Pro-oxidant Effects Research Articles

Cellular pathway disturbances elicited by realistic dexamethasone concentrations in gills of mussel Mytilus galloprovincialis as assessed by a multi-biomarker approach

The growing usage of glucocorticoids for a variety of diseases raises concerns since these drugs, including the anti-inflammatory dexamethasone (DEX), are frequently found in the environment. The impact of DEX was evaluated on mussels Mytilus galloprovincialis (Lamarck, 1819) by exposure to environmental concentrations (C1: 4ng/L; C2: 40ng/L; C3: 400ng/L; C4: 2000 ng/L), and sampling at 3 (T3), 6 (T6), and 12 (T12) days. A multi-biomarker approach was applied on gills, involved in gas exchange, feed filtering, and osmoregulation. A dose- and time-dependent uptake of DEX was recorded, besides haemocyte infiltration, increased neutral and acid mucopolysaccharides, and a general pro-oxidant effect witnessed by lipid peroxidation and altered antioxidant system. Metabolomics revealed rise in protein turnover and energy demand by fluctuations in free amino acids (alanine, glycine) and energy-related metabolites (succinate, ATP/ADP). It is necessary to reduce DEX dosage from the environment by recovery strategies and effective eco-pharmacovigilance programs.

Catechol-derived Mannich bases: radical regulatory properties, cytotoxicity and interaction with biomolecules

Free radicals are ubiquitous in biological systems, being responsible for pathogenesis of degenerative diseases and participating in vitally important biochemical processes, which are mediated by radical regulatory agents. The effects of the aliphatic amine substituents in the catechol-derived Mannich bases on their antioxidant and pro-oxidant activity were investigated. It has been found that the presence of catechol moiety in the structure of Mannich bases allows them to act as Cu(II) reductants, efficient Fe(II) chelators and potent DPPH radical scavengers. It has been found that the plausible mechanism of the DPPH radical scavenging proceeds via quinone formation, followed by their interaction with ethanol via the Michael addition reaction. In the neutrophil respiratory burst assay, several compounds have demonstrated a weak antioxidant activity at the micromolar level (0.1–10 µM), whereas at the millimolar level (0.1 mМ) a strong pro-oxidant effect has been observed. Additionally, at the highest used concentrations a pronounced cytotoxicity against dermal fibroblasts DF-2 and an immunosuppressive effect against T-lymphocytes have been observed for all the synthesized compounds. It has been demonstrated that the oxidation of catechols in the presence of low-molecular thiols results in the formation of covalent adducts, which provides an insight into their cytotoxicity and detoxification pathways.

Antibacterial efficacy of berry juices against Bacillus cereus relative to their phytochemical composition and antioxidant properties

Ensuring the safety and stability of minimally processed foods using natural preservatives is of great scientific and commercial interest in modern biotechnology. Berry juice supplementation is increasingly recognized within this field. This study investigated the effectiveness of juices from four berry species Aronia melanocarpa, Ribes nigrum, Vaccinium macrocarpon, and Sambucus nigra, against the food pathogen Bacillus cereus. Overall, the antibacterial potency of juice supplements (up to 10% v/v in tryptic soy broth) followed the order of chokeberry > blackcurrant > cranberry > elderberry, with the latter showing no inhibitory effects. Notably, chokeberry and elderberry juices presented lower acidity and significantly greater phenolic contents (p < 0.05) than blackcurrant and cranberry juices did, suggesting that B. cereus susceptibility is not strictly dependent upon low extracellular pH or elevated anthocyanin levels. Instead, it is inferred to correlate with pro-oxidative effects induced directly at the intracellular level. Accordingly, this paper discusses the antioxidative, acidic, and lipophilic attributes of juices and their constituent fractions, including anthocyanins, to elucidate their biopreservative potential. The results of this study increase our understanding of the antibacterial susceptibility of B. cereus.

