Antioxidants & redox signaling最新文献

Significance: Peroxisome proliferator-activated receptors (PPARs) have a moderately preserved amino-terminal domain, an extremely preserved DNA-binding domain, an integral hinge region, and a distinct ligand-binding domain that are frequently encountered with the other nuclear receptors. PPAR-β/δ is among the three nuclear receptor superfamily members in the PPAR group. Recent Advances: Emerging studies provide an insight on natural compounds that have gained increasing attention as potential anticancer agents due to their ability to target multiple pathways involved in cancer development and progression. Critical Issues: Modulation of PPAR-β/δ activity has been suggested as a potential therapeutic strategy for cancer management. This review focuses on the ability of bioactive phytocompounds to impact reactive oxygen species (ROS) and redox signaling by targeting PPAR-β/δ for cancer therapy. The rise of ROS in cancer cells may play an important part in the initiation and progression of cancer. However, excessive levels of ROS stress can also be toxic to the cells and cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents, such as phytocompounds and therapeutic agents. Therefore, redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells. However, use of antioxidants together with cancer drugs may risk the effect of treatment as both act through opposite mechanisms. Future Directions: It is advisable to employ more thorough and detailed methodologies to undertake mechanistic explorations of numerous phytocompounds. Moreover, conducting additional clinical studies is recommended to establish optimal dosages, efficacy, and the impact of different phytochemicals on PPAR-β/δ.

Aims: Intervertebral disc degeneration (IDD) is closely related to low back pain, which is a prevalent age-related problem worldwide; however, the mechanism underlying IDD is unknown. Glutamine, a free amino acid prevalent in plasma, is recognized for its anti-inflammatory and antioxidant properties in various diseases, and the current study aims to clarify the effect and mechanism of glutamine in IDD. Results: A synergistic interplay was observed between pyroptosis and ferroptosis within degenerated human disc specimens. Glutamine significantly mitigated IDD in both ex vivo and in vivo experimental models. Moreover, glutamine protected nucleus pulposus (NP) cells after tert-butyl hydroperoxide (TBHP)-induced pyroptosis, ferroptosis, and extracellular matrix (ECM) degradation in vitro. Glutamine protected NP cells from TBHP-induced ferroptosis by promoting the nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation by inhibiting its ubiquitin-proteasome degradation and inhibiting lipid oxidation. Innovation and Conclusions: A direct correlation is evident in the progression of IDD between the processes of pyroptosis and ferroptosis. Glutamine suppressed oxidative stress-induced cellular processes, including pyroptosis, ferroptosis, and ECM degradation through deubiquitinating Nrf2 and inhibiting lipid oxidation in NP cells. Glutamine is a promising novel therapeutic target for the management of IDD.

Significance: Stringent regulation of protein homeostasis pathways, under both physiological and pathological conditions, is necessary for the maintenance of proteome fidelity and optimal cell functioning. However, when challenged by endogenous or exogenous stressors, these proteostasis pathways can become dysregulated with detrimental consequences for protein fate, cell survival, and overall organism health. Most notably, there are numerous somatic pathologies associated with a loss of proteostatic regulation, including neurodegenerative disorders, type 2 diabetes, and some cancers. Recent Advances: Lipid oxidation-derived reactive carbonyl species (RCS), such as 4-hydroxynonenal (4HNE) and malondialdehyde, are relatively underappreciated purveyors of proteostatic dysregulation, which elicit their effects via the nonenzymatic post-translational modification of proteins. Emerging evidence suggests that a subset of germline proteins can serve as substrates for 4HNE modification. Among these, prevalent targets include succinate dehydrogenase, heat shock protein A2 and A-kinase anchor protein 4, all of which are intrinsically associated with fertility. Critical Issues: Despite growing knowledge in this field, the RCS adductomes of spermatozoa and oocytes are yet to be comprehensively investigated. Furthermore, the manner by which RCS-mediated adduction impacts protein fate and drives cellular responses, such as protein aggregation, requires further examination in the germline. Given that RCS-protein adduction has been attributed a role in infertility, there has been sparked research investment into strategies to prevent lipid peroxidation in germ cells. Future Directions: An increased depth of knowledge regarding the mechanisms and substrates of RCS-mediated protein modification in reproductive cells may reveal important targets for the development of novel therapies to improve fertility and pregnancy outcomes for future generations.

