Antioxidant Effects of Irisin in Liver Diseases: Mechanistic Insights

Oxidative stress is a crucial factor in the development of various liver diseases. Irisin, a metabolic hormone discovered in 2012, is mainly produced by proteolytic cleavage of fibronectin type III domain containing 5 (FNDC5) in skeletal muscles. Irisin is induced by physical exercise, and a rapidly growing body of literature suggests that irisin is, at least partially, responsible for the beneficial effects of regular exercise. The major biological function of irisin is believed to be involved in the maintenance of metabolic homeostasis. However, recent studies have suggested the therapeutic potential of irisin against a variety of liver diseases involving its antioxidative function. In this review, we aim to summarize the accumulating evidence demonstrating the antioxidative effects of irisin in liver diseases, with an emphasis on the current understanding of the potential molecular mechanisms.

Glutathione Is Required for the Early Alert Response and Subsequent Acclimation in Cadmium-Exposed Arabidopsis thaliana Plants

Pollution by cadmium (Cd) is a worldwide problem, posing risks to human health and impacting crop yield and quality. Cadmium-induced phytotoxicity arises from an imbalance between antioxidants and pro-oxidants in favour of the latter. The Cd-induced depletion of the major antioxidant glutathione (GSH) strongly contributes to this imbalance. Rather than being merely an adverse effect of Cd exposure, the rapid depletion of root GSH levels was proposed to serve as an alert response. This alarm phase is crucial for an optimal stress response, which defines acclimation later on. To obtain a better understanding on the importance of GSH in the course of these responses and how these are defined by the rapid GSH depletion, analyses were performed in the GSH-deficient cadmium-sensitive 2-1 (cad2-1) mutant. Cadmium-induced root and leaf responses related to oxidative challenge, hydrogen peroxide (H2O2), GSH, ethylene, and aminocyclopropane-1-carboxylic acid (ACC) were compared between wild-type (WT) and mutant Arabidopsis thaliana plants. Although the cad2-1 mutant has significantly lower GSH levels, root GSH depletion still occurred, suggesting that the chelating capacity of GSH is prioritised over its antioxidative function. We demonstrated that responses related to GSH metabolism and ACC production were accelerated in mutant roots and that stress persisted due to suboptimal acclimation. In general, the redox imbalance in cad2-1 mutant plants and the lack of proper transient ethylene signalling contributed to this suboptimal acclimation, resulting in a more pronounced Cd effect.

Arabidopsis iron superoxide dismutase 1 protects against methyl viologen-induced oxidative stress in a copper-dependent manner

Iron superoxide dismutase 1 (FSD1) was recently characterized as a plastidial, cytoplasmic, and nuclear superoxide dismutase with osmoprotective and antioxidative functions. However, its role in oxidative stress tolerance is not well understood. Here, we characterized the role of FSD1 in response to methyl viologen (MV)-induced oxidative stress in Arabidopsis thaliana. The findings demonstrated that the antioxidative function of FSD1 depends on the availability of Cu2+ in growth media. Prolonged MV exposure led to a decreased accumulation rate of superoxide, higher levels of hydrogen peroxide production, and higher protein carbonylation in the fsd1 mutants and transgenic plants lacking a plastidial pool of FSD1, compared to the wild type. MV led to a rapid increase in FSD1 activity, followed by a decrease. Chloroplastic localization of FSD1 is necessary for these changes. Proteomic analysis showed that the sensitivity of the fsd1 mutants coincided with decreased abundance of ferredoxin and light PSII harvesting complex proteins, with altered levels of signaling proteins. Collectively, the study provides evidence for the conditional antioxidative function of FSD1 and its possible role in signaling.