Abstract 4136905: EF-24, a curcumin analog, reverses interleukin-18-induced miR-30b or miR-342-dependent TRAF3IP2 expression, RECK suppression, and the proinflammatory phenotype of human aortic smooth muscle cells

Curcumin, a polyphenolic compound derived from the widely used spice Curcuma longa, has shown anti-atherosclerotic effects in cultured vascular cells and animal models. We previously reported that the induction of the proinflammatory molecule TRAF3IP2 (TRAF3 Interacting protein 2) or inhibition of the matrix metalloproteinase (MMP) regulator RECK (Reversion Inducing Cysteine Rich Protein with Kazal Motifs) contributes to agonist-induced proinflammatory, pro-oxidant, pro-mitogenic and pro-migratory effects in vascular smooth muscle cells. Here we hypothesized that, EF-24 ((3E,5E)-3,5-bis[2-fluorophenyl (methylene]-4piperidinone), a curcumin analog with better bioavailability and potency, reverses interleukin (IL)-18-induced TRAF3IP2 induction, RECK suppression and the proinflammatory phenotype of primary human aortic smooth muscle cells (ASMC). Exposure to recombinant human IL-18 (10 ng/ml) induced TRAF3IP2 mRNA and protein expression, but markedly suppressed RECK in a time-dependent manner. Further investigations revealed that IL-18 induced miR-30b, but suppressed miR-342, in a p38 MAPK and JNK-dependent manner. While miR-30b inhibitor blunted IL-18-induced TRAF3IP2 expression, miR-30b inhibitor and miR-342 mimic each restored RECK expression. Further, IL-18 induced ASMC migration (Boyden chamber assay) and proliferation (CyQUANT Cell Proliferation assay), and these effects were reversed by TRAF3IP2 knockdown or RECK overexpression. Our results also show that IL-18 induced MMP2 and MMP9 expression and activity, and targeting their expression inhibited IL-18-induced ASMC migration. TRAF3IP2 knockdown or RECK overexpression also reversed IL-18-induced ASMC proinflammatory phenotype switching as evidenced by the enhanced expression of the SMC markers ACTA2 and MYH11, and reduced expression of the proinflammatory markers Galectin 3, Olr1, VCAM, CCL2, IL-6, IL-8, and TNF-α. Importantly, preincubation with EF-24 markedly suppressed IL-18-induced SMC proliferation, MMP expression, migration and the proinflammatory phenotype switching. Together, these results suggest that the curcumin analog EF-24 has therapeutic potential in vascular inflammatory and proliferative diseases, including atherosclerosis, by differentially regulating TRAF3IP2 and RECK in vascular SMC.

Electronic cigarettes Alter cardiac rhythm and heart rate variability hyperacutely in mice

AimsThere has been an unprecedented rise in electronic cigarette (EC) usage likely because of its perception of being safer than smoking. Recent studies show that EC exposures impact heart rate (HR) and heart rate variability (HRV), but how they are affected by the timing and frequency of exposures remain unclear. We examine the electrocardiographic (EKG) effects induced by brief EC exposures over time, their relation to EC aerosol particle and mass concentrations, and potential to promote prooxidative effects in the lungs. Methods & resultsSix 10-week-old C57BL/6 mice, implanted with telemetry devices to monitor EKG activity continuously, were exposed once per week for three weeks to two EC exposures, each lasting 15-min followed by 45-min post-exposure periods. Filtered air (primary) and PBS (secondary) were used as controls. EC aerosol induced bradycardia and increased time domain parameters during EC exposures with significant reductions in the post-exposure periods. Log-transformed frequency domain parameters were significantly elevated during and after exposures (p < 0.001). HRV changes occurred within minutes with similar trends observed in particle number and mass concentrations of EC aerosol. HR and HRV varied by week and parameter, with Week 2 and 3 effects overshadowing those in Week 1. ECs induced prooxidative effects in the lungs as evidenced by elevated potential for hydroxyl radical generation in bronchoalveolar lavage fluid of exposed mice (p = 0.003). ConclusionShort-term EC exposures altered murine HR and HRV within minutes during and after exposures, effects that were modulated by the timing and frequency of EC exposures.

In situ endoscopic photodynamic therapy combined with immature DC vaccination induces a robust T cell response against peritoneal carcinomatosis.

