Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance in which oxidative stress is thought to be a primary cause. Considering that mitochondria are the ...main source of ROS, we have set out to provide a general overview on how oxidative stress is generated and related to T2D. Enhanced generation of reactive oxygen species (ROS) and oxidative stress occurs in mitochondria as a consequence of an overload of glucose and oxidative phosphorylation. Endoplasmic reticulum (ER) stress plays an important role in oxidative stress, as it is also a source of ROS. The tight interconnection between both organelles through mitochondrial-associated membranes (MAMs) means that the ROS generated in mitochondria promote ER stress. Therefore, a state of stress and mitochondrial dysfunction are consequences of this vicious cycle. The implication of mitochondria in insulin release and the exposure of pancreatic β-cells to hyperglycemia make them especially susceptible to oxidative stress and mitochondrial dysfunction. In fact, crosstalk between both mechanisms is related with alterations in glucose homeostasis and can lead to the diabetes-associated insulin-resistance status. In the present review, we discuss the current knowledge of the relationship between oxidative stress, mitochondria, ER stress, inflammation, and lipotoxicity in T2D.
Background
To evaluate the relationship between leukocyte‐endothelial cell interactions and oxidative stress parameters in non‐diabetic patients with different grades of obesity.
Material and methods
...For this cross‐sectional study, 225 subjects were recruited from January 1, 2014 to December 31, 2016 and divided into groups according to BMI (<30 kg/m2, 30‐40 kg/m2 and >40 kg/m²). We determined clinical parameters, systemic inflammatory markers, soluble cellular adhesion molecules, leukocyte‐endothelium cell interactions—rolling flux, velocity and adhesion—, oxidative stress parameters—total ROS, total superoxide, glutathione—and mitochondrial membrane potential in leukocytes.
Results
We verified that HOMA‐IR and hsCRP increased progressively as obesity developed, whereas A1c, IL6 and TNFα were augmented in the BMI > 40 kg/m² group. The cellular adhesion molecule sP‐selectin was increased in patients with obesity, while sICAM, total ROS, total superoxide and mitochondrial membrane potential were selectively higher in the BMI > 40 kg/m² group. Obesity induced a progressive decrease in rolling velocity and an enhancement of rolling flux and leukocyte adhesion.
Conclusion
Our findings reveal that endothelial dysfunction markers are altered in human obesity and are associated with proinflammatory cytokines and increased oxidative stress parameters.
Aim
The effect of dietary weight loss intervention on periodontal therapy is unknown. Therefore, we aimed to evaluate whether weight loss improves the response of obese subjects to non‐surgical ...periodontal treatment.
Materials and methods
This interventional study in obese patients was conducted at the University Hospital Dr. Peset (Valencia, Spain). Patients were divided into two groups with and without dietary therapy. All participants received non‐surgical periodontal treatment. Periodontal, anthropometric and biochemical parameters were assessed at baseline and 12 weeks.
Results
A total of 78 patients were re‐evaluated after intervention. All periodontal parameters improved in both groups after periodontal treatment, but the reductions in mean probing depth (PD) (0.23 mm vs. 0.12 mm) and in percentage of sites with PD 4–5 mm (10.4% vs. 5.89%) were significantly higher in the dietary group. Additionally, complement component 3 (C3) and tumour necrosis factor alpha (TNFα) decreased in the dietary group after intervention. Percentage of change in mean PD correlated with change in C3 (r = 0.233, p = 0.043), and percentage of change in sites with PD 4–5 mm correlated with change in TNFα (r = 0.414, p = 0.012).
Conclusions
This study suggests that dietary weight loss intervention causes a greater reduction in systemic inflammation, which may enhance the response to periodontal treatment.
Aim
To evaluate the relationship between oxidative stress parameters in polymorphonuclear leucocytes (PMNs) and PMN–endothelial cell interactions in patients with chronic periodontitis (CP) according ...to different degrees of severity of the disease.
