Search Results (241)

Some studies performed in our laboratory on pyrrole and its derivatives pointed towards the enrichment of the evaluations of these promising chemical structures for the potential treatment of neurodegenerative conditions in general and Parkinson’s disease in particular. A classical Paal-Knorr cyclization approach is applied to synthesize the basic hydrazine used for the formation of the designed series of hydrazones (15a–15g). The potential neurotoxic and neuroprotective effects of the newly synthesized derivatives were investigated in vitro using different models of induced oxidative stress at three subcellular levels (rat brain synaptosomes, mitochondria, and microsomes). The results identified as the least neurotoxic molecules, 15a, 15d, and 15f applied at a concentration of 100 µM to the isolated fractions. In addition, the highest statistically significant neuroprotection was observed for 15a and 15d at a concentration of 100 µM using three different injury models on subcellular fractions, including 6-hydroxydopamine in rat brain synaptosomes, tert-butyl hydroperoxide in brain mitochondria, and non-enzyme-induced lipid peroxidation in brain microsomes. The hMAOA/MAOB inhibitory activity of the new compounds was studied at a concentration of 1 µM. The lack of a statistically significant hMAOA inhibitory effect was observed for all tested compounds, except for 15f, which showed 40% inhibitory activity. The most prominent statistically significant hMAOB inhibitory effect was determined for 15a, 15d, and 15f, comparable to that of selegiline. The corresponding selectivity index defined 15f as a non-selective MAO inhibitor and all other new hydrazones as selective hMAOB inhibitors, with 15d indicating the highest selectivity index of >471. The most active and least toxic representative (15d) was evaluated in vivo on Rotenone based model of Parkinson’s disease. The results revealed no microscopically visible alterations in the ganglion and glial cells in the animals treated with rotenone in combination with 15d. Full article

In this study, we evaluated the antioxidant activities of esculetin and four synthesized derivatives (E1, 2-oxo-2H-1-benzopyran-6,7-diyl diacetate; E2, 7-hydroxy-2-oxo-2H-1-benzopyran-6-yl acetate; E3, 7-(methoxymethoxy)-2-oxo-2H-1-benzopyran-6-yl acetate; E4, 7-hydroxy-2-oxo-2H-1-benzopyran-6-yl 2,4-dinitrobenzene-1-sulfonate) against oxidative stress in hepatocytes. In HepG2 cells, treatment with 1 mM tert-butyl hydroperoxide (TBHP) reduced cell viability to 40%, while co-treatment with esculetin restored cell viability. Among the esculetin derivatives, E2 exhibited the most significant cytoprotective effect, while E4 showed the lowest. Furthermore, E2 at 25 µM concentration showed the similar effects to esculetin in reducing ROS generation and preventing glutathione depletion. The treatment of E2 also enhanced the expression of HO-1 and GCLC proteins against oxidative stress. On the other hand, TBHP-induced oxidative stress decreased antioxidant activities including glutathione reductase, glutathione peroxidase, and catalase; however, E2 significantly increased these antioxidant activities. These findings suggest that the esculetin derivative, particularly E2, possesses potential as an antioxidant aimed at enhancing physiological functions. Full article

Oxidative stress is a common feature of various pathological conditions, including tissue remodeling and dysfunction. Cardiac fibroblasts, which play a key role in maintaining extracellular matrix homeostasis, are sensitive to oxidative injury. Curcumin and tetrahydrocurcumin are plant-derived polyphenols with antioxidant properties, yet their relative efficacy in preventing oxidative stress–induced dysfunction in cardiac fibroblasts remains unclear. In this study, cardiac fibroblasts were treated with curcumin or tetrahydrocurcumin prior to exposure to tert-butyl hydroperoxide (t-BHP), a widely used inducer of oxidative stress. Cell viability, apoptosis, reactive oxygen species (ROS) production, and Tgfb1 expression were assessed. Both curcuminoids significantly attenuated oxidative stress–induced cell death, decreased cell viability, and reduced Tgfb1 expression. Notably, tetrahydrocurcumin demonstrated superior protective effects across most parameters. These findings suggest that both compounds help mitigate oxidative-stress–induced cellular dysfunction in cardiac fibroblasts and highlight tetrahydrocurcumin as a potentially more effective antioxidant. Further studies are needed to explore their role in the context of tissue remodeling and fibrotic progression. Full article