Immunogenic cell death (ICD) and ferroptosis have recently emerged as key factors in the anticancer immune response. Among the treatments able to induce ICD and the associated release of danger signals is photodynamic therapy (PDT). Ferroptosis for its part results from lipid peroxidation and is induced by CD8+ T cells to kill nearby cancer cells on IFN-γ production. We aimed to combine the two concepts, that is, to evaluate whether the strong pro-oxidant effects of PDT may promote ferroptosis and antigen release and to develop a procedure for in situ PDT to prepare the soil for highly endocytotic immature dendritic cell (iDC) adoptive transfer. This approach was implemented for managing peritoneal carcinomatosis, a lesion often associated with poor outcomes. We used three-dimensional (3D) heterotypic spheroids made of cancer cells, exposed them to a white light-activated OR141 photosensitizer (PS), and subsequently complexified them by adding iDC and naive lymphocytes. We next used a model of mouse peritoneal carcinomatosis and administered PDT using laparoscopy to locally induce photoactivation using the endoscope light. The immune response following adoptive transfer of iDC was tracked both in vivo and ex vivo using isolated immune cells from in situ vaccinated mice. Cancer cells undergoing PDT-induced cell death significantly increased ICD markers and the infiltration of iDCs in spheroids, relying on ferroptosis. These actions induced the sequential activation of CD8+ and CD4+ T cells as revealed by a significant spheroid 3D structure deterioration and, remarkably, were not recapitulated by conventional ferroptosis inducer RSL3. Using LED light from an endoscope for in situ photoactivation of PS enabled us to apply the vaccination modality in mice with peritoneal tumors. Consecutive intraperitoneal injection of iDCs resulted in delayed tumor growth, increased survival rates, and prevented tumor relapse on rechallenge. CD8+ T cell response was supported by depletion experiments, nodal detection of early activated T cells, and ex vivo T cell-induced cytotoxicity toward spheroids. The combination of in situ PDT locally delivered by an endoscope light and iDC administration induces a durable memory immune response against peritoneal carcinomatosis thereby opening new perspectives for the treatment of a life-threatening condition.

Evaluation of Vincamine Loaded with Silver Nanoparticles as a New Potential Therapeutic Agent Against Ehrlich's Solid Carcinoma in Mice.

Vincamine, a monoterpenoid indole alkaloid with vasodilatory properties, is extracted from the leaves of Vinca minor. The present study aimed to determine the potential anticancer effects of vincamine loaded in silver nanoparticles (VCN-AgNPs) in mice with Ehrlich solid carcinoma (ESC). After tumor transplantation, the mice were divided into five groups: ESC, ESC+Cisplatin (CPN; 5 mg/kg), ESC+VCN (40 mg/kg), ESC+AgNPs (6 mg/kg), and ESC+VCN-AgNPs (20 mg/kg). The administration of VCN-AgNPs to ESC-bearing mice improved their survival rate and reduced their body weight, tumor size, and tumor weight compared to the ESC group. Furthermore, VCN-AgNPs intensified oxidative stress in tumor tissues, as evidenced by elevated levels of lipid peroxidation (LPO) and nitric oxide (NO), along with a reduction in the levels of the antioxidants investigated (GSH, GPx, GR, SOD, CAT, and TAC). Furthermore, VCN-AgNPs increased the apoptotic proteins Bax and caspase-3, decreased the anti-apoptotic protein (Bcl-2), increased the inflammatory markers TNF-α and IL-1β, and inhibited angiogenesis by lowering VEGF levels in tumor tissues, all of which led to apoptosis. Furthermore, histopathological studies showed that VCN-AgNPs suppressed the progression of Ehrlich carcinoma and induced the formation of clusters of necrotic and fragmented tumor cells. VCN-AgNPs possess cytotoxic and genotoxic effects against ESC because of their pro-oxidant, pro-apoptotic, pro-inflammatory, and antiangiogenic effects. Additionally, the combination of VCN-AgNPs was more effective and safer than chemically synthesized AgNPs, as indicated by an increase in the lifespan of animals and the total tumor inhibition index.

Vitamin C in the Management of Thyroid Cancer: A Highway to New Treatment?

