Search Results (8,681)

Cisplatin-induced acute kidney injury (AKI) is an important factor that limits the clinical use of this drug for the treatment of malignancies. Oxidative stress and inflammation are considered to be the main causes of not only cisplatin-induced death of cancer cells but also cisplatin-induced AKI. Therefore, developing agents that exert antioxidant and anti-inflammatory effects without weakening the anti-tumor effects of cisplatin is highly desirable. Carbon monoxide (CO) has recently attracted interest due to its antioxidant, anti-inflammatory, and anti-tumor properties. Herein, we report that CO-loaded red blood cell (CO-RBC) exerts renoprotective effects on cisplatin-induced AKI. Cisplatin treatment was found to reduce cell viability in proximal tubular cells via oxidative stress and inflammation. Cisplatin-induced cytotoxicity, however, was suppressed by the CO-RBC treatment. The intraperitoneal administration of cisplatin caused an elevation in the blood urea nitrogen and serum creatinine levels. The administration of CO-RBC significantly suppressed these elevations. Furthermore, the administration of CO-RBC also reduced the deterioration of renal histology and tubular cell injury through its antioxidant and anti-inflammatory effects in cisplatin-induced AKI mice. Thus, our data suggest that CO-RBC has the potential to substantially prevent the onset of cisplatin-induced AKI, which, in turn, may improve the usefulness of cisplatin-based chemotherapy. Full article

Carlina vulgaris is a poorly understood plant in the context of biological activity, despite its widespread application in ethnomedicine in numerous European countries. The aim of this study was to assess the cytotoxic potential of the plant against human colorectal adenocarcinoma (HT29) and to isolate the plant components linked to this effect. Ultra-high performance liquid chromatography with a high-resolution/quadrupole time-of-flight mass spectrometer (UHPLC–HR/QTOF/MS–PDA) was used for the phytochemical characterization of the extract. Liquid–liquid extraction and preparative chromatography were employed for fractionation purposes. Our investigation demonstrated that the ethyl acetate fraction from C. vulgaris showed significant cytotoxicity, and a bioactivity-guided approach led to the isolation of oxylipins, including traumatic acid, pinellic acid, and 9,10-dihydroxy-8-oxsooctadec-12-enic acid. The structures of the compounds were confirmed by nuclear magnetic resonance spectroscopy. Among these compounds, the last one exhibited significant cytotoxicity, though without selectivity, and traumatic acid was characterized by mild cytotoxicity. The cytotoxicity was linked to intracellular reactive oxygen species generation. Full article

The type III intermediate filament proteins vimentin and GFAP are modulated by oxidants and electrophiles, mainly through perturbation of their single cysteine residues. Desmin, the type III intermediate filament protein specific to muscle cells, is critical for muscle homeostasis, playing a key role in sarcomere organization and mitochondrial function. Here, we have studied the impact of oxidants and cysteine-reactive agents on desmin behavior. Our results show that several reactive species and drugs induce covalent modifications of desmin in vitro, of which its single cysteine residue, C333, is an important target. Moreover, stimuli eliciting oxidative stress or lipoxidation, including H₂O₂, 15-deoxy-prostaglandin J₂, and CoCl₂-elicited chemical hypoxia, provoke desmin disorganization in H9c2 rat cardiomyoblasts transfected with wild-type desmin, which is partially attenuated in cells expressing a C333S mutant. Notably, in cells lacking other cytoplasmic intermediate filaments, network formation by desmin C333S appears less efficient than that of desmin wt, especially when these proteins are expressed as fluorescent fusion constructs. Nevertheless, in these cells, the desmin C333S organization is also protected from disruption by oxidants. Taken together, our results indicate that desmin is a target for oxidative and electrophilic stress, which elicit desmin remodeling conditioned by the presence of its single cysteine residue. Full article

Candida auris, a multidrug-resistant fungal pathogen, significantly threatens global public health. Recent studies have identified melanin production, a key virulence factor in many pathogenic fungi that protects against external threats like reactive oxygen species, in C. auris. However, the melanin regulation mechanism remains elusive. This study explores the role of the Ras/cAMP/PKA signaling pathway in C. auris melanization. It reveals that the catalytic subunits Tpk1 and Tpk2 of protein kinase A (PKA) are essential, whereas Ras1, Gpr1, Gpa2, and Cyr1 are not. Under melanin-promoting conditions, the tpk1Δ tpk2Δ strain formed melanin granules in the supernatant akin to the wild-type strain but failed to adhere them properly to the cell wall. This discrepancy is likely due to a decreased expression of chitin-synthesis-related genes. Our findings also show that Tpk1 primarily drives melanization, with Tpk2 having a lesser impact. To corroborate this, we found that C. auris must deploy Tpk1-dependent melanin deposition as a defensive mechanism against antioxidant exposure. Moreover, we confirmed that deletion mutants of multicopper oxidase and ferroxidase genes, previously assumed to influence C. auris melanization, do not directly contribute to the process. Overall, this study sheds light on the role of PKA in C. auris melanization and enhances our understanding of the pathogenicity mechanisms of this emerging fungal pathogen. Full article