Materials and methods
For this cross‐sectional study, 182 subjects were divided into four groups according to degree of CP: without CP (n = 37), mild CP (n = 59), moderate CP (n = 51), and severe CP (n = 35). We determined anthropometric and biochemical variables, periodontal parameters, inflammatory markers, oxidative stress parameters (superoxide and mitochondrial membrane potential), and PMN–endothelium cell interactions (rolling flux, velocity, and adhesion).
Results
Systemic inflammatory markers—C‐reactive protein, leucocyte count, TNFα, and retinol‐binding protein 4—were altered in the group with CP. Total superoxide was augmented in patients with moderate and severe periodontitis, whereas mitochondrial membrane potential did not change. Furthermore, PMNs adhesion and rolling flux were increased in subjects with CP.
Conclusion
In a systemic proinflammatory environment, PMNs from patients with CP exhibit hyperactivity and produce higher amounts of superoxide. In parallel with this, an increase in PMNs rolling flux and cell adhesion to the endothelium suggests the presence of alterations of PMN–endothelium interactions in patients with CP that can lead to atherosclerosis and cardiovascular complications.
Senescence of the immune system is characterized by a state of chronic, subclinical, low-grade inflammation termed 'inflammaging', with increased levels of proinflammatory cytokines, both at the ...tissue and systemic levels. Age-related inflammation can be mainly driven by self-molecules with immunostimulant properties, named Damage/death Associated Molecular Patterns (DAMPs), released by dead, dying, injured cells or aged cells. Mitochondria are an important source of DAMPs, including mitochondrial DNA - the small, circular, double-stranded DNA molecule found in multiple copies in the organelle. mtDNA can be sensed by at least three molecules: the Toll-like receptor 9, the NLRP3 inflammasomes, and the cyclic GMP-AMP synthase (cGAS). All these sensors can lead to the release of proinflammatory cytokines when engaged. The release of mtDNA by damaged or necrotic cells has been observed in several pathological conditions, often aggravating the course of the disease. Several lines of evidence indicate that the impairment of mtDNA quality control and of the organelle homeostasis associated with aging determines an increase in the leakage of mtDNA from the organelle to the cytosol, from the cell to the extracellular space, and into plasma. This phenomenon, mirrored by an increase in mtDNA circulating levels in elderly people, can lead to the activation of different innate immune cell types, sustaining the chronic inflammatory status that is characteristic of aging.
This study assessed the effects of an inositol-enriched beverage (IEB) on blood glucose levels and inflammation status in subjects with an impaired fasting glucose (IFG) state according to body mass ...index (BMI). This was a 12 week, double-blind, randomized, controlled trial employing forty-four IFG subjects (fasting glucose levels 100-125 mg dl
) that were divided into two intervention groups: one receiving a IEB (n = 24) containing mainly pinitol (2.0 g twice a day), and the other a sweetened beverage based on sucrose (SB; n = 20). Anthropometric and biochemical measurements, postprandial and fasting nocturnal glycaemia (continuous glucose monitoring system), and inflammatory parameters (IL-6 and TNF-α) were analyzed at baseline and after intervention according to BMI (non-obese: BMI < 30 kg m
or obese: BMI ≥ 30 kg m
). Non-obese subjects who consumed IEB exhibited a significant decrease in insulin (-14.4%), HOMA-IR index (-15.1%) and percentage of glucose change after postprandial and fasting nocturnal periods (-10.0% and -10.3%, respectively) compared with the SB group (-2.35% and 10.2%, respectively) although they did not show any change in inflammatory cytokine levels. By contrast, obese subjects who consumed IEB showed a smaller variation in glucose levels after nocturnal fasting (-4.34%) and a marked decrease in IL-6 and TNF-α (p < 0.05). These findings support that consumption of IEB in prediabetic subjects produces a response that is dependent on BMI, with a clear improvement of insulin resistance and postprandial and nocturnal glycemia in non-obese subjects and a marked anti-inflammatory response in obese subjects.
Aim
We aimed to evaluate serum RBP4 levels before and after periodontal therapy in lean and obese subjects with chronic periodontitis (CP) in order to determine its possible association with ...periodontitis.