Thyroid cancer (TC) is the most common endocrine malignancy, with an increased global incidence in recent decades, despite a substantially unchanged survival. While TC has an excellent overall prognosis, some types of TC are associated with worse patient outcomes, depending on the genetic setting. Furthermore, oxidative stress is related to more aggressive features of TC. Vitamin C, an essential nutrient provided with food or as a dietary supplement, is a well-known antioxidant and a scavenger of reactive oxygen species; however, at high doses, it can induce pro-oxidant effects, acting through multiple biological mechanisms that play a crucial role in killing cancer cells. Although experimental data and, less consistently, clinical studies, suggest the possibility of antineoplastic effects of vitamin C at pharmacological doses, the antitumor efficacy of this nutrient in TC remains at least partly unexplored. Therefore, this review discusses the current state of knowledge on the role of vitamin C, alone or in combination with other conventional therapies, in the management of TC, the mechanisms underlying this association, and the perspectives that may emerge in TC treatment strategies, and, also, in light of the development of novel functional foods useful to this extent, by implementing novel sensory analysis strategies.

EF24, a Curcumin Analog, Reverses Interleukin-18-Induced miR-30a or miR-342-Dependent TRAF3IP2 Expression, RECK Suppression, and the Proinflammatory Phenotype of Human Aortic Smooth Muscle Cells.

Curcumin, a polyphenolic compound derived from the widely used spice Curcuma longa, has shown anti-atherosclerotic effects in animal models and cultured vascular cells. Inflammation is a major contributor to atherosclerosis development and progression. We previously reported that the induction of the proinflammatory molecule TRAF3IP2 (TRAF3 Interacting Protein 2) or inhibition of the matrix metallopeptidase (MMP) regulator RECK (REversion Inducing Cysteine Rich Protein with Kazal Motifs) contributes to pro-oxidant, proinflammatory, pro-mitogenic and pro-migratory effects in response to external stimuli in vascular smooth muscle cells. Here we hypothesized that EF24, a curcumin analog with a better bioavailability and bioactivity profile, reverses interleukin (IL)-18-induced TRAF3IP2 induction, RECK suppression and the proinflammatory phenotype of primary human aortic smooth muscle cells (ASMC). The exposure of ASMC to functionally active recombinant human IL-18 (10 ng/mL) upregulated TRAF3IP2 mRNA and protein expression, but markedly suppressed RECK in a time-dependent manner. Further investigations revealed that IL-18 inhibited both miR-30a and miR-342 in a p38 MAPK- and JNK-dependent manner, and while miR-30a mimic blunted IL-18-induced TRAF3IP2 expression, miR-342 mimic restored RECK expression. Further, IL-18 induced ASMC migration, proliferation and proinflammatory phenotype switching, and these effects were attenuated by TRAF3IP2 silencing, and the forced expression of RECK or EF24. Together, these results suggest that the curcumin analog EF24, either alone or as an adjunctive therapy, has the potential to delay the development and progression of atherosclerosis and other vascular inflammatory and proliferative diseases by differentially regulating TRAF3IP2 and RECK expression in ASMC.

Effect of curcumin on the embryotoxic effect of ethanol in a zebrafish model

Curcumin, a natural polyphenol found in the turmeric plant, has been shown to have anti-inflammatory and antioxidant properties. It has been widely studied for its potential protective effect against various health conditions, including ethanol-induced malformation.Ethanol exposure during pregnancy can lead to various developmental abnormalities, known as fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD). Due to the high prevalence of FASD and FAS and no effective treatment, it is essential to develop preventive strategies. Recent studies have investigated the potential protective effect of curcumin against ethanol-induced malformation in animal models.This study aimed to examine whether curcumin can reduce the toxic effects of ethanol in zebrafish embryos. The present study showed that pure curcumin applied together with 1.5 % ethanol (v/v) did not lead to a protective effect on ethanol-induced malformations such as disturbances of body length and width or pericardia oedema in growing zebrafish embryos. Moreover, curcumin extract showed a pro-oxidant effect in the Fenton reaction in the presence of ethanol.

