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Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. Although the mutations involved in this condition have been characterized, the correlation between the molecular defects and the plethora of clinical symptoms is not well understood. Recently the presence of a redox unbalance in TTD has been suggested although not clear evidences have been reported on this aspect.
Therefore, in the present study, we evaluated the redox status of fibroblasts isolated from a TTD patient. In addition, to understand the ability of TTD cells to respond to oxidative insults, the cells were challenged with H2O2 and mitochondrial O2- and mitochondrial membrane potential were measured in different oxidative conditions. In addition, NRF2/BACH protein levels were also analysed in response to H2O2.
The results suggested an aberrant mitochondrial response to oxidative stimuli, an increased baseline oxidative stress status in TTD and an altered NRF2/BACH level.
This study emphasises that altered redox homeostasis might play a role in TTD pathogenesis and mitochondria functionality could represent an alternative therapeutic target for this condition to improve patients clinical features.
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Objective: This work characterized fluctuations in cell components involved in the regulation of cell redox homeostasis during Caco-2 cell differentiation into enterocytes.
Methods: Caco-2 cells were differentiated for 10 days. Gene expression of NADPH oxidases; enzymes that metabolize superoxide anion and hydrogen peroxide, proteins involved in the production and/or regeneration of glutathione, thioredoxin, and in NADPH production, and Nrf2-dependent genes were measured by qPCR at 0, 1, 4, 7, and 10 days post-confluence.
Results: NADPH oxidase 1 mRNA levels decreased with Caco-2 cell differentiation, in agreement with its role in regulating cell proliferation. NADPH oxidase 4, DUOX2, superoxide dismutase 1 and catalase mRNA levels increased with differentiation. Nrf2 mRNA levels increased with differentiation up to day 4 post-confluence, reaching a plateau until day 10. A similar pattern was observed for the Nrf2-regulated genes: NAD(P)H quinone dehydrogenase 1, glutathione reductase 1, and thioredoxin reductase 1. On the contrary, glutamate-cysteine ligase catalytic subunit mRNA levels decreased after reaching a maximum 4 days post-confluence. This and the finding of a correlation between glutathione reductase 1 and thioredoxin reductase 1 mRNA levels, suggest that recycling of glutathione and thioredoxin is more relevant than their synthesis during Caco-2 cell differentiation.
Conclusion: Results support the relevance of redox homeostasis for cell fate decisions and in preparing enterocytes to interact with their environment.
Significance statement: Current findings resemble changes in redox components previously characterized in vivo. This stresses the concept that Caco-2 cells are an appropriate model to be used to evaluate redox-regulated mechanisms in human enterocytes.
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Graphical abstract
Abstract
Chronic wounds take longer to heal and, if left untreated, can result in severe repercussions such as sepsis, gangrene, and amputation. The current treatment procedures followed are wound cleaning and debridement, specialized dressings, antibiotics and antiseptics, hyperbaric oxygen therapy, and vacuum-assisted wound closure. Some of the limitations of these treatment options are multidrug resistance and tissue toxicity. Cold plasma is an emerging technology that has opened a new frontier in biomedical applications and is found to have great utility in wound healing. Cold plasma comprises reactive oxygen and nitrogen species (RONS) that can be targeted against bacterial inactivation and improve wound healing. The amount of RONS produced can be controlled by several parameters such as gas composition, flow rate, power, frequency, voltage, distance, and exposure time. The reactive species causes damage to the cell membrane as well as the intracellular components which ultimately lead to bacterial cell death. It can also accelerate wound healing by activating neutrophils, macrophages, endothelial cells, keratinocytes, and fibroblasts. These help in maintaining tissue oxygenation, initiating angiogenesis, collagen synthesis which aids in rapid wound closure. In this review, we summarize the various characteristics of cold plasma that can be optimized to produce an effective antimicrobial effect. The different mechanisms of bacterial inactivation and the stimulation of wound healing processes by the reactive species are discussed. Furthermore, numerous pieces of evidence from in vitro and in vivo experiments and clinical trials that prove that cold plasma is an effective approach are presented.
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Department of Translational Medicine, University of East Piedmont, Novara, Italy
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Graphical abstract
Redox-induction of expression and synthesis of ATP binding cassette transporters in CaCo-2 cells by externally added 27-hydroxycholesterol.
27OHC: 27-hydroxycholesterol; NOX: NADPH oxidase; ROS: reactive oxygen species; ABCA1: ATP binding cassette A1; ABCG8: ATP binding cassette G8; DPI: diphenylene iodonium.