Materials and Methods
This is an interventional study for which a total of 112 lean and 119 obese subjects were recruited. Patients with CP were evaluated before and after three months of non‐surgical periodontal treatment. Periodontal, anthropometric, biochemical parameters and serum levels of TNF‐α, IL‐6, hs‐CRP and RBP4 were assessed.
Results
Serum RBP4 levels were associated with an increased probability of periodontitis (OR = 1.60; 95% CI: 1.02‐2.50), showing patients with CP to have higher RBP4 levels than those without CP in both lean and obese populations (3.35 vs 3.06 and 3.74 vs 3.21, respectively). Following periodontal treatment, RBP4 and TNF‐α decreased, and all periodontal parameters improved to the same extent in both groups, except for number of teeth with probing depth (PD) ≥4 mm, which improved to a less extent in obese than in lean subjects. In the multivariable regression model, the number of teeth with PD ≥4 mm was independently associated with RBP4 (β = 0.192).
Conclusion
RBP4 was associated with chronic periodontitis before and after non‐surgical periodontal treatment.
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.
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•Metformin promoted electron transport chain expression on type 2 diabetic patients.•Metformin restored mitophagy levels via PINK1 and PARKIN on type 2 diabetic patients.•Mitochondrial biogenesis was enhanced by metformin on type 2 diabetic patients.•Metformin restored AMPK activation on type 2 diabetic patients.
Cellular pathways such as inflammation or oxidative stress are the cause and triggers of disease-related malnutrition (DRM), but the influence of these markers on endoplasmic reticulum (ER) stress is ...unknown. The objective of this study was to analyze the relationship between mitochondrial function and ER stress parameters in a DRM population. The study population was composed of 82 outpatient subjects, of whom 45 were diagnosed with DRM and 37 were confirmed to be normonourished according to the American Society for Parenteral and Enteral Nutrition ASPEN criteria. We evaluated anthropometrical and biochemical parameters, pro-inflammatory cytokines in serum. Oxidative and ER stress markers were analyzed in leukocytes. DRM patients showed significant reductions in albumin and transferrin concerning the normonourished group, and also displayed higher levels of hsCRP, IL6, and TNFα, and the soluble adhesion molecules VCAM-1 and ICAM-1. Besides, oxygen consumption and mitochondrial membrane potential were reduced and Radical Oxygen Species ROS production was enhanced in DRM patients. In the case of ER markers, protein and mRNA expression revealed that CHOP, ATF6, and the P-eIF2α signal were enhanced in malnourished patients compared to control subjects. Correlation studies supported a relationship between weight loss and increased inflammation, mitochondrial dysfunction, and compromised function of the ER. Our results demonstrate that ER stress signaling pathways are influenced by inflammation and mitochondrial function in the leukocytes of a DRM population.
Cancer is first a localized tissue disorder, whose soluble and exosomal molecules and invasive cells induce a host response providing the stromal components of the primary tumor microenvironment ...(TME). Once the TME is developed, cancer-derived molecules and cells can more efficiently spread out and a whole-body response takes place, whose pathophysiological changes may result in a paraneoplastic syndrome. Remote organ-specific prometastatic reactions may also occur at this time, facilitating metastatic activities of circulating tumor cells (CTCs) through premetastatic niche development at targeted organs. However, additional signaling factors from the inter-organ communication network involved in the pathophysiology and comorbidities of cancer patients may also regulate prometastatic reaction-stimulating effects of cancer and non-cancer tissue factors.
This article provides a conceptual overview of our ongoing clinical research on the liver prometastatic reaction (LPR) of patients with colorectal cancer (CRC), their portal vein- and hepatic artery-driven LPR-Stimulating Factors (LPR-SF), and their resulting LPR-derived Metastasis-Stimulating Factors (LPR-MSF) acting on liver-invading CRC cells. In addition, we also provide new insights on the molecular subtyping of LPR-responsive cancer phenotypes in patients with CRC and melanoma; and on how to investigate and interpret the prometastatic infrastructure in the real pathophysiological context of patients with cancer undergoing surgical procedures and receiving pharmacological treatments with multiple side effects, including those affecting the LPR, its stimulating factors and responsive cancer phenotypes.
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