Synthesis and Evaluation of Water-Soluble Antioxidants Derived from L-carnosine and Syringaldehyde (or Vanillin)

Polyphenols are well known for their health-related benefits, including antioxidant activities, but most of them are hydrophobic, decreasing their bioavailability. This study reports water-soluble trimeric antioxidants synthesized with L-carnosine and the hydrophobic ortho-methoxy-substituted phenolic unit, syringaldehyde or vanillin.In the DPPH assay, carnosine-syringaldehyde (7.5 μM) and carnosine-vanillin (19 μM) derivatives showed much lower IC50 values than ascorbic acid (27.5 μM) and sodium ascorbate (30.5 μM) standards. According to the AAPH assay, carnosine-syringaldehyde and carnosine-vanillin protect DNA at concentrations as low as 6.5 μM and 26 μM, respectively, while both sodium ascorbate and ascorbic acid protected until 52 μM. Another notable property of these antioxidants is they can protect DNA well against hydroxyl radicals, produced via the Fenton reaction: carnosine-syringaldehyde showed DNA protection at all tested concentrations (833−1.6 μM), but the protection was slightly weaker between 26−1.6 μM. Carnosine-vanillin showed strong protection in the 833−104 μM range and some protection between 52−3.2 μM. Conversely, both sodium ascorbate and ascorbic acid did not protect DNA at any test concentration. In the pro-oxidant potential assessments, the synthesized antioxidants did not show any pro-oxidant effects at all concentrations, whereas sodium ascorbate showed severe pro-oxidant effects between 833−13 μM and ascorbic acid, 833−52 μM.Our study stresses the importance of ortho-methoxy group(s) for antioxidants as its electron-donating nature contributes to enhancing antioxidant activities, while steric bulk eliminates pro-oxidant effects by preventing the effective binding of transition metal ions to the phenolic hydroxyl group. The hydrophobicity of hindered phenols can be overcome if attached to a water-soluble scaffold.

Exploration of the shared gene signatures and comorbidity mechanisms of primary aldosteronism and atrial fibrillation.

Primary aldosteronism (PA) is a prevalent cause of endocrine hypertension characterized by an excess of aldosterone that can induce proinflammatory, prooxidant, and profibrotic effects on the heart. Emerging evidence indicates a heightened incidence of atrial fibrillation (AF) in patients with PA, suggesting a significant association between the two conditions. However, the underlying mechanisms remain unclear. The purpose of this study was to investigate the molecular networks associated with the development of both PA and AF. Datasets were obtained from the Gene Expression Omnibus (GEO) database. Hub genes were identified by enrichment and protein‒protein interaction analysis. These hub genes were subsequently validated via two independent external datasets: GSE60042 and GSE41177. Following the identification of shared genes, quantitative real-time polymerase chain reaction (qPCR) was employed to verify the reliability of the dataset and to further confirm the presence of shared genes in clinical samples. The results of the common gene analysis revealed that immune and inflammatory responses may be shared features in the pathophysiology of PA and AF. One hub gene, specifically tumor necrosis factor superfamily member 10 (TNFSF10), was identified through various analyses and subsequently validated via qPCR. Compared with that in healthy controls, the expression level of TNFSF10 was lower in PA patients with AF. Our findings indicate that TNFSF10 may play a role in the pathophysiology of AF complications associated with PA conditions, suggesting that it could serve as a potential target for the diagnosis or treatment of PA patients complicated with AF.

L-gulono-γ-lactone Oxidase, the Key Enzyme for L-Ascorbic Acid Biosynthesis.

L-ascorbic acid (AsA, vitamin C) plays a vital role in preventing various diseases, particularly scurvy. AsA is known for its antioxidant properties, which help protect against reactive oxygen species generated from metabolic activities; however, at high doses, it may exhibit pro-oxidative effects. The final step in AsA biosynthesis is catalyzed by L-gulono-γ-lactone oxidase (GULO). This enzyme is present in many organisms, but some animals, including humans, guinea pigs, bats, and other primates, are unable to synthesize AsA due to the absence of a functional GULO gene. The GULO enzyme belongs to the family of aldonolactone oxidoreductases (AlORs) and contains two conserved domains, an N-terminal FAD-binding region and a C-terminal HWXK motif capable of binding the flavin cofactor. In this review, we explore AsA production, the biosynthetic pathways of AsA, and the localization of GULO-like enzymes in both animal and plant cells. Additionally, we compare the amino acid sequences of AlORs across different species and summarize the findings related to their enzymatic activity. Interestingly, a recombinant C-terminal rat GULO (the cytoplasmic domain of the rat GULO expressed in Escherichia coli) demonstrated enzymatic activity. This suggests that the binding of the flavin cofactor to the HWXK motif at the C-terminus is sufficient for the formation of the enzyme's active site. Another enzyme, GULLO7 from Arabidopsis thaliana, also lacks the N-terminal FAD-binding domain and is strongly expressed in mature pollen, although its activity has not been specifically measured.

