Oxidative Medicine and Cellular Longevity

Vinegar is good for health. Tetramethylpyrazine (TMP) is the main component of its flavor, quality, and function. We hypothesized that vinegar/TMP pretreatment could induce myocardial protection of “nutritional preconditioning (NPC)” by low-dose, long-term supplementation and alleviate the myocardial injury caused by anoxia/reoxygenation (A/R). To test this hypothesis, TMP content in vinegar was detected by HPLC; A/R injury model was prepared by an isolated mouse heart and rat cardiomyocyte to evaluate the myocardial protection and mechanism of vinegar/TMP pretreatment by many enzymatic or functional, or cellular and molecular biological indexes. Our results showed that vinegar contained TMP, and its content was in direct proportion to storage time. Vinegar/TMP pretreatment could improve hemodynamic parameters, decrease lactate dehydrogenase (LDH) and creatine phosphokinase activities, and reduce infarct size and apoptosis in the isolated hearts of mice with A/R injury. Similarly, vinegar/TMP pretreatment could increase cell viability, decrease LDH activity, and decrease apoptosis against A/R injury of cardiomyocytes. Vinegar/TMP pretreatment could also maintain the mitochondrial function of A/R-injured cardiomyocytes, including improving oxygen consumption rate and extracellular acidification rate, reducing reactive oxygen species generation, mitochondrial membrane potential loss, mitochondrial permeability transition pore openness, and cytochrome c releasing. However, the protective effects of vinegar/TMP pretreatment were accompanied by the downregulation of VDAC1 expression in the myocardium and reversed by pAD/VDAC1, an adenovirus that upregulates VDAC1 expression. In conclusion, this study is the first to demonstrate that vinegar/TMP pretreatment could induce myocardial protection of NPC due to downregulating VDAC1 expression, inhibiting oxidative stress, and preventing mitochondrial dysfunction; that is, VDAC1 is their target, and the mitochondria are their target organelles. TMP is one of the most important myocardial protective substances in vinegar.

Introduction. Mortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality. Methods. We performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients. Results. The mean patient age was 65.6 years (range, 29–92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25^th to 75^th percentile: 6–18), while the median total number of hospital stay was 18 (25^th to 75^th percentile: 12–28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis. Conclusion. In the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality.

TF IIB-related factor 1 (Brf1) is a key transcription factor of RNA polymerase III (Pol III) genes. Our early studies have demonstrated that Brf1 and Pol III genes are epigenetically modulated by histone H3 phosphorylation. Here, we have further investigated the relationship of the abnormal expression of Brf1 with a high level of phosphorylated AMPKα (pAMPKα) and explored the role and molecular mechanism of pAMPKα-mediated dysregulation of Brf1 and Pol III genes in lung cancer. Brf1 is significantly overexpressed in lung cancer cases. The cases with high Brf1 expression display short overall survival times. Elevation of Brf1 expression is accompanied by a high level of pAMPKα. Brf1 and pAMPKα colocalize in nuclei. Further analysis indicates that the carcinogen MNNG induces pAMPKα to upregulate Brf1 expression, resulting in the enhancement of Pol III transcription. In contrast, inhibiting pAMPKα decreases cellular levels of Brf1, resulting in the reduction of Pol III gene transcription to attenuate the rates of cell proliferation and colony formation of lung cancer cells. These outcomes demonstrate that high Brf1 expression reveals a worse prognosis in lung cancer patients. pAMPKα-mediated dysregulation of Brf1 and Pol III genes plays important roles in cell proliferation, colony formation, and tumor development of lung cancer. Brf1 may be a biomarker for establishing the prognosis of lung cancer. It is a new mechanism that pAMPKα mediates dysregulation of Brf1 and Pol III genes to promote lung cancer development.

