Iron-induced Lipid Peroxidation Research Articles

Kigelia africana (Lam.) Benth. fruit inhibits iron-induced lipid peroxidation and ?-amylase enzyme activity

Insufficiencies in insulin secretion and/or action cause diabetes mellitus (DM), a complex condition characterized by abnormal blood glucose levels. Diabetes is often treated by modifying either glucose metabolism, lipids metabolism, or both. A direct correlation has been found between high levels of lipid peroxide in individuals with diabetes and lower intracellular antioxidant activity. Therefore, this study was designed to investigate the effect of the aqueous extract of Kigelia africana fruit on the carbohydrate hydrolyzing enzyme, ?-amylase, and FeSO4-induced lipid peroxidation in the rat pancreas. The in vitro antioxidant potential, including assays for (1,1 diphenyl-2-picryl hydrazyl (DPPH), ferric reducing antioxidant property (FRAP), nitric oxide (NO), hydroxyl (OH) scavenging, and Fe2+ chelating abilities, of the fruit extract was also evaluated. The effect of the fruit extract on the ?-amylase enzyme, and FeSO4-induced lipid peroxidation in the rat pancreas was also evaluated. K. africana at a concentration of 0.5 mg/mL and 1 mg/mL scavenged DPPH radicals, with the lower concentration showing significant differences compared to the control. The K. africana fruit extract reduced ferric compounds significantly compared to the standard. The OH* radical scavenging results revealed that all concentrations of K. africana fruit scavenged OH* radicals without significant differences compared to the control. K. africana fruit also chelated iron significantly compared to the control. The fruit extract inhibited iron-induced lipid peroxidation in the rat pancreas and ?-amylase activity compared to the control. K. africana fruit displayed promising potential in inhibiting ?-amylase activity and associated lipid peroxidation in diabetics. Therefore, it holds strong promise for use in diabetes treatment, validating its traditional use for managing the condition.

Contribution of Autophagy to Cellular Iron Homeostasis and Stress Adaptation in Alternaria alternata.

The tangerine pathotype of Alternaria alternata produces the Alternaria citri toxin (ACT), which elicits a host immune response characterized by the increase in harmful reactive oxygen species (ROS) production. ROS detoxification in A. alternata relies on the degradation of peroxisomes through autophagy and iron acquisition using siderophores. In this study, we investigated the role of autophagy in regulating siderophore and iron homeostasis in A. alternata. Our results showed that autophagy positively influences siderophore production and iron uptake. The A. alternata strains deficient in autophagy-related genes 1 and 8 (ΔAaatg1 and ΔAaatg8) could not thrive without iron, and their adaptability to high-iron environments was also reduced. Furthermore, the ability of autophagy-deficient strains to withstand ROS was compromised. Notably, autophagy deficiency significantly reduced the production of dimerumic acid (DMA), a siderophore in A. alternata, which may contribute to ROS detoxification. Compared to the wild-type strain, ΔAaatg8 was defective in cellular iron balances. We also observed iron-induced autophagy and lipid peroxidation in A. alternata. To summarize, our study indicates that autophagy and maintaining iron homeostasis are interconnected and contribute to the stress resistance and the virulence of A. alternata. These results provide new insights into the complex interplay connecting autophagy, iron metabolism, and fungal pathogenesis in A. alternata.

Ferroptosis: underlying mechanisms and involvement in neurodegenerative diseases.

Ferroptosis, a mode of cell death that was recently identified in 2012, is driven by iron-dependent lipid peroxidation and distinct from other mechanisms of cell death such as autophagy and apoptosis. Ferroptosis has the unique features of disruptions in iron equilibrium, iron-induced lipid peroxidation, and the accumulation of glutamate-induced cellular toxicity. The regulation of ferroptosis mainly involves the iron, lipid, and amino acid metabolic pathways, which are controlled by system Xc-, voltage-dependent anion channels, p53 and other pathways. Neurodegenerative diseases involve gradual neuronal loss predominantly within the central nervous system and are categorized into both sporadic and rare hereditary disorders. These diseases result in the progressive decline of specific neuron populations and their interconnections. Recent investigations have revealed a strong correlation between the manifestation and progression of neurodegenerative diseases and ferroptosis. The pharmacological modulation of ferroptosis, whether by induction or inhibition, exhibits promising prospects for therapeutic interventions for these diseases. This review aims to examine the literature on ferroptosis and its implications in various neurodegenerative diseases. We hope to offer novel insights into the potential therapies targeting ferroptosis in central nervous system neurodegenerative diseases. However, there are still limitations of this review. First, despite our efforts to maintain objectivity during our analysis, this review does not cover all the studies on ferroptosis and neurodegenerative diseases. Second, cell death in neurodegenerative diseases is not solely caused by ferroptosis. Future research should focus on the interplay of different cell death mechanisms to better elucidate the specific disease pathogenesis.

