Dietary weight loss intervention improves subclinical atherosclerosis and oxidative stress markers in leukocytes of obese humans.

BACKGROUND: The relationship between caloric restriction-mediated weight loss and the generation of ROS and its effects on atherosclerotic markers in obesity is not fully understood. Therefore, we set out to investigate whether dietary weight loss intervention improves markers of oxidative stress in leukocytes and subclinical parameters of atherosclerosis. SUBJECTS AND METHODS: This was an interventional study of 59 obese subjects (BMI > 35 kg/m2) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical parameters, inflammatory markers-hsCRP, TNFα and NFκB -, oxidative stress parameters-total superoxide, glutathione, catalase activity and protein carbonyl groups-, soluble cellular adhesion molecules-sICAM, sP-selectin, sPSGL-1 -, myeloperoxidase (MPO), leukocyte-endothelium cell interactions-rolling flux, velocity and adhesion-and LDL subfractions, before and after the dietary intervention. RESULTS: After losing weight, an improvement was observed in the patients' anthropometric, blood pressure and metabolic parameters, and was associated with reduced inflammatory response (hsCRP, TNFα and NFκB). Oxidative stress parameters improved, since superoxide production and protein carbonyl content were reduced and antioxidant systems were enhanced. In addition, a significant reduction of subclinical markers of atherosclerosis-small and dense LDL particles, MPO, sP-selectin and leukocyte adhesion-and an increase in soluble PSGL-1 were reported. CONCLUSIONS: Our findings reveal that the improvement of subclinical atherosclerotic markers after dietary weight loss intervention is associated with a reduction of oxidative stress in leukocytes and inflammatory pathways, suggesting that these are the underlying mechanisms responsible for the reduced risk of cardiovascular disease in obese subjects after losing weight.

Frailty and physical function in older HIV-infected adults.

Background and Objectives: HIV patients have seen accelerated ageing. Our objective was to determine the prevalence of frailty, to evaluate factors associated with frailty and to evaluate physical function in older HIV-infected adults. Design: this was a cross-sectional study. Setting: outpatient clinics of two public university hospitals in Madrid (Spain). Methods: frailty was defined according to the criteria of Fried: shrinking, weakness, poor endurance and energy, slowness and low physical activity level, being frail those who met at least three criteria, prefrail one or two criteria and robust when they met no criteria. Physical function was assessed using standardised methods. Results: we evaluated 117 HIV-infected patients. Mean age was 61.3 ([standard deviation] 6.87) years. All patients were on antiretroviral therapy. Median current CD4+ T-cell count was 638 (144-1871) cells/µl, and median CD4/CD8 ratio was 0.79 (0.00-3.62). The prevalence of frailty was 15.4%, and that of prefrailty was 52.1%. In the multivariate analyses depressive symptoms (OR [95% CI], 9.20 [2.17-39.05]) and CD4/CD8 ratio (OR 0.11 [0.02-0.61]) were associated with frailty. Even though 100% of the patients were able to walk and perform basic activities of daily life independently, functional impairment was high (20% slow gait and 55% Short Physical Performance Battery ≤9). Conclusions: HIV-infected patients aged ≥55 years have a high prevalence of frailty and a high burden of functional impairment. Optimal management of this population requires close collaboration between infectious diseases specialists and geriatricians.

High Dialysate Calcium Concentration May Cause More Sympathetic Stimulus During Hemodialysis.