Microgravity affects human cardiovascular function inducing heart rhythm disturbances and even cardiac atrophy. The mechanisms triggered by microgravity and the search for protection strategies are difficult to be investigated in vivo. This study is aimed at investigating the effects induced by simulated microgravity on a cardiomyocyte-like phenotype. The Random Positioning Machine (RPM), set in a CO₂ incubator, was used to simulate microgravity, and H9C2 cell line was used as the cardiomyocyte-like model. H9C2 cells were exposed to simulated microgravity up to 96 h, showing a slower cell proliferation rate and lower metabolic activity in comparison to cell grown at earth gravity. In exposed cells, these effects were accompanied by increased levels of intracellular reactive oxygen species (ROS), cytosolic Ca²⁺, and mitochondrial superoxide anion. Protein carbonyls, markers of protein oxidation, were significantly increased after the first 48 h of exposition in the RPM. In these conditions, the presence of an antioxidant, the N-acetylcysteine (NAC), counteracted the effects induced by the simulated microgravity. In conclusion, these data suggest that simulated microgravity triggers a concomitant increase of intracellular ROS and Ca²⁺ levels and affects cell metabolic activity which in turn could be responsible for the slower proliferative rate. Nevertheless, the very low number of detectable dead cells and, more interestingly, the protective effect of NA, demonstrate that simulated microgravity does not have “an irreversible toxic effect” but, affecting the oxidative balance, results in a transient slowdown of proliferation.

Objective. The objective of this study was to investigate the potential molecular mechanisms of ATPase H⁺ transporting V1 subunit A (ATP6V1A) underlying Alzheimer’s disease (AD). Methods. Microarray expression data of human temporal cortex samples from the GSE118553 dataset were profiled to screen for differentially expressed genes (DEGs) between AD/control and ATP6V1A-low/high groups. Correlations of coexpression modules with AD and ATP6V1A were assessed by weight gene correlation network analysis (WGCNA). DEGs strongly interacting with ATP6V1A were extracted to construct global regulatory network. Further cross-talking pathways of ATP6V1A were identified by functional enrichment analysis. Diagnostic performance of ATP6V1A in AD prediction was evaluated using area under the curve (AUC) analysis. Results. The mean expression of ATP6V1A was significantly downregulated in AD compared with nondementia controls. A total of 1,364 DEGs were overlapped from AD/control and ATP6V1A-low/high groups. Based on these DEGs, four coexpression modules were predicted by WGCNA. The blue, brown, and turquoise modules were significantly correlated with AD and low ATP6V1A, whose DEGs were enriched in phagosome, oxidative phosphorylation, synaptic vesicle cycle, focal adhesion, and gamma-aminobutyric acidergic (GABAergic) synapse. Global regulatory network was constructed to identify the cross-talking pathways of ATP6V1A, such as synaptic vesicle cycle, phagosome, and oxidative phosphorylation. According to the AUC value of 74.2%, low ATP6V1A expression accurately predicted the occurrence of AD. Conclusions. Our findings highlighted the pleiotropic roles of low ATP6V1A in AD pathogenesis, possibly mediated by synaptic vesicle cycle, phagosome, and oxidative phosphorylation.

Together with nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H₂S) is now recognized as a vital gaseous transmitter. The ubiquitous distributions of H₂S-producing enzymes and potent chemical reactivities of H₂S in biological systems make H₂S unique in its ability to regulate cellular and organ functions in both health and disease. Acting as an antioxidant, H₂S can combat oxidative species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) and protect the skin from oxidative stress. The aberrant metabolism of H₂S is involved in the pathogenesis of several skin diseases, such as vascular disorders, psoriasis, ulcers, pigment disorders, and melanoma. Furthermore, H₂S donors and some H₂S hybrids have been evaluated in many experimental models of human disease and have shown promising therapeutic results. In this review, we discuss recent advances in understanding H₂S and its antioxidant effects on skin pathology, the roles of altered H₂S metabolism in skin disorders, and the potential value of H₂S as a therapeutic intervention in skin diseases.