Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression.

Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet ß-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early ß-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. ß-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is mediated by hyperglycemia alone or in combination with lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. Under metabolic-related stress conditions, EV-mediated cross-talk between ß-cells and skeletal muscle likely trigger mitochondrial anomalies leading to prediabetes and T2D. This article reviews the underlying molecular mechanisms in ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. Further, this review will describe the potential of various therapeutic avenues for attenuating oxidative damage, reversing prediabetes and preventing progression to T2D.

FOXE1 polymorphisms and chronic exposure to nitrates in drinking water cause metabolic dysfunction, thyroid abnormalities, and genotoxic damage in women.

Nitrates in drinking water has been associated to adverse health effects, including changes in glucose and lipid levels, thyroid hormone imbalance and adverse reproductive effects. We analyzed metabolic and thyroid hormone alterations and genotoxic damage in women with chronic exposure to nitrates in drinking water. The concentration of nitrates in drinking water was quantified and according to this parameter, participants were divided into three exposure scenarios. Blood and urine samples were collected from 420 women living in Durango, Mexico and biomarkers were determined. We found nitrates concentrations in drinking water above the permissible limit (>50 mg/L), and an increase in the percentage of methemoglobin (p=0.0001), nitrite in blood plasma and urine (p=0.0001), glucose (p=0.0001), total cholesterol (p=0.001), LDL (p=0.001) and triglycerides (p=0.0001). We also found alterations in TSH (p=0.01), fT3 (p=0.0003), T4T (p=0.01) and fT4 (p=0.0004) hormones. Frequency of subclinical hypothyroidism was 8.33%; differences in FOXE1 (rs965513, rs1867277) genotypes distribution were found and both polymorphisms were associated with a decrease in TSH. A high percentage of micronucleus in binucleate lymphocyte cells was found (35%, p=0.0001). In conclusion, the chronic exposure to nitrates in water for human consumption caused metabolic and hormonal alterations and genotoxic damage in women.

Glutathione Directly Intercepts DNA Radicals To Inhibit Oxidative DNA-Protein Cross-Linking Induced by the One-Electron Oxidation of Guanine.

Oxidative DNA damage can lead to cancer, and as enzymatic DNA repair systems become compromised during the aging process, the role of exogenous antioxidants becomes more critical. Here, we examined whether such non-enzymatic DNA repair can be effected by the common cellular antioxidant glutathione, investigating both permanent DNA damage products and the guanine radical intermediates that form them, using the flash-quench technique to carry out the one-electron oxidation of guanine. In gel-shift assays, the presence of reduced glutathione at physiological (millimolar) concentrations strongly inhibits oxidative DNA-protein cross-linking. In contrast, the oxidized glutathione dimer affords only a minimal amount of protection, even at elevated pH where there is more of the strongly reducing thiolate form. In flash photolysis experiments, the formation and decay of the guanine neutral radical were monitored at 510 nm. Transient absorption measurements with a guanine-rich 22-mer DNA duplex on the millisecond time scale show that the yield of this long-lived signal is significantly diminished in the presence of reduced glutathione, suggesting a reduction process that is fast relative to the measurement. Indeed, transient absorption experiments carried out on faster time scales show that the microsecond decay of the guanine radical signal is visibly faster with glutathione present. Glutathione is perhaps best known as an electron source in enzymatic reactions, to maintain cysteines in reduced states in proteins and to deactivate reactive oxygen species. However, these results show that another important task for glutathione may be to directly intercept DNA radicals before permanent DNA damage can occur.

Bioinformatic miRNA-mRNAs Analysis Revels to miR-934 as a Potential Regulator of the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer and has the worst prognosis. In patients with TNBC tumors, the tumor cells have been reported to have mesenchymal features, which help them migrate and invade. Various studies on cancer have revealed the importance of microRNAs (miRNAs) in different biological processes of the cell in that aberrations, in their expression, lead to alterations and deregulations in said processes, giving rise to tumor progression and aggression. In the present work, we determined the miRNAs that are deregulated in the epithelial-mesenchymal transition process in breast cancer. We discovered that 25 miRNAs that regulate mesenchymal genes are overexpressed in patients with TNBC. We found that miRNA targets modulate different processes and pathways, such as apoptosis, FoxO signaling pathways, and Hippo. We also found that the expression level of miR-934 is specific to the molecular subtype of the triple-negative breast cancer and modulates a set of related epithelial-mesenchymal genes. We determined that miR-934 inhibition in TNBC cell lines inhibits the migratory abilities of tumor cells.

MicroRNAs Regulate Metabolic Phenotypes During Multicellular Tumor Spheroids Progression.

During tumor progression, cancer cells rewire their metabolism to face their bioenergetic demands. In recent years, microRNAs (miRNAs) have emerged as regulatory elements that inhibit the translation and stability of crucial mRNAs, some of them causing direct metabolic alterations in cancer. In this study, we investigated the relationship between miRNAs and their targets mRNAs that control metabolism, and how this fine-tuned regulation is diversified depending on the tumor stage. To do so, we implemented a paired analysis of RNA-seq and small RNA-seq in a breast cancer cell line (MCF7). The cell line was cultured in multicellular tumor spheroid (MCTS) and monoculture conditions. For MCTS, we selected two-time points during their development to recapitulate a proliferative and quiescent stage and contrast their miRNA and mRNA expression patterns associated with metabolism. As a result, we identified a set of new direct putative regulatory interactions between miRNAs and metabolic mRNAs representative for proliferative and quiescent stages. Notably, our study allows us to suggest that miR-3143 regulates the carbon metabolism by targeting hexokinase-2. Also, we found that the overexpression of several miRNAs could directly overturn the expression of mRNAs that control glycerophospholipid and N-Glycan metabolism. While this set of miRNAs downregulates their expression in the quiescent stage, the same set is upregulated in proliferative stages. This last finding suggests an additional metabolic switch of the above mentioned metabolic pathways between the quiescent and proliferative stages. Our results contribute to a better understanding of how miRNAs modulate the metabolic landscape in breast cancer MCTS, which eventually will help to design new strategies to mitigate cancer phenotype.

The 300 Most-Cited Articles in Implant Dentistry.

PURPOSE: The purpose of this study was to review and evaluate the characteristics of the 300 most-cited articles that have been published in the most important implant dentistry journals. MATERIALS AND METHODS: A search and selection of the most-cited articles up to October 2014 was conducted for implant journals with the highest impact factors, according to the ISI Web of Science. The 300-most-cited articles were evaluated according to the most commonly studied topics and methodological designs used. The most-cited journals and the number of articles cited by year were calculated. Descriptive statistics were used to summarize the results. RESULTS: The most-cited topics consisted of implant success/survival and guided bone regeneration, and the most-cited methodological designs were case series and cohort studies. The most frequently referenced journal was The International Journal of Oral and Maxillofacial Implants, with 47% of the citations, and the period with the most citations was 1996 to 2000. CONCLUSION: Longitudinal studies of success and survival have had great scientific impact on the practice of implant dentistry. Awareness of the most-cited articles in implant dentistry will contribute to scientific advances, as it serves to identify the most researched areas, the most frequently used study designs, and areas that require further research.