BACKGROUND/AIMS: Acute activation of sympathetic activation during hemodialysis is essential to maintain blood pressure (BP), albeit long-term overactivity contributes to higher mortality. Low heart rate variability (HRV), a measure of autonomic nervous system activity, and abnormal ankle-brachial index (ABI) are associated with higher mortality in patients on hemodialysis. In this study, we assessed HRV and ABI pre and post dialysis in incident patients on hemodialysis using high (1.75mmol/l) and low (1.25mmol/l) dialysate calcium concentration (DCa). METHODS: HRV was measured as the ratio between low frequency and high frequency power (LF/HF). Thirty patients (age 47±16 years, 67% men) were studied in two consecutive mid-week hemodialysis sessions. RESULTS: Mean BP variation was positive with DCa 1.75 and negative with DCa 1.25 [4.0 (-6.0, 12.2 mmHg) vs. -3.2 (-9.8, 1.3 mmHg); p=0.050]. Reduction of ABI from pre to post HD was related to higher sympathetic activity (p=0.031). The increase in LF/HF ratio was higher with DCa 1.75 (58.3% vs. 41.7% in DCa 1.75 and 1.25, respectively, RR 2.8; p=0.026). CONCLUSION: Although higher DCa is associated with better hemodynamic tolerability during hemodialysis, this occurs at the expense of increased sympathetic activity. Higher sympathetic activity was associated with a decrease of ABI during hemodialysis.

Gingival inflammation and leukocyte-endothelium cell interactions in women with polycystic ovary syndrome.

BACKGROUND: Given the link between chronic inflammation and periodontal pathologies and increased cardiovascular risk, this study aims to investigate if gingivitis exacerbates the inflammatory response and subclinical atherosclerotic markers in women with polycystic ovary syndrome (PCOS). METHODS: For this case-control study, women were assigned to three groups: two PCOS groups (with and without gingivitis) and a control group. Anthropometric and biochemical variables were determined, along with periodontal parameters (probing pocket depth [PPD], clinical attachment level [CAL], bleeding on probing [BOP], plaque index, calculus index, and tooth loss), systemic and neutrophil inflammatory markers (tumor necrosis factor alpha [TNFα], C-reactive protein [CRP], and c-Jun N-terminal kinase [JNK]), systemic oxidative stress mediators (myeloperoxidase [MPO] and glutathione), soluble cellular adhesion molecules, and neutrophil-endothelium cell interactions (rolling flux, velocity, and adhesion). RESULTS: Of 104 women recruited, 68 had PCOS, 24 of whom presented gingivitis, and 36 were controls. PCOS patients presented altered sexual hormone, lipid, and carbohydrate profiles. Levels of systemic inflammatory markers, MPO, and soluble platelet selectin (sP-selectin) were higher, and glutathione levels were lower in PCOS patients. BOP, plaque, and calculus index values were higher in PCOS patients with gingivitis. Neutrophils from PCOS patients showed increased JNK and decreased adhesion under flow conditions, with reduced rolling velocity and increased rolling flux and cellular adhesion, all of which were more pronounced in those with gingivitis. BOP was independently associated with rolling velocity, rolling flux, and cellular adhesion. CONCLUSION: Neutrophils of PCOS patients with gingivitis exhibit hyperactivity, promoting interaction with the endothelium and potentially contributing to atherosclerotic disease. PLAIN LANGUAGE SUMMARY: Currently, there is a high prevalence of diseases that affect tooth-supporting tissues (periodontal diseases) and negatively influence the oral health and quality of life of the adult population. These pathologies lead to movement of the teeth and impairment of chewing function, eventually resulting in the loss of teeth. In recent years, the concept of periodontal medicine has arisen and consists of studying how periodontal diseases can influence our general inflammatory system and how systemic inflammatory pathologies can affect our oral health. In the present study, we evaluate a group of women with polycystic ovary syndrome (PCOS), a condition characterized by alterations of sex hormones and lipid profile and weight gain (body mass index). Our results show a high prevalence of gum inflammation among women with PCOS, which affects the interaction of their leukocytes and endothelial cells. The leukocytes of these women are hyper-responsive, presenting greater endothelial adhesion, lower flow velocity and enhanced rolling compared to those in a PCOS group without gum inflammation or controls. This study has generated a new line of research to analyze how neutrophils from patients with gingivitis exhibit hyperactivity, which promotes their interaction with the endothelium, thus contributing to the development of atherosclerotic disease.

Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.

BACKGROUND: Although it is established that caloric restriction offers metabolic and clinical benefits, the molecular mechanisms underlying these effects remain unclear. Thus, this study aimed to investigate whether caloric restriction can modulate mitochondrial function and remodeling and stimulate autophagic flux in the PBMCs of patients with obesity. METHODS: This was an interventional study of 38 obese subjects (BMI >35 kg/m2) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical variables, mitochondrial function parameters (by fluorescence imaging of mitochondrial ROS and membrane potential), and protein expression of markers of mitochondrial dynamics (MNF1, MFN2, OPA, DRP1 and FIS1) and autophagy (LC3, Beclin, BCL2 and NBR1) by Western blot. RESULTS: Caloric restriction induced an improvement in metabolic outcomes that was accompanied by an increase in AMPK expression, a decrease of mitochondrial ROS and mitochondrial membrane potential, which was associated with increased markers of mitochondrial dynamics (MFN2, DRP1 and FIS1) and activation of autophagy as evidenced by augmented LC3 II/I, Beclin1 and NBR1, and a decrease in BCL2. CONCLUSION: These findings shed light on the specific molecular mechanisms by which caloric restriction facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis and cell recovery, including mitochondrial function and dynamics and autophagy.

When is the best moment to assess the ankle brachial index: pre- or post-hemodialysis?

BACKGROUND: Cardiovascular disease is an important cause of death in patients on dialysis. Peripheral arterial disease (PAD) is a prognostic factor for cardiovascular disease. The ankle brachial index (ABI) is a noninvasive method used for the diagnosis of PAD. The difference between ABI pre- and post-dialysis had not yet been formally tested, and it was the main objective of this study. METHODS: The ABI was assessed using an automated oscillometric device in incident patients on hemodialysis. All blood pressure readings were taken in triplicate pre- and post-dialysis in three consecutive dialysis sessions (times 1, 2, and 3). RESULTS: One hundred and twenty-three patients (85 men) aged 53 ± 19 years were enrolled. We found no difference in ABI pre- and post-dialysis on the right or left side, and there was no difference in times 1, 2, and 3. In patients with a history of PAD, the ABI pre- versus post-dialysis were of borderline significance on the right side (p = 0.088). CONCLUSION: ABI measured pre- and post-dialysis presented low variability. The ABI in patients with a history of PAD should be evaluated with caution. The applicability of the current method in predicting mortality among patients on hemodialysis therefore needs further investigation.

The Role of Mitochondrial Dynamic Dysfunction in Age-Associated Type 2 Diabetes.

Mitochondrial dynamics, such as fusion and fission, play a critical role in maintaining cellular metabolic homeostasis. The molecular mechanisms underlying these processes include fusion proteins (Mitofusin 1 [MFN1], Mitofusin 2 [MFN2], and optic atrophy 1 [OPA1]) and fission mediators (mitochondrial fission 1 [FIS1] and dynamin-related protein 1 [DRP1]), which interact with each other to ensure mitochondrial quality control. Interestingly, defects in these proteins can lead to the loss of mitochondrial DNA (mtDNA) integrity, impairment of mitochondrial function, a severe alteration of mitochondrial morphology, and eventually cell death. Emerging evidence has revealed a causal relationship between dysregulation of mitochondria dynamics and age-associated type 2 diabetes, a metabolic disease whose rates have reached an alarming epidemic-like level with the majority of cases (59%) recorded in men aged 65 and over. In this sense, fragmentation of mitochondrial networks is often associated with defects in cellular energy production and increased apoptosis, leading, in turn, to excessive reactive oxygen species release, mitochondrial dysfunction, and metabolic alterations, which can ultimately contribute to ß-cell dysfunction and insulin resistance. The present review discusses the processes of mitochondrial fusion and fission and their dysfunction in type 2 diabetes, with special attention given to the therapeutic potential of targeting mitochondrial dynamics in this complex metabolic disorder.