On the dose-response association of fine and ultrafine particles in an urban atmosphere: toxicological outcomes on bronchial cells at realistic doses of exposure at the Air Liquid Interface

Air pollution and particulate matter (PM) are the leading environmental cause of death worldwide. Exposure limits have lowered to increase the protection of human health; accordingly, it becomes increasingly important to understand the toxicological mechanisms on cellular models at low airborne PM concentrations which are relevant for actual human exposure. The use of air liquid interface (ALI) models, which mimic the interaction between airborne pollutants and lung epithelia, is also gaining importance in inhalation toxicological studies. This study reports the effects of ALI direct exposure of bronchial epithelial cells BEAS-2B to ambient PM1 (i.e. particles with aerodynamic diameter lower than 1 μm). Gene expression (HMOX, Cxcl-8, ATM, Gadd45-a and NQO1), interleukin (IL)-8 release, and DNA damage (Comet assay) were evaluated after 24 h of exposure. We report the dose-response curves of the selected toxicological outcomes, together with the concentration-response association and we show that the two curves differ for specific responses highlighting that concentration-response association may be not relevant for understanding toxicological outcomes. Noteworthy, we show that pro-oxidant effects may be driven by the deposition of freshly emitted particles, regardless of the airborne PM1 mass concentration. Furthermore, we show that reference airborne PM1 metrics, namely airborne mass concentration, may not always reflect the toxicological process triggered by the aerosol.These findings underscore the importance of considering different aerosol metrics to assess the toxicological potency of fine and ultrafine particles. To better protect human health additional metrics should be defined, than account for the properties of the entire aerosol mixture including specific as particle size (i.e. particles with aerodynamic diameter lower than 20 nm), the relevant aerosol sources (e.g., traffic combustion, secondary organic aerosol …) as well as their atmospheric processing (freshly emitted vs aged ones).

Antioxidant and Pro-Oxidant Properties of Selected Clinically Applied Antibiotics: Therapeutic Insights.

The balance between antioxidants and pro-oxidants plays a significant role in the context of oxidative stress, influenced by both physiological and non-physiological factors. In this study, 18 prescribed antibiotics (including doxycycline hydrochloride, tigecycline, rifampicin, tebipenem, cefuroxime, cefixime, potassium clavulanate, colistin, ampicillin, amoxicillin, amikacin, nalidixic acid, azithromycin, pipemidic acid trihydrate, pivmecillinam, aztreonam, fosfomycin sodium, and ciprofloxacin) were subjected to simultaneous determination of antioxidant and pro-oxidant potential to assess if pro-oxidant activity is a dominant co-mechanism of antibacterial activity or if any antibiotic exhibits a balanced effect. This study presents a recently developed approach for the simultaneous assessment of antioxidant and pro-oxidant potential on a single microplate in situ, applied to prescribed antibiotics. Ten antibiotics from eighteen showed lower antioxidant or pro-oxidant potential, while five exhibited only mild potential with DPPH50 values over 0.5 mM. The pro-oxidant antioxidant balance index (PABI) was also calculated to determine whether antioxidant or pro-oxidant activity was dominant for each antibiotic. Surprisingly, three antibiotics-doxycycline hydrochloride, tigecycline, and rifampicin-showed significant measures of both antioxidant and pro-oxidant activities. Especially notable was tebipenem, a broad-spectrum, orally administered carbapenem, showed a positive PABI index ratio, indicating a dominant antioxidant over pro-oxidant effect. These findings could be significant for both therapy, where the antibacterial effect is enhanced by radical scavenging activity, and biotechnology, where substantial pro-oxidant activity might limit microbial viability in cultures and consequently affect yield.

From 2D to 3D In Vitro World: Sonodynamically-Induced Prooxidant Proapoptotic Effects of C60-Berberine Nanocomplex on Cancer Cells.

