The Potential Role of Peripheral Oxidative Stress on the Neurovascular Unit in Amyotrophic Lateral Sclerosis Pathogenesis: A Preliminary Report from Human and In Vitro Evaluations.

Oxidative stress, the alteration of mitochondrial function, and changes in the neurovascular unit (NVU) could play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. Our aim was to analyze the plasma redox system and nitric oxide (NO) in 25 ALS new-diagnosed patients and five healthy controls and the effects of plasma on the peroxidation/mitochondrial function in human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. In plasma, thiobarbituric acid reactive substances (TBARS), glutathione (GSH), and nitric oxide (NO) were analyzed by using specific assays. In HUVEC/astrocytes, the effects of plasma on the release of mitochondrial reactive oxygen species (mitoROS) and NO, viability, and mitochondrial membrane potential were investigated. In the plasma of ALS patients, an increase in TBARS and a reduction in GSH and NO were found. In HUVEC/astrocytes treated with a plasma of ALS patients, mitoROS increased, whereas cell viability and mitochondrial membrane potential decreased. Our results show that oxidative stress and NVU play a central role in ALS and suggest that unknown plasma factors could be involved in the disease pathogenesis. Quantifiable changes in ALS plasma related to redox state alterations can possibly be used for early diagnosis.

Oxidative and Nitrosative Stress in Age-Related Macular Degeneration: A Review of Their Role in Different Stages of Disease.

Although the exact pathogenetic mechanisms leading to age-related macular degeneration (AMD) have not been clearly identified, oxidative damage in the retina and choroid due to an imbalance between local oxidants/anti-oxidant systems leading to chronic inflammation could represent the trigger event. Different in vitro and in vivo models have demonstrated the involvement of reactive oxygen species generated in a highly oxidative environment in the development of drusen and retinal pigment epithelium (RPE) changes in the initial pathologic processes of AMD; moreover, recent evidence has highlighted the possible association of oxidative stress and neovascular AMD. Nitric oxide (NO), which is known to play a key role in retinal physiological processes and in the regulation of choroidal blood flow, under pathologic conditions could lead to RPE/photoreceptor degeneration due to the generation of peroxynitrite, a potentially cytotoxic tyrosine-nitrating molecule. Furthermore, the altered expression of the different isoforms of NO synthases could be involved in choroidal microvascular changes leading to neovascularization. The purpose of this review was to investigate the different pathways activated by oxidative/nitrosative stress in the pathogenesis of AMD, focusing on the mechanisms leading to neovascularization and on the possible protective role of anti-vascular endothelial growth factor agents in this context.

Exposure to Plasma From Non-alcoholic Fatty Liver Disease Patients Affects Hepatocyte Viability, Generates Mitochondrial Dysfunction, and Modulates Pathways Involved in Fat Accumulation and Inflammation.

Changes of lipidic storage, oxidative stress and mitochondrial dysfunction may be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Although the knowledge of intracellular pathways has vastly expanded in recent years, the role and mechanisms of circulating triggering factor(s) are debated. Thus, we tested the hypothesis that factors circulating in the blood of NAFLD patients may influence processes underlying the disease. Huh7.5 cells/primary human hepatocytes were exposed to plasma from 12 NAFLD patients and 12 healthy subjects and specific assays were performed to examine viability, H2O2 and mitochondrial reactive oxygen species (ROS) release, mitochondrial membrane potential and triglycerides content. The involvement of NLRP3 inflammasome and of signaling related to peroxisome-proliferator-activating-ligand-receptor-γ (PPARγ), sterol-regulatory-element-binding-protein-1c (SREBP-1c), nuclear-factor-kappa-light-chain-enhancer of activated B cells (NF-kB), and NADPH oxidase 2 (NOX2) was evaluated by repeating the experiments in the presence of NLRP3 inflammasome blocker, MCC950, and through Western blot. The results obtained shown that plasma of NAFLD patients was able to reduce cell viability and mitochondrial membrane potential by about 48 and 24% (p < 0.05), and to increase H2O2, mitochondrial ROS, and triglycerides content by about 42, 19, and 16% (p < 0.05), respectively. An increased expression of SREBP-1c, PPARγ, NF-kB and NOX2 of about 51, 121, 63, and 46%, respectively, was observed (p < 0.05), as well. Those effects were reduced by the use of MCC950. Thus, in hepatocytes, exposure to plasma from NAFLD patients induces a NAFLD-like phenotype by interference with NLRP3-inflammasome pathways and the activation of intracellular signaling related to SREBP-1c, PPARγ, NF-kB and NOX2.

Association Between Plasma Redox State/Mitochondria Function and a Flu-Like Syndrome/COVID-19 in the Elderly Admitted to a Long-Term Care Unit.

Background/Aims: It is widely known that the imbalance between reactive oxygen species (ROS)/antioxidants and mitochondrial function could play a pivotal role in aging and in the physiopathology of viral infections. Here, we correlated the plasma oxidants/antioxidants levels of the elderly admitted to a long-term care (LTC) unit with clinical data in relation to flu-like disease/COVID-19. Moreover, in vitro we examined the effects of plasma on cell viability, ROS release and mitochondrial function. Materials and Methods: In 60 patients admitted to LTC unit for at least 1 year at moderate or high care load, demographic and clinical variables were taken. Blood samples were collected for the evaluations of oxidants/antioxidants, as thiobarbituric acid reactive substances, 8-hydroxy-2-deoxyguanosine, 8-isoprostanes, superoxide dismutase activity, glutathione, and vitamin D. In vitro, human umbilical vascular endothelial cells (HUVEC) were used to examine the effects of plasma on viability, ROS release and mitochondrial membrane potential. Results: The results obtained showed that the redox state of the elderly was quite balanced; mitochondrial membrane potential of HUVEC was reduced by about 20%, only. Also, the correlation analysis evidenced the association between mitochondrial function and the patients' outcomes. Interestingly, lower levels of mitochondrial membrane potential were found in the elderly who had symptoms suggestive of COVID-19 or with a confirmed diagnosis of COVID-19. Conclusion: The results of this study highlight the importance of mitochondrial function in the tendency to get a flu-like syndrome like COVID-19 in the elderly admitted to LTC unit. This information could have clinical implications for the management of old population.