Significance: Aging is a complex process associated with an increased risk of many diseases, including thrombosis. This review summarizes age-related prothrombotic mechanisms in clinical settings of thromboembolism, focusing on the role of fibrin structure and function modified by oxidative stress. Recent Advances: Aging affects blood coagulation and fibrinolysis via multiple mechanisms, including enhanced oxidative stress, with an imbalance in the oxidant/antioxidant mechanisms, leading to loss of function and accumulation of oxidized proteins, including fibrinogen. Age-related prothrombotic alterations are multifactorial involving enhanced platelet activation, endothelial dysfunction, and changes in coagulation factors and inhibitors. Formation of more compact fibrin clot networks displaying impaired susceptibility to fibrinolysis represents a novel mechanism, which might contribute to atherothrombosis and venous thrombosis. Alterations to fibrin clot structure/function are at least in part modulated by post-translational modifications of fibrinogen and other proteins involved in thrombus formation, with a major impact of carbonylation. Fibrin clot properties are also involved in the efficacy and safety of therapy with oral anticoagulants, statins, and/or aspirin. Critical Issues: Since a prothrombotic state is observed in very elderly individuals free of diseases associated with thromboembolism, the actual role of activated blood coagulation in health remains elusive. It is unclear to what extent oxidative modifications of coagulation and fibrinolytic proteins, in particular fibrinogen, contribute to a prothrombotic state in healthy aging. Future Directions: Ongoing studies will show whether novel therapies that may alter oxidative stress and fibrin characteristics are beneficial to prevent atherosclerosis and thromboembolic events associated with aging.

Aims: In addition to reducing the respiratory function, crystalline silica (SiO₂) disturbs the immune response by affecting immune cells during the progression of silicosis. Regulatory T cell (Treg) differentiation may play a key role in the abnormal polarization of T helper cell (Th)1 and Th2 cells in the development of silicosis-induced fibrosis. Alpha-lipoic acid (ALA) has immunomodulatory effects by promoting Tregs differentiation. Thus, ALA may have a therapeutic potential for treating autoimmune disorders in patients with silicosis. However, little is known regarding whether ALA regulates the immune system during silicosis development. Results: We found that the expression levels of collagen increased, and the antioxidant capacity was lower in the Lias^-/-+SiO₂ group than in the Lias^+/++SiO₂ group. The proportion of Tregs decreased in the peripheral blood and spleen tissue in mice exposed to SiO₂. The proportion of Tregs in the Lias^-/-+SiO₂ group was significantly lower than that in the Lias^+/++SiO₂ group. Supplementary exogenous ALA attenuates the accumulation of inflammatory cells and extracellular matrix in lung tissues. ALA promotes the immunological balance between Th17 and Treg responses during the development of silicosis-induced fibrosis. Innovation and Conclusion: Our findings confirmed that low expression of lipoic acid synthase aggravates SiO₂-induced silicosis, and that supplementary exogenous ALA has therapeutic potential by improving Tregs in silicosis fibrosis.

Aims: Protein disulfide isomerases (PDIs) are a family of chaperones resident in the endoplasmic reticulum (ER). In addition to holdase function, some members catalyze disulfide bond formation and isomerization, a crucial step for native folding and prevention of aggregation of misfolded proteins. PDIs are characterized by an arrangement of thioredoxin-like domains, with the canonical protein disulfide isomerase A1 (PDIA1) organized as four thioredoxin-like domains forming a horseshoe with two active sites, a and a', at the extremities. We aimed to clarify important aspects underlying the catalytic cycle of PDIA1 in the context of the full pathways of oxidative protein folding operating in the ER. Results: Using two fluorescent redox sensors, redox green fluorescent protein 2 (roGFP2) and HyPer (circularly permutated yellow fluorescent protein containing the regulatory domain of the H₂O₂-sensing protein OxyR), either unfolded or native, as client substrates, we identified the N-terminal a active site of PDIA1 as the main oxidant of thiols. From there, electrons can flow to the C-terminal a' active site, with the redox-dependent conformational flexibility of PDIA1 allowing the formation of an interdomain disulfide bond. The a' active site then acts as a crossing point to redirect electrons to ER downstream oxidases or back to client proteins to reduce scrambled disulfide bonds. Innovation and Conclusions: The two active sites of PDIA1 work cooperatively as an interdomain redox relay mechanism that explains PDIA1 oxidative activity to form native disulfides and PDIA1 reductase activity to resolve scrambled disulfides. This mechanism suggests a new rationale for shutting down oxidative protein folding under ER redox imbalance. Whether it applies to physiological substrates in cells remains to be shown.