Aging is associated with increased oxidative stress, which contributes to cellular dysfunction and age-related diseases. Pomegranate extract (PE), rich in antioxidant polyphenols, may help mitigate oxidative damage. This study evaluated whether PE supplementation modulates oxidative stress by reducing reactive oxygen species (ROS) levels in white blood cells of aging mice. Aged mice (18 months) were supplemented with PE for four months, and cytoplasmic and mitochondrial ROS levels were assessed in leukocytes under basal conditions and oxidative stress conditions induced by tert-butyl hydroperoxide (t-BHP) using flow cytometry. Our results indicate that aged mice exhibit increased basal ROS levels in both the mitochondrial and cytoplasmic compartments, which were mitigated by PE supplementation. Furthermore, PE reversed the increase in hydrogen peroxide levels induced by τ-BHP and protected neutrophils by reducing mitochondrial ROS levels. These findings suggest that PE supplementation modulates the oxidative stress response, potentially improving immune function in aging. Given the central role of oxidative stress in age-related decline, PE may represent a valuable nutritional strategy to promote healthy aging. Full article

Multiple sclerosis (MS) is a neuroinflammatory disease where oxidative stress and DNA damage may influence disease progression. We investigated whether defects in base excision repair (BER) pathways contribute to MS by combining functional DNA repair assays, gene expression profiling, and genotype analysis. We collected peripheral blood mononuclear cells from 70 MS patients and 61 healthy controls. These cells were subjected to tert-butyl hydroperoxide (TBH)-induced oxidative stress, and comet assay kinetics were measured over a period of 60 min. Additionally, we quantified the mRNA expression of nine key BER genes and genotyped selected polymorphisms related to DNA repair capacity. Samples from MS patients exhibited significantly higher levels of TBH-induced DNA lesions and displayed a distinct repair trajectory over time, as indicated by area-under-the-curve (AUC) analyses (p < 0.001). The transcripts of MBD4 and NTHL1 were notably reduced in MS patients compared to those in the controls (p < 0.0001). A logistic regression analysis revealed an association between the specific BER-related single nucleotide polymorphisms (SNPs) rs3087404, rs4135054, and rs1052133 and ineffective DNA repair. Subset analyses of B cells, CD4⁺ cells, and CD8⁺ cells further supported the presence of altered repair kinetics in MS, even though some subsets exhibited similar baseline lesion levels. Our findings suggest that impaired oxidative DNA repair is present in MS, likely driven by functional deficits in repair kinetics and alterations in the expression of BER genes and polymorphisms. This integrated approach highlights DNA repair pathways as potential therapeutic or prognostic targets in MS. Full article

Neurodegenerative diseases involve oxidative stress and enzyme dysregulation, necessitating novel neuroprotective agents. This study evaluates the neuroprotective and antioxidant potential of seven pyrrole-based compounds with predicted radical scavenging activity and inhibitory effects on monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE). The compounds were tested in vitro using SH-SY5Y neuroblastoma cells and subcellular rat brain fractions, including synaptosomes, mitochondria, and microsomes. Neuroprotective and antioxidant effects were assessed in oxidative stress models, including H₂O₂-induced stress in SH-SY5Y cells, 6-hydroxydopamine toxicity in synaptosomes, tert-butyl hydroperoxide-induced stress in mitochondria, and non-enzyme lipid peroxidation in microsomes. In silico screening for lipophilicity, hydrogen bonding, total polar surface area (TPSA), and ionization properties, was performed to evaluate bioavailability. All compounds exhibited a weak neurotoxic effect on the subcellular fractions at a concentration of 100 µM. However, in oxidative stress models, they demonstrated significant neuroprotective and antioxidant effects at 100 µM. In SH-SY5Y cells, compounds 7, 9, 12, 14, and 15 exhibited low toxicity and strong protective effects at concentrations as low as 1 µM. In silico analysis prioritized compounds 1, 7, 9, 12, and 14 for further development based on their favorable bioavailability. The tested pyrrole-based compounds exhibit promising neuroprotective and antioxidant properties, with several candidates showing potential for further development based on both in vitro efficacy and predicted oral bioavailability. Full article