Geranylgeranylacetone (GGA) exerts cytoprotective activity against various toxic stressors via the thioredoxin (TRX) redox system; however, its effect on skin inflammation and molecular mechanism on inducing the TRX of GGA is still unknown. We investigated the effects of GGA in a murine irritant contact dermatitis (ICD) model induced by croton oil. Both a topical application and oral administration of GGA induced TRX production and Nrf2 activation. GGA ameliorated ear swelling, neutrophil infiltration, and inhibited the expression of TNF-α, IL-1β, GM-CSF, and 8-OHdG. GGA’s cytoprotective effect was stronger orally than topically in mice. In vitro studies also showed that GGA suppressed the expression of NLRP3, TNF-α, IL-1β, and GM-CSF and scavenged ROS in PAM212 cells after phorbol myristate acetate stimulation. Moreover, GGA induced endogenous TRX production and Nrf2 nuclear translocation in PAM212 cells (dependent on the presence of ROS) and activated the PI3K-Akt signaling pathway. GGA significantly downregulated thioredoxin-interacting protein (TXNIP) levels in PAM212 cells treated with or without Nrf2 siRNA. After knocking down Nrf2 in PAM212 cells, the effect of GGA on TRX induction was significantly inhibited. This suggests that GGA suppress ICD by inducing endogenous TRX, which may be regulated by PI3K/Akt/Nrf2 mediation of the TRX redox system. Full article

Stress has brought about a variety of harmful impacts on different animals, leading to difficulties in the management of animal husbandry and aquaculture. Curcumin has been recognized as a potential component to ameliorate the adverse influence of animal stress induced by toxicity, inflammation, diseases, thermal effect, and so on. In detail, this compound is known to offer various outstanding functions, including antibacterial properties, antioxidant effects, immune response recovery, and behavioral restoration of animals under stress conditions. However, curcumin still has some limitations, owing to its low bioavailability. This review summarizes the latest updates on the regulatory effects of curcumin in terms of stress management in terrestrial, avian, and aquatic animals. Full article

Cocoa shell is a by-product of cocoa manufacturing. We obtained an aqueous extract (CSE) rich in polyphenols and methylxanthines with antioxidant and vasodilatory properties. We aimed to evaluate the effects of CSE supplementation in aged hypertensive rats on blood pressure and the mechanism implicated. Eighteen-month-old male and female rats exposed to undernutrition during the fetal period who developed hypertension, with a milder form in females, were used (MUN rats). Systolic blood pressure (SBP; tail-cuff plethysmography) and a blood sample were obtained before (basal) and after CSE supplementation (250 mg/kg; 2 weeks, 5 days/week). Plasma SOD, catalase activity, GSH, carbonyls, and lipid peroxidation were assessed (spectrophotometry). In hearts and aortas from supplemented and non-supplemented age-matched rats, we evaluated the protein expression of SOD-2, catalase, HO-1, UCP-2, total and phosphorylated Nrf2 and e-NOS (Western blot), and aorta media thickness (confocal microscopy). MUN males had higher SBP compared with females, which was reduced via CSE supplementation with a significant difference for group, sex, and interaction effect. After supplementation with plasma, GSH, but not catalase or SOD, was elevated in males and females. Compared with non-supplemented rats, CSE-supplemented males and females exhibited increased aorta e-NOS and Nrf2 protein expression and cardiac phosphorylated-Nrf2, without changes in SOD-2, catalase, HO-1, or UCP-2 in cardiovascular tissues or aorta remodeling. In conclusion, CSE supplementation induces antihypertensive actions related to the upregulation of e-NOS and Nrf2 expression and GSH elevation and a possible direct antioxidant effect of CSE bioactive components. Two weeks of supplementation may be insufficient to increase antioxidant enzyme expression. Full article

Lesch–Nyhan syndrome (LN) is an is an X-linked recessive inborn error of metabolism that arises from a deficiency of purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). The disease manifests severely, causing intellectual deficits and other neural abnormalities, hypercoagulability, uncontrolled self-injury, and gout. While allopurinol is used to alleviate gout, other symptoms are less understood, impeding treatment. Herein, we present a high-throughput multi-omics analysis of red blood cells (RBCs) from three pediatric siblings carrying a novel S162N HPRT1 mutation. RBCs from both parents—the mother, a heterozygous carrier, and the father, a clinically healthy control—were also analyzed. Global metabolite analysis of LN RBCs shows accumulation of glycolytic intermediates upstream of pyruvate kinase, unsaturated fatty acids, and long chain acylcarnitines. Similarly, highly unsaturated phosphatidylcholines are also elevated in LN RBCs, while free choline is decreased. Intracellular iron, zinc, selenium, and potassium are also decreased in LN RBCs. Global proteomics documented changes in RBC membrane proteins, hemoglobin, redox homeostasis proteins, and the enrichment of coagulation proteins. These changes were accompanied by elevation in protein glutamine deamidation and methylation in the LN children and carrier mother. Treatment with allopurinol incompletely reversed the observed phenotypes in the two older siblings currently on this treatment. This unique data set provides novel opportunities for investigations aimed at potential therapies for LN-associated sequelae. Full article