Hyperforin Enhances Heme Oxygenase-1 Expression Triggering Lipid Peroxidation in BRAF-Mutated Melanoma Cells and Hampers the Expression of Pro-Metastatic Markers.

Hyperforin (HPF) is an acylphloroglucinol compound found abundantly in Hypericum perforatum extract which exhibits antidepressant, anti-inflammatory, antimicrobial, and antitumor activities. Our recent study revealed a potent antimelanoma effect of HPF, which hinders melanoma cell proliferation, motility, colony formation, and induces apoptosis. Furthermore, we have identified glutathione peroxidase-4 (GPX-4), a key enzyme involved in cellular protection against iron-induced lipid peroxidation, as one of the molecular targets of HPF. Thus, in three BRAF-mutated melanoma cell lines, we investigated whether iron unbalance and lipid peroxidation may be a part of the molecular mechanisms underlying the antimelanoma activity of HPF. Initially, we focused on heme oxygenase-1 (HO-1), which catalyzes the heme group into CO, biliverdin, and free iron, and observed that HPF treatment triggered the expression of this inducible enzyme. In order to investigate the mechanism involved in HO-1 induction, we verified that HPF downregulates the BTB and CNC homology 1 (BACH-1) transcription factor, an inhibitor of the heme oxygenase 1 (HMOX-1) gene transcription. Remarkably, we observed a partial recovery of cell viability and an increase in the expression of the phosphorylated and active form of retinoblastoma protein when we suppressed the HMOX-1 gene using HMOX-1 siRNA while HPF was present. This suggests that the HO-1 pathway is involved in the cytostatic effect of HPF in melanoma cells. To explore whether lipid peroxidation is induced, we conducted cytofluorimetric analysis and observed a significant increase in the fluorescence of the BODIPY C-11 probe 48 h after HPF administration in all tested melanoma cell lines. To discover the mechanism by which HPF triggers lipid peroxidation, along with the induction of HO-1, we examined the expression of additional proteins associated with iron homeostasis and lipid peroxidation. After HPF administration, we confirmed the downregulation of GPX-4 and observed low expression levels of SLC7A11, a cystine transporter crucial for the glutathione production, and ferritin, able to sequester free iron. A decreased expression level of these proteins can sensitize cells to lipid peroxidation. On the other hand, HPF treatment resulted in increased expression levels of transferrin, which facilitates iron uptake, and LC3B proteins, a molecular marker of autophagy induction. Indeed, ferritin and GPX-4 have been reported to be digested during autophagy. Altogether, these findings suggest that HPF induced lipid peroxidation likely through iron overloading and decreasing the expression of proteins that protect cells from lipid peroxidation. Finally, we examined the expression levels of proteins associated with melanoma cell invasion and metastatic potential. We observed the decreased expression of CD133, octamer-4, tyrosine-kinase receptor AXL, urokinase plasminogen activator receptor, and metalloproteinase-2 following HPF treatment. These findings provide further support for our previous observations, demonstrating the inhibitory effects of HPF on cell motility and colony formation in soft agar, which are both metastasis-related processes in tumor cells.

New Indole-3-Propionic Acid and 5-Methoxy-Indole Carboxylic Acid Derived Hydrazone Hybrids as Multifunctional Neuroprotectors.

In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects < 5% (200 μM) and IC50 > 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against H2O2-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders.

Can Iron and Polyunsaturated Fatty Acid Supplementation Induce Ferroptosis?

Ferroptosis is a regulated non-apoptotic cell death process triggered by excessive iron-induced lipid peroxidation. Excess intracellular iron promotes lipid peroxidation by increasing reactive oxygen species formation through the Fenton reaction. Thus, iron and polyunsaturated fatty acid intake may trigger ferroptosis under certain conditions. The aims of this review were to compile and examine evidence in the literature for the effects of iron and polyunsaturated fatty acid supplementation on ferroptosis. Omega-6 polyunsaturated fatty acids have relatively greater susceptibility to lipid peroxidation and could, therefore, participate in ferroptosis. By contrast, omega-3 polyunsaturated fatty acids promote intracellular antioxidants synthesis and reduce the formation of hydroperoxides that induce ferroptosis. As intestinal iron absorption is regulated by iron nutritional status, individuals with normal functioning of the hepcidin-ferroportin axis are at low risk of developing iron overload in response to ingestion of iron-rich foods. Therefore, iron supplementation is potentially toxic mainly for the intestinal epithelium and the microbiota. In animal models, iron-rich diets increased oxidative damage, lowered the glutathione concentration within hepatocytes, and downregulated desaturases that synthesize long-chain polyunsaturated fatty acids. These adverse effects of iron supplementation were prevented by omega-3 fatty acid co-supplementation. The impact of food and supplement intake on ferroptosis has seldom been investigated. Scientific evidence still does not allow us to know for sure whether iron and PUFA supplementation are capable of inducing ferroptosis. As the mechanisms that control ferroptosis can determine whether cells proliferate or die, future studies should directly investigate the effects of nutrient supplementation and food intake on the ferroptosis process in different types of cells and tissues.

