Mitochondrial dysfunction promoted by Porphyromonas gingivalis lipopolysaccharide as a possible link between cardiovascular disease and periodontitis

Oxidative stress is one of the factors that could explain the pathophysiological mechanism of inflammatory conditions that occur in cardiovascular disease (CVD) and periodontitis. Such inflammatory response is often evoked by specific bacteria, as the lipopolysaccharide (LPS) of Porphyromonas gingivalis is a key factor in this process. The aim of this research was to study the role of mitochondrial dysfunction in peripheral blood mononuclear cells (PBMCs) from periodontitis patients and to evaluate the influence of LPS on fibroblasts to better understand the pathophysiology of periodontitis and its relationship with CVD. PBMCs from patients showed lower CoQ10 levels and citrate synthase activity, together with high levels of ROS production. LPS-treated fibroblasts provoked increased oxidative stress and mitochondrial dysfunction by a decrease in mitochondrial protein expression, mitochondrial mass, and mitochondrial membrane potential. Our study supports the hypothesis that LPS-mediated mitochondrial dysfunction could be at the origin of oxidative stress in periodontal patients. Abnormal PBMC performance may promote oxidative stress and alter cytokine homeostasis. In conclusion, mitochondrial dysfunction could represent a possible link to understanding the interrelationships between two prominent inflammatory diseases: periodontitis and CV

Metabolic Syndrome and Periodontitis: Is Oxidative Stress a Common Link?

Ponencia basada en este artículo en la 2nd International Mediterranean Meeting - Nutrition and Metabolism, Granada, 2010A review of pathological mechanisms that can explain the relationship between periodontitis and cardiovascular disease (CVD) is necessary to improve the management of both conditions. Metabolic syndrome is a combination of obesity, hypertension, impaired glucose tolerance or diabetes, hyperinsulinemia, and dyslipidemia. All these have been examined in recent years in terms of their relationship to periodontitis. Reviewed data indicate an association between some of them (body mass index, high-density lipoprotein-cholesterol [HDL-C], triglycerides, high blood pressure, among others) and periodontitis. Oxidative stress may act as a potential common link to explain relationships between each component of metabolic síndrome and periodontitis. Both conditions show increased serum levels of products derived from oxidative damage, with a pro-inflammatory state likely influencing each other bidirectionally. Adipocytokines might modulate the oxidant/anti-oxidant balance in this relationship

Autophagy in periodontitis patients and gingival fibroblasts: unraveling the link between chronic diseases and inflammation

Authors are indebted with Ms Monica Glebocki for extensive editing of the manuscriptBackground: Periodontitis, the most prevalent chronic inflammatory disease, has been related to cardiovascular diseases. Autophagy provides a mechanism for the turnover of cellular organelles and proteins through a lysosome-dependent degradation pathway. The aim of this research was to study the role of autophagy in peripheral blood mononuclear cells from patients with periodontitis and gingival fibroblasts treated with a lipopolysaccharide of Porphyromonas gingivalis. Autophagy-dependent mechanisms have been proposed in the pathogenesis of inflammatory disorders and in other diseases related to periodontitis, such as cardiovascular disease and diabetes. Thus it is important to study the role of autophagy in the pathophysiology of periodontitis. Methods: Peripheral blood mononuclear cells from patients with periodontitis (n = 38) and without periodontitis (n = 20) were used to study autophagy. To investigate the mechanism of autophagy, we evaluated the influence of a lipopolysaccharide from P. gingivalis in human gingival fibroblasts, and autophagy was monitored morphologically and biochemically. Autophagosomes were observed by immunofluorescence and electron microscopy. Results: We found increased levels of autophagy gene expression and high levels of mitochondrial reactive oxygen species production in peripheral blood mononuclear cells from patients with periodontitis compared with controls. A significantly positive correlation between both was observed. In human gingival fibroblasts treated with lipopolysaccharide from P. gingivalis, there was an increase of protein and transcript of autophagy-related protein 12 (ATG12) and microtubule-associated protein 1 light chain 3 alpha LC3. A reduction of mitochondrial reactive oxygen species induced a decrease in autophagy whereas inhibition of autophagy in infected cells increased apoptosis, showing the protective role of autophagy. Conclusion: Results from the present study suggest that autophagy is an important and shared mechanism in other conditions related to inflammation or alterations of the immune system, such as periodontiti

Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling

Purpose: On the basis of the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in patients with triple-negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on patients with breast cancer survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature.Experimental Design: Patient survival data were determined by Kaplan-Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and in vivo using patient-derived xenografts (PDX).Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFβ/SMAD and mTOR/RAC1-RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2,509 patients with breast cancer.Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer

Does consumption of two portions of salmon per week enhance the antioxidant defense system in pregnant women?

Salmon is a rich source of marine n-3 fatty acids, which may increase oxidative stress and, in turn, could affect the antioxidant defense system in blood plasma and erythrocytes of pregnant women. The Salmon in Pregnancy Study provided two meals of salmon per week to pregnant women from week 20 of gestation; the control group maintained their habitual diet low in oily fish. Higher selenium and retinol plasma concentrations were observed after dietary salmon supplementation. Besides, a concomitant increase in selenium and glutathione concentration as well as glutathione peroxidase and reductase activities were detected as pregnancy progressed. However, tocopherols, retinol, ?-carotene, and coenzyme Q10 decreased in late pregnancy. Collectively, our findings lead to the hypothesis that increased farmed salmon intake may increase antioxidant defenses during pregnancy

Doxorubicin-Induced Oxidative Stress in Rats Is Efficiently Counteracted by Dietary Anthocyanin Differently Enriched Strawberry (Fragaria×ananassaDuch.)

This study investigated the effects of two different strawberry cultivars, Adria and Sveva, against doxorubicin (DOX)-induced toxicity in rats. A controlled dietary intervention was conducted over 16 weeks with four groups: (i) normal diet; (ii) normal diet + DOX injection; (iii) Adria supplementation + DOX injection; and (iv) Sveva supplementation + DOX injection. Sveva presented higher total antioxidant capacity value and phenol and and vitamin C levels than Adria, which in turn presented higher anthocyanin contents. DOX drastically increased lymphocyte DNA damage, liver biomarkers of protein and lipid oxidation, and mitochondrial ROS content and markedly decreased plasma retinol level, liver antioxidant enzymes, and mitochondrial functionality. After 2 months of strawberry supplementation, rats presented a significant reduction of DNA damage and ROS concentration and a significant improvement of oxidative stress biomarkers, antioxidant enzyme activities, and mitochondrial performance. These results suggest that strawberry supplementation can counteract DOX toxicity, confirming the potential health benefit of strawberry in vivo against oxidative stress