Background: Oxidative stress is a key therapeutic target in neurological disorders. As processing wastes from the peanut industry, peanut skins are great sources of antioxidants and possess potential in neuroprotection. Methods: We prepared a peanut skin extract (PSE) and investigated its protective effects against tert-butyl hydroperoxide (t-BHP)-induced oxidative injury in HT-22 neuronal cells. Results: PSE was rich in phenolic compounds (123.90 ± 0.46 mg GAE/g), comprising flavonoids (75.97 ± 0.23 mg RE/g) and proanthocyanidins (53.34 ± 1.58 mg PE/g), and displayed potent radical scavenging activities in chemical-based assays. In HT-22 cells, PSE pretreatment restored oxidative balance and endogenous antioxidant defense disrupted by t-BHP, as evidenced by significant reductions in ROS generation and lipid peroxidation levels, along with enhanced endogenous antioxidants. Specifically, 25 μg/mL PSE pretreatment reduced ROS levels by 53.03%, decreased MDA content by 78.82%, enhanced superoxide dismutase (SOD) activity by 12.42%, and improved the ratio of glutathione (GSH) to oxidized glutathione (GSSG) by 80.34% compared to the t-BHP group. Furthermore, PSE rescued mitochondrial membrane potential collapse, inhibited cytochrome c (Cyt.c) release, and prevented subsequent apoptotic death. Notably, the neuroprotective efficacy of PSE was comparable to that of edaravone, an approved neuroprotective drug. Mechanistic investigations combining network pharmacology and experimental validation revealed that the PI3K/Akt/Nrf2 signaling pathway played a pivotal role in mediating the neuroprotective effects of PSE. Compared to t-BHP-treated cells, 25 µg/mL PSE pretreatment significantly upregulated PI3K/Akt phosphorylation, the expression of Nrf2, and its downstream antioxidant proteins heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1). Conclusions: Collectively, these findings demonstrate the potential of PSE as a natural protective agent against oxidative-related neurological disorders. Full article

A heterogeneous polybenzimidazole-supported Mo(VI) catalyst and tert-butyl hydroperoxide (TBHP) as an oxidising reagent have been utilised to establish a more environmentally friendly and greener alkene epoxidation process. A polybenzimidazole-supported Mo(VI) complex (PBI.Mo) has been prepared, characterised and evaluated successfully. The stability and catalytic activity of the produced catalyst have been evaluated for the epoxidation of 1,7-octadiene and 1,5-hexadiene in a jacketed stirred batch reactor to assess its performance towards these alkenes. The suitability and efficiency of the catalyst have been compared by studying the effect of reaction temperature, feed mole ratio of alkene to TBHP, catalyst loading, and reaction time on the yield of 1,2-epoxy-5-hexene and 1,2-epoxy-7-octene. Response surface methodology (RSM) using Box–Behnken Design (BBD) has been employed to design experimental runs and study the catalytic performance of the PBI.Mo catalyst for all batch experimental results. A quadratic regression model has been developed representing an empirical relationship between reaction variables and response, which is the yield of epoxides. The numerical optimisation technique concluded that the maximum yield that can be reached is 66.22% for 1,7-octadiene and 64.2% for 1,5-hexadiene. The reactivity of alkenes was observed to follow the sequence 1,5-hexadiene > 1,7-octadiene. The findings of this study confirm that the optimal reaction conditions vary between the two reactions, indicating differences in catalytic performance for each alkene. Full article

Cataracts, the leading cause of blindness globally, are caused by oxidative stress and inflammation, which disrupt lens transparency due to increased accumulation of reactive oxygen species (ROS) as well as protein and DNA damage during aging. Using in vitro, ex vivo, and in vivo models, we determined the protective efficacy of N-acetylcysteine amide (NACA) against oxidative stress-induced and aging-induced cataractogenesis. We found that lens epithelial cells exposed to the oxidative stress inducers hydrogen peroxide (H₂O₂) or tert-butyl hydroperoxide showed significant ROS accumulation and reduced cellular viability. These effects were inhibited by NACA via the suppression of ROS and thioredoxin-interacting protein (Txnip) expression, a regulator of oxidative stress-related cellular damage and inflammation. In ex vivo lens experiments, NACA significantly reduced H₂O₂-induced lens opacity and preserved lens integrity. Similarly to NACA-treated lenses ex vivo, the integrity and opacity of aged mouse lenses, when topically instilled with NACA, were preserved and reduced, respectively, and are directly related to reduced Txnip and increased thioredoxin (Trx) expression levels. Overall, our findings demonstrated the protective ability of NACA to abate aberrant redox-active pathways, particularly the ROS/TRX/TXNIP axis, thereby preventing cataractogenesis and preserving eye lens integrity and ultimately impeding aging-related cataracts. Full article