The primary objective of this research targeted the biochemical effects of SDT on human cervix carcinoma (HeLa) and mouse Lewis lung carcinoma (LLC) cells grown in 2D monolayer and 3D spheroid cell culture. HeLa and LLC monolayers and spheroids were treated with a 20 µM C60-Ber for 24 h, followed by irradiation with 1 MHz, 1 W/cm2 US. To evaluate the efficacy of the proposed treatment on cancer cells, assessments of cell viability, caspase 3/7 activity, ATP levels, and ROS levels were conducted. Our results revealed that US irradiation alone had negligible effects on LLC and HeLa cancer cells. However, both monolayers and spheroids irradiated with US in the presence of the C60-Ber exhibited a significant decrease in viability (32% and 37%) and ATP levels (42% and 64%), along with a notable increase in ROS levels (398% and 396%) and caspase 3/7 activity (437% and 246%), for HeLa monolayers and spheroids, respectively. Similar tendencies were observed with LLC cells. In addition, the anticancer effects of C60-Ber surpassed those of C60, Ber, or their mixture (C60 + Ber) in both cell lines. The detected intensified ROS generation and ATP level drop point to mitochondria dysfunction, while increased caspase 3/7 activity points on the apoptotic pathway induction. The combination of 1 W/cm2 US with C60-Ber showcased a promising platform for synergistic sonodynamic chemotherapy for cancer treatment.

Cytotoxic and pro-oxidant profile of a photosensitive ruthenium nitrosyl candidate for NO delivery in healthy human fibroblasts.

Ruthenium nitrosyl (Ru-NO) complexes are of interest as photoactive nitric oxide (NO) donor candidates for local therapeutic applications. NO plays a crucial regulatory role in skin homeostasis, concentration-dependently affecting processes like the proliferation, apoptosis, autophagy and redox balance. In this context, we investigated HE-10, a ruthenium-based photoinducible NO donor, for its pro-oxidant and cytotoxic effects under light and dark conditions in VH10 human foreskin fibroblast cells. We also tested its intracellular and extracellular NO-releasing function. Our study reveals a significant dose-dependent cytotoxic effect of HE-10, an increase in intracellular reactive oxygen and nitrogen species, and the occurrence of apoptosis in skin fibroblast cells. Furthermore, exposure to both increasing doses of HE-10 and white LED light led to substantial cellular events, including a significant induction of autophagy and G2/M phase cell cycle arrest. Paradoxically, these effects were not solely attributable to NO release based on DAF2-DA NO probe results, suggesting that intracellular photochemical reactions additional to NO photolysis contribute to HE-10's biological activity. This study shows that HE-10 exhibits both cytotoxic and potential therapeutic effects, depending on concentration and light exposure. These findings are crucial for developing targeted Ru-NO complex treatments for skin diseases and potentially certain types of skin cancer, where controlled NO release could be beneficial.

EFFECT OF MONOAMINE OXIDASE INHIBITOR ON FREE RADICAL OXIDATION IN RAT KIDNEYS WITH ALLOXAN-INDUCED HYPERGLYCEMIA

Introduction. One of the most severe and dangerous complications of diabetes mellitus (DM) is diabetic nephropathy, the leading pathogenetic factor of which is considered to be prolonged hyperglycemia with the development of oxidative stress. Several leading redox-dependent mechanisms of diabetic nephropathy have been described, among which an important role is played by oxidases, as a key link in the redox balance in podocytes. The kidneys are characterized by high activity of monoamine oxidases (MAO), which are active producers of hydrogen peroxide. Meanwhile, the contribution of monoamine oxidases to the development of oxidative stress in the kidneys under conditions of prolonged hyperglycemia remains unexplored. Purpose of the study – to assess the contribution of monoamine oxidases to the development of oxidative stress in the kidneys under conditions of long-term hyperglycemia induced by alloxan. Material and methods. The study was conducted on 111 Wistar rats of both sexes, weighing 180–250 grams. Diabetes mellitus was modeled by intraperitoneal administration of alloxan monohydrate at a dose of 163 mg/kg. To assess the contribution of MAO-B to the development of oxidative stress, the selective MAO-B inhibitor selegiline was used at a dose of 5 mg/kg. Throughout the experiment, glycemia and body weight of the animals were monitored. Animals were removed from the experiment on the seventeenth day. The levels of oxidative modification of proteins, lipid peroxidation products, as well as the activity of monoamine oxidases A and B in kidney homogenates were determined by spectrophotometric methods. Results. It was found that on the fourteenth day from the moment of alloxan administration, signs of oxidative stress (increased oxidative modification of proteins) are revealed in the kidneys. The results of the correlation analysis demonstrate direct correlations in the "Alloxan" group of animals between the level of blood glucose on the 14th day of the experiment and the levels of products of oxidative modification of proteins, as well as the activity of MAO-B and the levels of products of oxidative modification of proteins and primary heptane-soluble lipid peroxidation products in kidneys. The absence of this kind of relationship in the group of animals that additionally received a MAO-B inhibitor ("Alloxan + selegiline"). Conclusions. The results of the study confirms the contribution of the intensification of free radical oxidation to the development of diabetic nephropathy during prolonged hyperglycemia, on the one hand, and the prooxidant effect of MAO-B on the other