Sestrin2 protects dendrite cells against ferroptosis induced by sepsis

Ferroptosis is a nonapoptotic form of programmed cell death triggered by the accumulation of reactive oxygen species (ROS) depended on iron overload. Although most investigations focus on the relationship between ferroptosis and cancer, neurodegenerative diseases, and ischemia/reperfusion injury, research on ferroptosis induced by immune-related inflammatory diseases, especially sepsis, is scarce. Sestrin2 (Sesn2), a highly evolutionary and stress-responsive protein, is critically involved in defense against oxidative stress challenges. Upregulated expression of Sesn2 has been observed in preliminary experiments to have an antioxidative function in the context of an inflammatory response. Nevertheless, the underlying function of Sesn2 in inflammation-mediated ferroptosis in the immune system remains uncertain. The current study aimed to demonstrate the protective effect of Sesn2 on ferroptosis and even correlations with ferroptosis and the functions of ferroptotic-dendritic cells (DCs) stimulated with lipopolysaccharide (LPS). The mechanism underlying DCs protection from LPS-induced ferroptosis by Sesn2 was further explored in this study. We found that the immune response of DCs assessed by co-stimulatory phenotypes was gradually enhanced at the peak time of 12 h upon 1 μg/ml LPS stimulation while ferroptosis in DCs treated with LPS at 24 h was significantly detected. LPS-induced ferroptosis showed a suppressive impact on DCs in phenotypic maturation, which was conversely relieved by the ferroptotic inhibitor. Compared with wild-type (WT) mice, DCs in genetic defective mice of Sesn2 (Sesn2−/−) exhibited exacerbated ferroptosis. Furthermore, the protective effect of Sesn2 on ferroptosis was noticed to be associated with the ATF4-CHOP-CHAC1 pathway, eventually exacerbating ferroptosis by degrading of glutathione. These results indicate that Sesn2 can suppress the ferroptosis of DCs in sepsis by downregulating the ATF4-CHOP-CHAC1 signaling pathway, and it might play an antioxidative role.

Expression of TXNIP is associated with angiogenesis and postoperative relapse of conventional renal cell carcinoma

One of the common mediator of tumour progression is the oxidative stress induced by inflammatory tumour microenvironment (TME). Activated fibroblasts, local and immune cells produce reactive oxygen species (ROS) supporting tumour cell proliferation and pave the way for metastatic tumour growth. TXNIP regulates ROS generation by inhibiting the antioxidative function of thioredoxin (TXN). The shift of TXNIP/TXN balance towards overexpression of TXNIP is associated with proliferation of endothelial cells during tumor angiogenesis. The oxidative stress activates the hypoxia inducible factor-1 (HIF-1), which plays an important role in the biology of conventional RCC (cRCC). Under oxydative stress TXNIP interacts with NLRP3 inflammasome leading to maturation and secretion of inflammatory cytokine IL1β. To establish the role of TXNIP and downstream genes HIF1α and IL1β in the biology of cRCC, we have applied immunohistochemistry to multi-tissue arrays containing tumours of 691 patients without detectable metastases at the time of operation. We found that cRCC displaying a fine organised capillary network with nuclear translocation of TXNIP and expressing IL1β have a good prognosis. In contrary, we showed a significant correlation between cytoplasmic TXNIP expression, inefficient vascularisation by unorganized and tortuous vessels causing tumour cell necrosis and postoperative tumour relapse of cRCC.

Inhibition of Thioredoxin Reductase by Santamarine Conferring Anticancer Effect in HeLa Cells

Natural products frequently have unique physiological activities and new action mechanisms due to their structural diversity and novelty, and are an important source for innovative drugs and lead compounds. We present herein that natural product santamarine targeted thioredoxin reductase (TrxR) to weaken its antioxidative function in cells, accompanied by accumulation of high levels of reactive oxygen species (ROS), and finally induced a new mechanism of tumor cell oxidative stress-mediated apoptosis. TrxR knockdown or overexpression cell lines were employed to further evaluate the cytotoxicity of santamarine regulated by TrxR, demonstrated that TrxR played a key role in the physiological effect of santamarine on cells. Santamarine targeting TrxR reveals its previously unrecognized mechanism of antitumor and provides a basis for the further development of santamarine as a potential cancer therapeutic agent.