Background/objectives: Aging leads to increased oxidative stress and chronic inflammation in the skin, which contribute to various disorders such as dermatitis and cancer. This study explores the cytoprotective effects of oleanolic acid (OA), a natural triterpenoid compound known for its potential in mitigating oxidative damage, on human keratinocyte (HaCaT) cells exposed to oxidative stress from tert-butyl hydroperoxide (tBHP). Methods: Using in vitro experiments, we assessed cell viability, reactive oxygen species (ROS) levels, nitric oxide (NO) production, and protein expression following OA pre-treatment. Advanced imaging techniques were employed to visualize protein localization. Results: Results demonstrated that OA significantly improved cell viability and reduced intracellular ROS levels compared with those in controls. Additionally, OA inhibited inducible nitric oxide synthase (iNOS) expression and subsequent nitric oxide release, indicating a modulation of inflammatory responses. Notably, while tBHP activated the Nrf2/HO-1 signaling pathway, OA did not enhance this response, suggesting that OA exerts cytoprotective effects through mechanisms independent of Nrf2 activation. Conclusion: OA shows promise in protecting HaCaT cells from tBHP-induced oxidative stress, highlighting its potential role in promoting skin health and addressing aging-related damage. The study proposes that OA operates through pathways distinct from Nrf2 and MAPKs, paving the way for new therapeutic strategies aimed at improving skin health against oxidative stress. Full article

Research on the effects of melatonin on erythrocyte deformability has yielded mixed results. While some studies reported improvements, others found no effect, and a few even noted a deterioration in deformability. Moreover, the impact of melatonin may vary between healthy erythrocytes and those subjected to oxidative stress. This study investigated the dose-dependent effects of melatonin on erythrocytes under baseline conditions and oxidative stress, using both pre- and post-stress incubation protocols. Oxidative damage was induced with tert-butyl hydroperoxide (TBHP), and its extent was assessed via dichlorofluorescein fluorescence. Erythrocyte deformability was measured using ektacytometry, and osmotic resistance was assessed through hemolytic assays. The results showed that incubation with TBHP led to a dose-dependent decline in both erythrocyte deformability and osmotic resistance. While melatonin treatment had no observable effect on intact erythrocytes, it enhanced deformability in oxidatively damaged erythrocytes when administered before oxidative stress was induced. However, the beneficial effect was not evident when melatonin was applied after oxidative damage. Additionally, melatonin incubation had no impact on the ability of erythrocytes to resist the hypotonic environment. In conclusion, this study supports the notion that the antioxidant properties of melatonin can improve erythrocyte functional status, as reflected by enhanced deformability, but not osmotic resistance. Notably, this effect was observed only in erythrocytes that were exposed to oxidative damage after melatonin incubation, not in intact cells. Full article

Nucleic acid (NA)-based drugs are promising therapeutics agents. Beyond efficacy, addressing safety concerns—particularly those specific to this class of drugs—is crucial. Here, we propose an in vitro approach to screen for potential adverse off-target effects of NA-based drugs. Human peripheral blood mononuclear cells (PBMCs), purified from buffy coats of healthy donors, were used to investigate the ability of NA-drugs to trigger toxicity pathways and inappropriate immune stimulation. PBMCs were selected for their ability to represent potential human responses, given their likelihood of interacting with administered drugs. As proof of concept, a small interfering RNA (siRNA) targeting Ryanodine Receptor mRNA (RyR2) identified by the Italian National Center for Gene Therapy and Drugs based on RNA Technology as a potential therapeutic target for dominant catecholaminergic polymorphic ventricular tachycardia, was selected. This compound and its scramble were formulated within a calcium phosphate nanoparticle-based delivery system. Positive controls for four toxicity pathways were identified through literature review, each associated with a specific type of cellular stress: oxidative stress (tert-butyl hydroperoxide), mitochondrial stress (rotenone), endoplasmic reticulum stress (thapsigargin), and autophagy (rapamycin). These controls were used to define specific mRNA signatures triggered in PBMCs, which were subsequently used as indicators of off-target effects. To assess immune activation, the release of pro-inflammatory cytokines (interleukin-6, interleukin-8, tumor necrosis factor-α, and interferon-γ) was measured 24 h after exposure. The proposed approach provides a rapid and effective screening method for identifying potential unintended effects in a relevant human model, which also allows to address gender effects and variability in responses. Full article