Impact of Roux-en-Y Gastric Bypass on Mitochondrial Biogenesis and Dynamics in Leukocytes of Obese Women.

The chronic low-grade inflammation widely associated with obesity can lead to a prooxidant status that triggers mitochondrial dysfunction. To date, Roux-en-Y gastric bypass (RYGB) is considered the most effective strategy for obese patients. However, little is known about its molecular mechanisms. This interventional study aimed to investigate whether RYGB modulates oxidative stress, inflammation and mitochondrial dynamics in the leukocytes of 47 obese women at one year follow-up. We evaluated biochemical parameters and serum inflammatory cytokines -TNFα, IL6 and IL1ß- to assess systemic status. Total superoxide production -dHe-, mitochondrial membrane potential -TMRM-, leucocyte protein expression of inflammation mediators -MCP1 and NF-kB-, antioxidant defence -GPX1-, mitochondrial regulation-PGC1α, TFAM, OXPHOS and MIEAP- and dynamics -MFN2, MNF1, OPA1, FIS1 and p-DRP1- were also determined. After RYGB, a significant reduction in superoxide and mitochondrial membrane potential was evident, while GPX1 content was significantly increased. Likewise, a marked upregulation of the transcription factors PGC1α and TFAM, complexes of the oxidative phosphorylation chain (I-V) and MIEAP and MFN1 was observed. We conclude that women undergoing RYGB benefit from an amelioration of their prooxidant and inflammatory status and an improvement in mitochondrial dynamics of their leukocytes, which is likely to have a positive effect on clinical outcome.

Metformin modulates mitochondrial function and mitophagy in peripheral blood mononuclear cells from type 2 diabetic patients.

Type 2 diabetes is a chronic metabolic disease that affects mitochondrial function. In this context, the rescue mechanisms of mitochondrial health, such as mitophagy and mitochondrial biogenesis, are of crucial importance. The gold standard for the treatment of type 2 diabetes is metformin, which has a beneficial impact on the mitochondrial metabolism. In this study, we set out to describe the effect of metformin treatment on mitochondrial function and mitophagy in peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients. We performed a preliminary cross-sectional observational study complying with CONSORT requirements, for which we recruited 242 subjects, divided into 101 healthy volunteers, 93 metformin-treated type 2 diabetic patients and 48 non-metformin-treated type 2 diabetic patients. Mitochondria from the type 2 diabetic patients not treated with metformin displayed more reactive oxygen species (ROS) than those from healthy or metformin-treated subjects. Protein expression of the electron transport chain (ETC) complexes was lower in PBMCs from type 2 diabetic patients without metformin treatment than in those from the other two groups. Mitophagy was altered in type 2 diabetic patients, evident in a decrease in the protein levels of PINK1 and Parkin in parallel to that of the mitochondrial biogenesis protein PGC1α, both of which effects were reversed by metformin. Analysis of AMPK phosphorylation revealed that its activation was decreased in the PBMCs of type 2 diabetic patients, an effect which was reversed, once again, by metformin. In addition, there was an increase in the serum levels of TNFα and IL-6 in type 2 diabetic patients and this was reversed with metformin treatment. These results demonstrate that metformin improves mitochondrial function, restores the levels of ETC complexes, and enhances AMPK activation and mitophagy, suggesting beneficial clinical implications in the treatment of type 2 diabetes.

Roux-en-Y Gastric Bypass Modulates AMPK, Autophagy and Inflammatory Response in Leukocytes of Obese Patients.