The Antitumour Mechanisms of Carotenoids: A Comprehensive Review.

Carotenoids, known for their antioxidant properties, have garnered significant attention for their potential antitumour activities. This comprehensive review aims to elucidate the diverse mechanisms by which carotenoids exert antitumour effects, focusing on both well-established and novel findings. We explore their role in inducing apoptosis, inhibiting cell cycle progression and preventing metastasis by affecting oncogenic and tumour suppressor proteins. The review also explores the pro-oxidant function of carotenoids within cancer cells. In fact, although their overall contribution to cellular antioxidant defences is well known and significant, some carotenoids can exhibit pro-oxidant effects under certain conditions and are able to elevate reactive oxygen species (ROS) levels in tumoural cells, triggering mitochondrial pathways that would lead to cell death. The final balance between their antioxidant and pro-oxidant activities depends on several factors, including the specific carotenoid, its concentration and the redox environment of the cell. Clinical trials are discussed, highlighting the conflicting results of carotenoids in cancer treatment and the importance of personalized approaches. Emerging research on rare carotenoids like bacterioruberin showcases their superior antioxidant capacity and selective cytotoxicity against aggressive cancer subtypes, such as triple-negative breast cancer. Future directions include innovative delivery systems, novel combinations and personalized treatments, aiming to enhance the therapeutic potential of carotenoids. This review highlights the promising yet complex landscape of carotenoid-based cancer therapies, calling for continued research and clinical exploration.

Effect of Selol on Tumor Morphology and Biochemical Parameters Associated with Oxidative Stress in a Prostate Tumor-Bearing Mice Model.

Prostate cancer is the leading cause of cancer death in men. Some studies suggest that selenium Se (+4) may help prevent prostate cancer. Certain forms of Se (+4), such as Selol, have shown anticancer activity with demonstrated pro-oxidative effects, which can lead to cellular damage and cell death, making them potential candidates for cancer therapy. Our recent study in healthy mice found that Selol changes the oxidative-antioxidative status in blood and tissue. However, there are no data on the effect of Selol in mice with tumors, considering that the tumor itself influences this balance. This research investigated the impact of Selol on tumor morphology and oxidative-antioxidative status in blood and tumors, which may be crucial for the formulation's effectiveness. Our study was conducted on healthy and tumor-bearing animal models, which were either administered Selol or not. We determined antioxidant enzyme activities (Se-GPx, GPx, GST, and TrxR) spectrophotometrically in blood and the tumor. Furthermore, we measured plasma prostate-specific antigen (PSA) levels, plasma and tumor malondialdehyde (MDA) concentration as a biomarker of oxidative stress, selenium (Se) concentrations and the tumor ORAC value. Additionally, we assessed the impact of Selol on tumor morphology and the expression of p53, BCL2, and Ki-67. The results indicate that treatment with Selol influences the morphology of tumor cells, indicating a potential role in inducing cell death through necrosis. Long-term supplementation with Selol increased antioxidant enzyme activity in healthy animals and triggered oxidative stress in cancer cells, activating their antioxidant defense mechanisms. This research pathway shows promise in understanding the anticancer effects of Selol. Selol appears to increase the breakdown of cancer cells more effectively in small tumors than in larger ones. In advanced tumors, it may accelerate tumor growth if used as monotherapy. Therefore, further studies are necessary to evaluate its efficacy either in combination therapy or for the prevention of recurrence.