Herein, a high selective epoxidation of isobutene was achieved by heterogeneously dispersed MoSe₂ with tert-butyl hydroperoxide (TBHP), which further showed versatile substrate scopes and well-retained activity among recycling tests. A rational mechanism is proposed based on extensive control experiments and electron paramagnetic resonance spectroscopy, surprisingly unveiling the metal–oxo and radical mediated pathways dramatically accelerated by hydrogen bonds of hexafluoroisopropanol (HFIP). Full article

Three new acylated benzophenone O-glycosides named aucherosides A–C (4–6), together with five known compounds such as mangiferin (1), maclurin-6-O-β-D-glucopyranoside (2), 1-O-galloyl-β-D-glucose (3), vanillic acid (7), and 5-hydroxy-2-isopropylchromone-7-O-β-glucoside (8), were isolated from the aerial parts of Hypericum aucheri Jaub. and Spach and identified with spectroscopic methods (1D and 2D NMR, and HRESIMS). Compounds 2, 4–6, 8, and previously isolated from the title plant aucherines A–C (9–11), were tested for hMAO-A and B inhibitory effects and neuroprotection. All tested compounds (1 µM) did not exhibit any inhibitory effect on hMAO-A and showed significant inhibitory activity against the hMAO-B enzyme. Notably, compound 8 demonstrated the strongest hMAO-B inhibition, approaching that of the positive control selegiline. At high concentrations (100 µM), all tested compounds showed no neurotoxic or pro-oxidant effects on rat brain synaptosomes, mitochondria, and microsomes. All tested compounds exhibited good neuroprotective and antioxidant activities in various neurotoxicity models (6-hydroxydopamine-induced neurotoxicity on synaptosomes, tert-butyl hydroperoxide-induced oxidative stress on mitochondria, and non-enzymatic lipid peroxidation on microsomes). The neuroprotective mechanisms of these compounds may include MAO-B inhibition, reactive oxygen species (ROS) scavenging, membrane stabilization, and preservation of reduced glutathione (GSH), the primary nucleophilic ROS scavenger. Full article

A series of Fe–Ba mixed oxides, including a pure Fe-containing sample as a reference, have been synthesized via a sol–gel process using Fe³⁺ or Fe²⁺ salts and BaSO₄ as raw materials, with Pluronic P123 serving as a template. These oxides have been thoroughly characterized and subsequently utilized as catalysts for the chlorination of various organic molecules. Commercial hydrochloric acid, known for its relative safety, and environmentally friendly aqueous hydrogen peroxide were employed as the chlorine source and oxidant, respectively. The pure Fe-containing catalyst displays excellent thermal stability between 600 and 800 °C and exhibited moderate to high conversions in the chlorination of toluene, benzene, and tert-butyl hydroperoxide, with remarkable ortho-selectivity in chlorination of toluene. The combination of Fe³⁺ salt with BaSO₄ in the sol–gel process results in a Fe–Ba mixed oxide catalyst composed of BaO₂, BaFe₄O₇, and Fe₂O₃, significantly enhancing the chlorination activity compared to that displayed by the pure Fe catalyst. Notably, the chlorination of tert-butyl hydroperoxide (TBHP) does not require additional oxidants such as H₂O₂, and involves both electrophilic substitution and nucleophilic addition. Notably, the chlorination of bromobenzene yields chlorobenzene as the sole product, a transformation that has not been previously reported. Overall, this catalytic chlorination system holds promise for advancing the chlorination industry and enhancing pharmaceutical production. Full article