Obesity is characterized by low-grade chronic inflammation, metabolic overload, and impaired endothelial and cardiovascular function. Roux-en-Y gastric bypass (RYGB) results in amelioration of the pro-oxidant status of leukocytes and the metabolic profile. Nevertheless, little is known about the precise mechanism that drives systemic and metabolic improvements following bariatric surgery. In this cohort study, we investigated the effect of RYGB on molecular pathways involving energy homeostasis in leukocytes in 43 obese subjects one year after surgery. In addition to clinical and biochemical parameters, we determined protein expression of systemic proinflammatory cytokines by Luminex®, different markers of inflammation, endoplasmic reticulum (ER) stress, autophagy/mitophagy by western blot, and mitochondrial membrane potential by fluorescence imaging. Bariatric surgery induced an improvement in metabolic outcomes that was accompanied by a systemic drop in hsCRP, IL6, and IL1ß levels, and a slowing down of intracellular inflammatory pathways in leukocytes (NF-κB and MCP-1), an increase in AMPK content, a reduction of ER stress (ATF6 and CHOP), augmented autophagy/mitophagy markers (Beclin 1, ATG5, LC3-I, LC3-II, NBR1, and PINK1), and a decrease of mitochondrial membrane potential. These findings shed light on the specific molecular mechanisms by which RYGB facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis as key mediators of these outcomes. In addition, since leukocytes are particularly exposed to physiological changes, they could be used in routine clinical practice as a good sensor of the whole body's responses.

Does Metformin Modulate Mitochondrial Dynamics and Function in Type 2 Diabetic Patients?

Metformin is an effective drug against type 2 diabetes (T2D), a pathogenesis in which mitochondrial dysfunction is one of the main players. Thus, our first aim was to describe the effect of metformin on mitochondrial function in an outpatient population with T2D. For analyzing this hypothesis, we performed a preliminary cross-sectional study complying with the STROBE requirements. We studied leukocytes from 139 healthy controls, 39 T2D patients without metformin treatment, and 81 T2D patients who had been on said treatment for at least 1 year. Leukocytes from T2D patients displayed higher total and mitochondrial reactive oxygen species levels, lower mitochondrial membrane potential, and lower oxygen consumption. Moreover, their mitochondria expressed lower mRNA and protein levels of fusion proteins mitofusin-1 (MFN1), mitofusin-2 (MFN2), and optic atrophy 1 (OPA1), and higher protein and gene expression levels of mitochondrial fission protein 1 (FIS1) and dynamin-related protein 1 (DRP-1). In addition, we observed enhanced leukocyte/endothelial interactions in T2D patients. Metformin reversed most of these effects, ameliorating mitochondrial function and dynamics, and reducing the leukocyte/endothelial interactions observed in T2D patients. These results raise the question of whether metformin tackles T2D by improving mitochondrial dysfunction and regulating mitochondrial dynamics. Furthermore, it would seem that metformin modulates the alteration of interactions between leukocytes and the endothelium, a subclinical marker of early atherosclerosis. Antioxid. Redox Signal. 35, 377-385.

Characterization of Differentially Expressed Circulating miRNAs in Metabolically Healthy versus Unhealthy Obesity.

Obese individuals without metabolic comorbidities are categorized as metabolically healthy obese (MHO). MicroRNAs (miRNAs) may be implicated in MHO. This cross-sectional study explores the link between circulating miRNAs and the main components of metabolic syndrome (MetS) in the context of obesity. We also examine oxidative stress biomarkers in MHO vs. metabolically unhealthy obesity (MUO). We analysed 3536 serum miRNAs in 20 middle-aged obese individuals: 10 MHO and 10 MUO. A total of 159 miRNAs were differentially expressed, of which, 72 miRNAs (45.2%) were higher and 87 miRNAs (54.7%) were lower in the MUO group. In addition, miRNAs related to insulin signalling and lipid metabolism pathways were upregulated in the MUO group. Among these miRNAs, hsa-miR-6796-5p and hsa-miR-4697-3p, which regulate oxidative stress, showed significant correlations with glucose, triglycerides, HbA1c and HDLc. Our results provide evidence of a pattern of differentially expressed miRNAs in obesity according to MetS, and identify those related to insulin resistance and lipid metabolism pathways.