Abstract
Objective
We tested the effect of 27-hydroxycholesterol (27OHC) on the expression and synthesis of two membrane transporters involved in sterols extrusion from the intestinal epithelium into the gut lumen: ATP-binding cassette A1 (ABCA1) and G8 (ABCG8). Special attention was given to ABCG8, a key player in the intestinal cell discharge of plant sterols.
Methods
Differentiated CaCo-2 intestinal cells were supplemented with 27OHC, and added to the cell incubation medium at a final concentration of 1 or 5 µM. These 27OHC externally added amounts were proven to reach intracellular oxysterol levels within the range of those normally recovered in the human peripheral blood.
Results
An up-regulation of the ABCA1 and ABCG8 mRNAs was observed in the CaCo-2 cells supplemented with 27OHC. Moreover, both 1 µM and 5 µM 27OHC induced a net, and steady, statistically significant, increase of both ABCA1 and ABCG8 protein levels. Of interest, the cellular pre-treatment with diphenylene iodonium, a selective inhibitor of NADPH oxidase, i.e. a major intracellular source of reactive oxygen species, fully inhibited the 27OHC enhancement of both ABCA1 and ABCG8 protein synthesis.
Conclusion
This in vitro study shows for the first time that the addition of 27OHC to intestinal epithelial cells up-regulates ABCG8, the transporter discharging plant sterols into the gut lumen, besides confirming to induce ABCA1 as well. Importantly, the 27OHC-dependent up-regulation of the two transporters appears to involve a redox mechanism rather than the canonical liver-X-receptors-dependent pathway.
Significance statement
The 27OHC introduced with the diet might modulate the plant sterol extrusion in the gut, in parallel with that of cholesterol.
Search for other papers by Josh Thorley in
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Department of Clinical Nutrition, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, KSA
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Objective
The aim was to evaluate whether exercise induces different nuclear factor erythroid 2-related factor 2 (NRF2) responses in males and females.
Methods
Twenty-two males and females (n = 11 per group; mean (s.d.): age: 25 (6) years, height: 1.71 (0.10) m, weight: 69.6 (12.3) kg) performed 100 drop jumps and 50 squat jumps. NRF2/antioxidant response element (ARE) binding in peripheral blood mononuclear cells, glutathione peroxidase (GPX) activity, and immune markers influenced by NRF2 (interleukin 6 (IL-6), tumour necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), vascular cell adhesion molecule-1 (VCAM-1), total leukocytes, neutrophils, monocytes) were measured pre-exercise, post exercise, and 1 h post exercise.
Results
NRF2/ARE binding did not significantly alter following exercise (P = 0.59), and no sex differences were evident (P = 0.17). Similarly, GPX activity did not change post exercise (P = 0.74) and did not differ between sexes (P = 0.61). IL-6 and TNF-α did not increase post exercise (P > 0.05 for both) but were lower in females (P < 0.01 for both). MMP-9 increased post exercise (P = 0.02), but no group differences were found (P = 0.27). VCAM-1 was unchanged after exercise (P = 0.38) and did not differ between groups (P = 0.11). Total leukocytes, neutrophils, and monocytes all increased post exercise (P < 0.01 for all); neutrophils were lower (P < 0.01), and monocytes were higher (P = 0.03) in females vs males.
Conclusion
There were no sex differences in NRF2 activity at rest and in response to an exercise bout; however, several immune markers displayed sex-specific differences, independent to NRF2.
Pre-registration
Open Science Framework = osf.io/5fpvn; Thorley, J., & Clifford, T. (2022, August 12). Curcumin supplementation, exercise, Nrf2/NFkB activity. https://doi.org/10.17605/OSF.IO/C4UQ2. Identifier: osf-registrations-c4uq2-v1
Significance statement
Sex differences in NRF2 signaling were not evident, suggesting males and females may incur similar redox-specific adaptations post exercise.
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Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain
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Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain
Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Madrid, Spain
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The mammalian target of rapamycin (mTOR) is a master regulator of the cell metabolism which impacts numerous signaling involved in cell proliferation and death and recycling cell constituents to readapt to new physiological or pathological environments. mTOR is constituted by two structural and functional different complexes, mTORC1 and mTORC2. Both can be independently regulated, which has a great impact on the effectiveness of therapeutic interventions in different clinical and experimental situations. Furthermore, mTORC1 interacts with specific chaperones or immunophilins which are intracellular receptors of the immunosuppressive drugs. Low and high molecular weights of immunophilins have different intracellular functions. The present review updates the molecular structure and signaling of mTOR as well as their regulation by immunophilins and upstream and downstream signaling events, highlighting the potential therapeutic intervention of mTOR in cancer, metabolic disturbances, and aging.