Onion peels (OP) are rich in bioactive compounds with a plethora of benefits for human health, but this valuable material is often wasted and underutilized due to its inedibility. Likewise, grapevine pruning residues are commonly treated as agricultural waste, but biochar (BC) obtained from this material has favorable characteristics as an adsorbent. This study investigated the potential of BC in removal of targeted polyphenolic compounds from OP extracts. The OP extracts were obtained adhering to green chemistry principles using deionized water amplified by three methods: maceration (MAC), ultrasound-assisted extraction (UAE), and microwave-assisted extraction (MAE). The extraction efficiency on the polyphenolic profile and antioxidant capacity was investigated with different extraction temperatures and solid-to-liquid (s/l) ratios. For further analysis, UAE at 90 °C with an s/l ratio of 1:100 was used due to higher polyphenolic compound yield. The BC adsorption capacity of individual polyphenols was fitted with the Langmuir and Freundlich isotherm models. Quercetin-3,4′-diglucoside obtained the highest R² coefficient in both models, and the highest q_max value. The optimum conditions in the dosage experiment suggested an amount of 0.5 g of BC using 3 g/L extracts. The studied BC showed a high affinity for targeted phytochemicals from OP extracts, indicating its potential to be applied for the green adsorption of valuable polyphenolic compounds. Full article

Redox signaling from mitochondria (mt) to the cytosol and plasma membrane (PM) has been scarcely reported, such as in the case of hypoxic cell adaptation or (2-oxo-) 2-keto-isocaproate (KIC) β-like-oxidation stimulating insulin secretion in pancreatic β-cells. Mutual redox state influence between mitochondrial major compartments, the matrix and the intracristal space, and the cytosol is therefore derived theoretically in this article to predict possible conditions, when mt-to-cytosol and mt-to-PM signals may occur, as well as conditions in which the cytosolic redox signaling is not overwhelmed by the mitochondrial antioxidant capacity. Possible peroxiredoxin 3 participation in mt-to-cytosol redox signaling is discussed, as well as another specific case, whereby mitochondrial superoxide release is diminished, whereas the matrix MnSOD is activated. As a result, the enhanced conversion to H₂O₂ allows H₂O₂ diffusion into the cytosol, where it could be a predominant component of the H₂O₂ release. In both of these ways, mt-to-cytosol and mt-to-PM signals may be realized. Finally, the use of redox-sensitive probes is discussed, which disturb redox equilibria, and hence add a surplus redox-buffering to the compartment, where they are localized. Specifically, when attempts to quantify net H₂O₂ fluxes are to be made, this should be taken into account. Full article

The effects of repetitive magnetic stimulation (rMS) have predominantly been studied in excitable cells, with limited research in non-excitable cells. This study aimed to investigate the impact of rMS on macrophages, which are crucial cells in the innate immune defense. THP-1-derived macrophages subjected to a 5 min session of 10 Hz rMS exhibited increased Nrf2 activation and decreased Keap1 expression. We found that activation of the Nrf2 signaling pathway relied on rMS-induced phosphorylation of p62. Notably, rMS reduced the intracellular survival of Staphylococcus aureus in macrophages. Silencing Nrf2 using siRNA in THP-1-derived macrophages or utilizing Nrf2 knockout in alveolar macrophages abolished this effect. Additionally, rMS attenuated the expression of IL-1β and TNF-α inflammatory genes by S. aureus and inhibited p38 MAPK activation. These findings highlight the capacity of rMS to activate the non-canonical Nrf2 pathway, modulate macrophage function, and enhance the host’s defense against bacterial infection. Full article

Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy, affecting the photoreceptors, retinal pigment epithelium (RPE) and choroid, with no approved therapy. CHM is caused by mutations in the CHM gene, which encodes the ubiquitously expressed Rab escort protein 1 (REP1). REP1 is involved in prenylation, a post-translational modification of Rab proteins, and plays an essential role in intracellular trafficking. In this study, we examined oxidative and endoplasmic reticulum (ER) stress pathways in chm^ru848 zebrafish and CHM^Y42X patient fibroblasts, and screened a number of neuroprotectants for their ability to reduce stress. The expression of the oxidative stress markers txn, cat and sod3a, and the ER stress markers bip, atf4 and atf6, were dysregulated in chm^ru848 fish. The expression of SOD2 was also reduced in CHM^Y42X fibroblasts, along with reduced BIP and increased CHOP expression. The lack of REP1 is associated with defects in vesicular trafficking, photoreceptor outer segment phagocytosis and melanosome transport, leading to increased levels of stress within the retina and RPE. Drugs targeting oxidative and ER stress pathways represent novel therapeutic avenues. Full article