Microbiota-Mitochondria Inter-Talk: A Potential Therapeutic Strategy in Obesity and Type 2 Diabetes.

The rising prevalence of obesity and type 2 diabetes (T2D) is a growing concern worldwide. New discoveries in the field of metagenomics and clinical research have revealed that the gut microbiota plays a key role in these metabolic disorders. The mechanisms regulating microbiota composition are multifactorial and include resistance to stress, presence of pathogens, diet, cultural habits and general health conditions. Recent evidence has shed light on the influence of microbiota quality and diversity on mitochondrial functions. Of note, the gut microbiota has been shown to regulate crucial transcription factors, coactivators, as well as enzymes implicated in mitochondrial biogenesis and metabolism. Moreover, microbiota metabolites seem to interfere with mitochondrial oxidative/nitrosative stress and autophagosome formation, thus regulating the activation of the inflammasome and the production of inflammatory cytokines, key players in chronic metabolic disorders. This review focuses on the association between intestinal microbiota and mitochondrial function and examines the mechanisms that may be the key to their use as potential therapeutic strategies in obesity and T2D management.

Association between Proinflammatory Markers, Leukocyte-Endothelium Interactions, and Carotid Intima-Media Thickness in Type 2 Diabetes: Role of Glycemic Control.

Glycated hemoglobin monitorization could be a tool for maintaining type 2 diabetes (T2D) under control and delaying the appearance of cardiovascular events. This cross-sectional study was designed to assess the role of glycemic control in modulating early-stage markers of cardiovascular complications. One hundred and eight healthy controls and 161 type 2 diabetic patients were recruited and distributed according to their glycemic control, setting the threshold at 6.5% (good control). Biochemical and anthropometrical parameters were registered during the initial visit, and peripheral blood was extracted to obtain polymorphonuclear cells and analyze inflammatory markers, adhesion molecules, leukocyte-endothelium interactions, and carotid intima-media thickness. Correlations between these parameters were explored. We found that inflammatory markers and adhesion molecules were augmented in type 2 diabetic subjects with poor glycemic control. Polymorphonuclear leukocytes interacted more with the endothelium in the diabetic population, and even more significantly in the poorly controlled subjects. In parallel, carotid intima-media thickness was also increased in the diabetic population, and the difference was greater among poorly controlled subjects. Finally, correlation measurement revealed that carotid intima-media thickness was related to glycemic control and lipid metabolism in diabetic patients. Our results suggest that glycemic control delays the onset of cardiovascular comorbidities in diabetic subjects.

Mitochondrial Alterations and Enhanced Human Leukocyte/Endothelial Cell Interactions in Type 1 Diabetes.

Type 1 diabetes has been associated with oxidative stress. This study evaluates the rates of oxidative stress, mitochondrial function, leukocyte-endothelium interactions and adhesion molecules in type 1 diabetic patients. The study population consisted of 52 diabetic patients and 46 body-composition and age-matched controls. We assessed anthropometric and metabolic parameters, oxidative stress and mitochondrial function by evaluating reactive oxygen species (ROS) production, mitochondrial ROS production, mitochondrial membrane potential and superoxide dismutase (SOD) and catalase (CAT) expression in polymorphonuclear leukocytes from type 1 diabetic patients. In addition, we evaluated interactions between leukocytes and human umbilical vein endothelial cells (HUVEC), and serum expression of adhesion molecules (P-selectin, VCAM-1 and ICAM-1), proinflammatory cytokines (IL-6 and TNFα) and myeloperoxidase (MPO). HbA1C and glucose levels were higher in diabetic patients than in control subjects, as expected. Mitochondrial function was altered and leukocyte-endothelium interactions were enhanced in diabetic patients, which was evident in the increase in total and mitochondrial ROS production, higher mitochondrial membrane potential, enhanced leukocyte rolling and adhesion, and decreased rolling velocity. Furthermore, we observed an increase in levels of adhesion molecules P-selectin, VCAM-1, and ICAM-1 in these subjects. In addition, type 1 diabetic patients exhibited an increase in proinflammatory mediators TNFα and MPO, and a decreased expression of SOD. The enhancement of leukocyte-endothelium interactions and proinflammatory markers correlated with glucose and HbA1Clevels. Mitochondrial alteration, oxidative stress, and enhanced leukocyte-endothelium interactions are features of type 1 diabetes and may be related to cardiovascular implications.

