p, 636, 197- 3p, 296-3p and 708-3p in the S group. CONCLUSION: In the P Group, changes in the expression of some miRNAs were associated with lower concentrations of the enzymes involved in myocardial pre- and postconditioning. In contrast, in Group S, variations in miRNAs were associated with the activation of mediators of anesthetic-induced pre- and post-conditioning, a reduction in cell apoptosis, and a decrease in caspase and TnBF alpha concentrations. Changes in these miRNAs were associated with better prognosis in patients with ischemic heart disease. The main limitation of this study will be overcome in the second stage of the trial, where the specific role of each miRNA will be determined.

Variables Associated with Short-Term Weight Loss in a Cohort of Patients with Morbid Obesity According to Age and Three Types of Bariatric Surgery.

Background The percentage of excess weight lost (%EWL) after bariatric surgery (BS) shows great discrepancies from one individual to another. Objective To evaluate the %EWL one year after BS and to determine the existence of baseline biomarkers associated with weight loss. Methods We studied 329 patients with morbid obesity undergoing three types of BS (biliopancreatic diversion (BPD), Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG)), depending on the %EWL one year after surgery: good responders (GR) (%EWL≥50%) and non-responders (NR) (%EWL <50%). Results The GR presented a higher percentage of change in anthropometric and biochemical variables compared to the NR group, even within each type of BS. There was a greater percentage of GR among those who underwent RYGB. The patients who underwent SG showed the lowest decrease in biochemical variables, both in GR and NR. Within the GR group, those with a lower age showed greater improvement compared to the other age groups. A %EWL ≥50% was negatively associated with the age and atherogenic index of plasma (AIP), and positively with the type of BS (RYGB). Conclusions The GR group was associated with lower age and AIP and undergoing RYGB. Additionally, those patients who underwent SG showed a lower metabolic improvement.