Excessive oxidative stress and inflammatory responses are associated with the development of various diseases, including cancer. Glucosinolates (GSLs) are phytochemicals known for their antioxidant properties, and doubled haploid lines (DHLs) of Brassica rapa with high GSL contents (HGSL) were intentionally developed from two edible subspecies of Brassica rapa: B. rapa subsp. trilocularis and B. rapa subsp. chinensis. The purpose of the present study is to assess the capacity of HGSL DHLs to mitigate oxidative stress and inflammation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, compared to pak choi as a parental control. Our findings demonstrate that HGSL DH lines effectively suppressed the expression of inducible nitric oxide synthase, leading to the reduced levels of nitric oxide at non-toxic concentrations. Additionally, these lines exhibited scavenging activity against reactive oxygen species and free radicals. The enhanced antioxidant capacity of HGSL DHLs was mechanistically attributed to the upregulation of antioxidant enzymes, such as NADPH quinone oxidoreductase 1 (NQO1), the glutamate–cysteine ligase catalytic subunit (GCLC), and heme oxygenase-1 (HMOX1). Furthermore, we confirmed that these effects were mediated through the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway via p38 phosphorylation. Moreover, HGSL DHLs demonstrated inhibitory effects on pro-inflammatory cytokines and signal transducers and activators of transcription 3 (STAT3) phosphorylation. Collectively, our results indicate that HGSL DHLs possess better antioxidant and anti-inflammatory properties compared to the parental control pak choi in LPS-stimulated RAW264.7 cells, suggesting that HGSL DHLs of Brassica rapa could be considered as a beneficial daily vegetable for reducing the risk of inflammation-associated diseases. Full article

The cross-kingdom stress hormone abscisic acid (ABA) and its mammalian receptors LANCL1 and LANCL2 regulate the response of cardiomyocytes to hypoxia by activating NO generation. The overexpression of LANCL1/2 increases transcription, phosphorylation and the activity of eNOS and improves cell vitality after hypoxia/reoxygenation via the AMPK/PGC-1α axis. Here, we investigated whether the ABA/LANCL system also affects the mitochondrial oxidative metabolism and structural proteins. Mitochondrial function, cell cycle and the expression of cytoskeletal, contractile and ion channel proteins were studied in H9c2 rat cardiomyoblasts overexpressing or silenced by LANCL1 and LANCL2, with or without ABA. Overexpression of LANCL1/2 significantly increased, while silencing conversely reduced the mitochondrial number, OXPHOS complex I, proton gradient, glucose and palmitate-dependent respiration, transcription of uncoupling proteins, expression of proteins involved in cytoskeletal, contractile and electrical functions. These effects, and LANCL1/2-dependent NO generation, are mediated by transcription factor ERRα, upstream of the AMPK/PGC1-α axis and transcriptionally controlled by the LANCL1/2–ABA system. The ABA-LANCL1/2 hormone-receptor system controls fundamental aspects of cardiomyocyte physiology via an ERRα/AMPK/PGC-1α signaling axis and ABA-mediated targeting of this axis could improve cardiac function and resilience to hypoxic and dysmetabolic conditions. Full article

The repair of the damage produced to the genome and proteome by the action of ionizing radiation, oxidizing agents, and during aging is important to maintain cellular homeostasis. Many of the metabolic pathways influence multiple processes. In this way, this work aims to study the relationship between resistance/response to ionizing radiation, cellular aging, and the response mechanisms to oxidative stress, free radicals, reactive oxygen species (ROS), and antioxidant activity in the yeast S. cerevisiae. Systems biology allows us to use tools that reveal the molecular mechanisms common to different cellular response phenomena. The results found indicate that homologous recombination, non-homologous end joining, and base excision repair pathways are the most important common processes necessary to maintain cellular homeostasis. The metabolic routes of longevity regulation are those that jointly contribute to the three phenomena studied. This study proposes eleven common biomarkers for response/resistance to ionizing radiation and aging (EXO1, MEC1, MRE11, RAD27, RAD50, RAD51, RAD52, RAD55, RAD9, SGS1, YKU70) and two biomarkers for response/resistance to radiation and oxidative stress, free radicals, ROS, and antioxidant activity (NTG1, OGG1). In addition, it is important to highlight that the HSP104 protein could be a good biomarker common to the three phenomena studied. Full article