Effect of Non-Surgical Periodontal Treatment on Oxidative Stress Markers in Leukocytes and Their Interaction with the Endothelium in Obese Subjects with Periodontitis: A Pilot Study.

AIM: The primary objective of this pilot study was to evaluate the effect of non-surgical periodontal treatment. The secondary aim was to evaluate the effect of dietary therapy on both parameters of oxidative stress in leukocytes and leukocyte-endothelial cell interactions in an obese population. METHODS: This was a pilot study with a before-and-after design. Forty-nine obese subjects with periodontitis were randomized by means of the minimization method and assigned to one of two groups, one of which underwent dietary therapy while the other did not. All the subjects underwent non-surgical periodontal treatment. We determined periodontal, inflammatory and oxidative stress parameters-total reactive oxygen species (ROS), superoxide production, intracellular Ca2+, mitochondrial membrane potential and superoxide dismutase (SOD) activity. We also evaluated interactions between leukocytes and endothelium cells-velocity, rolling flux and adhesion-at baseline and 12 weeks after intervention. RESULTS: Periodontal treatment improved the periodontal health of all the patients, with a reduction in serum retinol-binding protein 4 (RBP4), total superoxide production and cytosolic Ca2+ in leukocytes. In the patients undergoing dietary therapy, there were less leukocyte adhesion to the endothelium, an effect that was accompanied by a decrease in TNFα, P-selectin and total ROS and an increase in SOD activity. CONCLUSIONS: Whereas non-surgical periodontal treatment induces an improvement in leukocyte homeostasis, dietary therapy as an adjuvant reduces systemic inflammation and increases antioxidant status which, in turn, modulates leukocyte-endothelium dynamics.

Systemic Oxidative Stress and Visceral Adipose Tissue Mediators of NLRP3 Inflammasome and Autophagy Are Reduced in Obese Type 2 Diabetic Patients Treated with Metformin.

Obesity is a low-grade inflammatory condition affecting a range of individuals, from metabolically healthy obese (MHO) subjects to type 2 diabetes (T2D) patients. Metformin has been shown to display anti-inflammatory properties, though the underlying molecular mechanisms are unclear. To study whether the effects of metformin are mediated by changes in the inflammasome complex and autophagy in visceral adipose tissue (VAT) of obese patients, a biopsy of VAT was obtained from a total of 68 obese patients undergoing gastric bypass surgery. The patients were clustered into two groups: MHO patients and T2D patients treated with metformin. Patients treated with metformin showed decreased levels of all analyzed serum pro-inflammatory markers (TNFα, IL6, IL1ß and MCP1) and a downwards trend in IL18 levels associated with a lower production of oxidative stress markers in leukocytes (mitochondrial ROS and myeloperoxidase (MPO)). A reduction in protein levels of MCP1, NFκB, NLRP3, ASC, ATG5, Beclin1 and CHOP and an increase in p62 were also observed in the VAT of the diabetic group. This downregulation of both the NLRP3 inflammasome and autophagy in VAT may be associated with the improved inflammatory profile and leukocyte homeostasis seen in obese T2D patients treated with metformin with respect to MHO subjects and endorses the cardiometabolic protective effect of this drug.

Effect of Roux-en-Y Bariatric Bypass Surgery on Subclinical Atherosclerosis and Oxidative Stress Markers in Leukocytes of Obese Patients: A One-Year Follow-Up Study.