Antioxidative Effects of Carrot-Derived Nanovesicles in Cardiomyoblast and Neuroblastoma Cells

Oxidative stress is implicated in many diseases, including cardiovascular and neurodegenerative diseases. Because an increased level of oxidative stress causes apoptosis, it is necessary to inhibit cellular responses to oxidative stress. In this study, Carex, a nanovesicle from carrot, was isolated and investigated as a novel biomaterial with antioxidative function in cardiomyoblasts and neuroblastoma cells. A high concentration of nanovesicles was purified from carrots, using size-exclusion chromatography in combination with ultrafiltration. The characterization of Carex demonstrated that it had properties similar to those of extracellular vesicles. Carex showed low cytotoxicity in both H9C2 cardiomyoblasts and SH-SY5Y neuroblastoma cells, when a high level of Carex was delivered to the cells. Carex was further investigated for its antioxidative and apoptotic effects, and it significantly inhibited ROS generation and apoptosis in vitro in myocardial infarction and Parkinson’s disease models. Carex inhibited the reduction of antioxidative molecule expression, including Nrf-2, HO-1, and NQO-1, in both models. Considering its antioxidative function and high production yield, Carex is a potential drug candidate for the treatment of myocardial infarction as well as Parkinson’s disease. Thus, the results demonstrated in this study will contribute to an exploration of a novel drug, using nanovesicles from plants, including carrots.

Telomerase as a Therapeutic Target in Cardiovascular Disease

Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials. Graphic Abstract: A graphic abstract is available for this article.

Changes in oxidation-antioxidation function on the thymus of chickens infected with reticuloendotheliosis virus

Background Reticuloendotheliosis virus (REV) is a retrovirus that causes severe immunosuppression in poultry. Animals grow slowly under conditions of oxidative stress. In addition, long-term oxidative stress can impair immune function, as well as accelerate aging and death. This study aimed to elucidate the pathogenesis of REV from the perspective of changes in oxidative-antioxidative function following REV infection. Methods A total of 80 one-day-old specific pathogen free (SPF) chickens were randomly divided into a control group (Group C) and an REV-infected group (Group I). The chickens in Group I received intraperitoneal injections of REV with 104.62/0.1 mL TCID50. Thymus was collected on day 1, 3, 7, 14, 21, 28, 35, and 49 for histopathology and assessed the status of oxidative stress. Results In chickens infected with REV, the levels of H2O2 and MDA in the thymus increased, the levels of TAC, SOD, CAT, and GPx1 decreased, and there was a reduction in CAT and Gpx1 mRNA expression compared with the control group. The thymus index was also significantly reduced. Morphological analysis showed that REV infection caused an increase in the thymic reticular endothelial cells, inflammatory cell infiltration, mitochondrial swelling, and nuclear damage. Conclusions These results indicate that an increase in oxidative stress enhanced lipid peroxidation, markedly decreased antioxidant function, caused thymus atrophy, and immunosuppression in REV-infected chickens.

Pretreatment of Ascorbic Acid Inhibits MPTP-Induced Astrocytic Oxidative Stress through Suppressing NF-κB Signaling

Astrocytes are a major constituent of the central nervous system (CNS). Astrocytic oxidative stress contributes to the development of Parkinson’s disease (PD). Maintaining production of antioxidant and detoxification of reactive oxygen and nitrogen species (ROS/RNS) in astrocytes is critical to prevent PD. Study has illuminated that ascorbic acid (AA) stimulates dopamine synthesis and expression of tyrosine hydroxylase in human neuroblastoma cells. However, the role and regulatory mechanisms of AA on detoxification of astrocytes are still unclear. The purpose of our study is in-depth study of the regulatory mechanism of AA on detoxification of astrocytes. We found that AA pretreatment decreased the expression of ROS and inducible nitric oxide synthase (iNOS) in MPP+-treated astrocytes. In contrast, the expression levels of antioxidative substances—including superoxide dismutase (SOD), glutathione (GSH), and glutamate-cysteine ligase modifier (GCLM) subunit—were upregulated after AA pretreatment in MPP+-treated astrocytes. However, inhibition of NF-κB prevented such AA induced increases in antioxidative substances following MPP+ treatment in astrocytes, suggesting that AA improved antioxidative function of astrocytes through inhibiting NF-κB-mediated oxidative stress. Furthermore, in vivo studies revealed that AA preadministration also suppressed NF-κB and upregulated the expression levels of antioxidative substances in the midbrain of MPTP-treated mice. Additionally, pretreatment of AA alleviated MPTP-induced PD-like pathology in mice. Taken together, our results demonstrate that preadministration of AA improves the antioxidative function of astrocytes through suppressing NF-κB signaling, following alleviated the pathogenesis of PD which induced by MPTP. Hence, our findings elucidate a novel protective mechanism of AA in astrocytes.