Department of Discovery Protein Science, Amgen Inc., South San Francisco, California, USA
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Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA
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University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Objective
UV irradiation of the skin induces photo damage and generates cytotoxic intracellular reactive oxygen species (ROS), activating the unfolded protein response (UPR) to adapt or reduce these UVB-mediated damages. This study was designed to understand the role of the UPR mediator IRE1α in the antioxidant response following UVB irradiation of mouse skin and keratinocytes.
Methods
We used mice with an epidermal deletion of IRE1α and primary mouse keratinocytes to examine effects of UV on different parameters of the antioxidant response in the presence and absence of functional IRE1α.
Results
In the absence of IRE1α, PERK activity and protein levels are significantly compromised following UVB irradiation. Additionally, the loss of IRE1α suppressed phosphorylation of the PERK target, nuclear factor erythroid-2-related factor 2 (NRF2), and NRF2-dependent antioxidant gene expression after UVB irradiation. Interestingly, IRE1α-deficient keratinocytes exhibit elevated basal ROS levels, while a robust ROS induction upon UVB exposure is abolished. Because UVB-induced ROS plays an essential role in regulating skin inflammation, we analyzed recruited immune cell populations and the expression of pro-inflammatory cytokines, Il-6 and Tnfα, in mice with epidermally targeted deletion of Ire1α. Following UVB irradiation, there was significantly less recruitment of neutrophils and leukocytes and reduced expression of pro-inflammatory cytokine genes in the skin of mice lacking IRE1α. Furthermore, keratinocyte proliferation was also significantly reduced after chronic UVB exposure in the skin of these mice.
Conclusion
Collectively, our findings indicate that IRE1α is essential for basal and UVB-induced oxidative stress response, UV-induced skin immune responses, and keratinocyte proliferation.
Significance statement
These findings shed new light on the protective function of IRE1α in the response to UV. IRE1α plays an important role in the regulation of ROS, PERK stability, and antioxidant gene expression in response to UVB in mouse keratinocytes and epidermis.
Division of Cardiology, Department of Medical Sciences, University of Turin, Italy
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Heart failure is a progressive disease, representing a growing cause of morbidity, hospitalization, and mortality. An increasingly common type of heart failure with preserved ejection fraction (HFpEF) is an immunoglobulin light chain and transthyretin cardiac amyloidosis, in the pathophysiology of which oxidative damage appears to exert a strong impact. Reactive oxygen and nitrogen species have physiological signaling functions, but their overaccumulation, as in cardiac amyloidosis, leads to cardiomyocyte damage and apoptosis, and to cardiac hypertrophy and fibrosis. Moreover, such pathological processes worsen the redox damage with the perpetuation of an inflammatory state, in a vicious cycle. Here, the role of oxidative damage in the transthyretin and immunoglobulin light chain cardiac amyloidosis, the underlying pathogenic mechanisms, the therapeutic implications, and possible future strategies are reviewed.
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Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
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Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
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Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
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Department of Genetics, Universitat de València, Valencia, Spain
INCLIVA Biomedical Research Institute, Unversitat de València, Valencia, Spain
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Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
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l-glutamate is one of the major neurotransmitters in the central nervous system, directly and indirectly involved in numerous brain functions. In several neurodegenerative diseases, it has been observed that an excess of extracellular glutamate overstimulates glutamate receptors, leading to exacerbated neuronal excitation in a process of excitotoxicity and oxidative damage that promotes neuronal death. A number of l-glutamate transporters have been identified in the membrane of neurons and astrocytes. They are responsible for the reuptake of glutamate released into the synaptic cleft after excitatory neurotransmission concomitantly regulating the extracellular concentration of glutamate, protecting neurons from its excitotoxic action. Among all of them, literature highlights glutamate transporter 1, known as excitatory amino acid transporter type 2 in humans and glutamate transporter type 1 in rodents, also known as solute carrier family 1 member 2. It is the predominant glutamate transporter in the brain and ensures the majority of l-glutamate reuptake. Decreased expression of this transporter along with increased levels of oxidative stress have been observed in several chronic and acute neurodegenerative disorders. For this reason, the use of drugs capable of both increasing the expression of glutamate transporter 1 and mitigating oxidative damage has been proposed as an effective therapeutic strategy for these pathologies. We present in this work an overview of the main drugs displaying such a double effect.