Little is known about the mechanisms underlying the cardioprotective effect of Roux en-Y gastric bypass (RYGB) surgery. Therefore, the aim of the present study was to investigate whether weight loss associated with RYGB improves the oxidative status of leukocytes and ameliorates subclinical atherosclerotic markers. This is an interventional study of 57 obese subjects who underwent RYGB surgery. We determined biochemical parameters and qualitative analysis of cholesterol, leukocyte and systemic oxidative stress markers -superoxide production, glutathione peroxidase 1 (GPX1), superoxide dismutase (SOD) activity and protein carbonylation-, soluble cellular adhesion molecules -sICAM-1 and sP-selectin-, myeloperoxidase (MPO) and leukocyte-endothelium cell interactions-rolling flux, velocity and adhesion. RYGB induced an improvement in metabolic parameters, including hsCRP and leukocyte count (p < 0.001, for both). This was associated with an amelioration in oxidative stress, since superoxide production and protein carbonylation were reduced (p < 0.05 and p < 0.01, respectively) and antioxidant systems were enhanced (GPX1; p < 0.05 and SOD; p < 0.01). In addition, a significant reduction of the following parameters was observed one year after RYGB: MPO and sICAM (p < 0.05, for both), sPselectin and pattern B of LDL particles (p < 0.001, for both), and rolling flux and adhesion of leukocytes (p < 0.05 and p < 0.01, respectively). Our results suggest that patients undergoing RYGB benefit from an amelioration of the prooxidant status of leukocytes, metabolic outcomes, and subclinical markers of atherosclerosis.

Relationship between PMN-endothelium interactions, ROS production and Beclin-1 in type 2 diabetes.

Type 2 diabetes is closely related to oxidative stress and cardiovascular diseases. In this study, we hypothesized that polymorphonuclear leukocytes (PMN)-endothelium interactions and autophagy are associated. We evaluated PMN-endothelial interactions, ROS production and autophagy parameters in 47 type 2 diabetic patients and 57 control subjects. PMNs from type 2 diabetic patients exhibited slower rolling velocity (p < 0.001), higher rolling flux (p < 0.001) and adhesion (p < 0.001) in parallel to higher levels of total (p < 0.05) and mitochondrial ROS (p < 0.05). When the protein expression of autophagy markers was analysed, an increase of Beclin-1 (p < 0.05), LC3I (p < 0.05), LC3II (p < 0.01) and LC3II/LC3I ratio (p < 0.05) was observed. Several correlations between ROS and leukocyte-endothelium parameters were found. Interestingly, in control subjects, an increase of Beclin-1 levels was accompanied by a decrease in the number of rolling (r = 0.561) and adhering PMNs (r = 0.560) and a rise in the velocity of the rolling PMNs (r = 0.593). In contrast, in the type 2 diabetic population, a rise in Beclin-1 levels was related to an increase in the number of rolling (r = 0.437), and adhering PMNs (r = 0.467). These results support the hypothesis that PMN-endothelium interactions, ROS levels and formation of autophagosomes, especially Beclin-1 levels, are enhanced in type 2 diabetes.

Frailty phenotype: a clinical marker of age acceleration in the older HIV-infected population.

AIM: To evaluate the association between DNA methylation and frailty in the HIV-infected population and to investigate the usefulness of assessing frailty as a clinical marker to identify age acceleration. METHODS: Frailty was assessed according to Fried's frailty phenotype. DNA methylation was analyzed in 10 frail patients, and compared with 10 robust control patients, all with HIV. Predicted age was inferred using the Weidner's formula. Age acceleration was assessed using the difference between predicted and chronological age. RESULTS: HIV-infected frail patients had significantly higher biological predicted ages than chronological ages (mean acceleration: 10.3 years; p = 0.012). CONCLUSIONS: We link age acceleration and frailty in an older HIV population. Frailty could be used in this population for implementing specific clinical approaches.