Mitochondria hormesis delays aging and associated diseases in Caenorhabditis elegans impacting on key ferroptosis players

Excessive iron accumulation or deficiency leads to a variety of pathologies in humans and developmental arrest in the nematode Caenorhabditis elegans. Instead, sub-lethal iron depletion extends C.elegans lifespan. Hypoxia preconditioning protects against severe hypoxia-induced neuromuscular damage across species but it has low feasible application. In this study, we assessed the potential beneficial effects of genetic and chemical interventions acting via mild iron instead of oxygen depletion. We show that limiting iron availability in C. elegans through frataxin silencing or the iron chelator bipyridine, similar to hypoxia preconditioning, protects against hypoxia-, age-, and proteotoxicity-induced neuromuscular deficits. Mechanistically, our data suggest that the beneficial effects elicited by frataxin silencing are in part mediated by counteracting ferroptosis, a form of non-apoptotic cell death mediated by iron-induced lipid peroxidation. This is achieved by impacting on different key ferroptosis players and likely via gpx-independent redox systems. We thus point to ferroptosis inhibition as a novel potential strategy to promote healthy aging.

Copper Deficiency Increases the Susceptibility of Lipoproteins and Tissues to Peroxidation in Rats

Male Wistar rats were pair-fed from weaning for 6 wk either a copper-deficient diet or a control diet containing sucrose. Hypercholesterolemia in copper-deficient animals was associated with a significantly greater plasma apolipoprotein B concentration and modifications in the lipid composition of triglyceride-rich lipoproteins containing apolipoprotein B. The proportion of triglycerides was elevated and the proportion of cholesterol was reduced in the VLDL + LDL fractions from copper-deficient rats compared with control animals. When the VLDL + LDL fractions were subjected to in vitro copper-induced oxidation, the lipoprotein fractions from copper-deficient rats were more susceptible to oxidative damage than lipoprotein fractions from control rats as indicated by the rate of diene conjugation. Hydroperoxide and thiobarbituric acid-reactive substance (TBARS) measurements performed 3 h after the induction of peroxidation were in agreement with the greater formation of conjugated dienes. Concentrations of TBARS were significantly greater in heart homogenates from copper-deficient rats compared with control rats. After exposure of tissue homogenates to iron-induced lipid peroxidation, TBARS were significantly higher in liver and heart from copper-deficient rats compared with control rats. Of particular importance is the observation that copper deficiency has a harmful effect on lipid peroxidation in the cardiovascular system.

Monitoring Lysosome Function in Ferroptosis.

Ferroptosis is a type of regulated cell death that occurs due to iron-induced membrane lipid peroxidation. Lysosomes, which are acidic, membrane-bound organelles containing various hydrolases, play a vital role in ferroptosis. They not only aid in the degradation of autophagic substrates, but also serve as signaling hubs in cell death. Specifically, lysosomes are involved in the induction and execution of ferroptosis through autophagy-mediated degradation of anti-ferroptotic proteins, lysosomal membrane permeability-mediated release of cathepsins, and iron-induced lysosomal membrane lipid peroxidation. Therefore, it is essential to have reliable methods for monitoring lysosomal functions, including lysosomal activity, pH, and membrane integrity, as well as iron accumulation and lipid peroxidation, to understand ferroptosis. This chapter introduces several protocols, such as western blotting, immunofluorescence, lysosomal probes, and lipid peroxidation assay kits, for monitoring the process of lysosome-related ferroptosis.

The inhibitory effect of Cannabis Sativa L. and Morus nigra L. against lipid peroxidation in goat liver and brain homogenates.

The present study was aimed to evaluate the antioxidant potential and inhibitory effect ofCannabis sativa and Morus nigra against lipid peroxidation in goat brain and liver homogenates. The formation of free radicals, highly reactive oxygen species (ROS) and reactive nitrogen species (RNS) is a normal metabolic process for cellular signaling and countering the antigens. However, they may cause serious damage if they produced at amplified tolls. In addition, metabolic disorders also serve as sources of these reactive species. Although the issue can be addressed through supplements and other phytochemicals. In this study, two plant species were evaluated for their biological potential by employing a spectrum of antioxidant assays. The antioxidant activity was performed by lipid peroxidation assay. The water extract prepared from leaves of Cannabis sativa and Morus nigra showed significant (P<0.05) inhibition as compared to control i.e., 522.6±0.06 and 659.97±0.03 µg/mL against iron-induced lipid peroxidation in goat brain homogenate while the inhibitions were 273.54±0.04 and 309.18±0.05 µg/mL against nitroprusside induced lipid peroxidation of the brain. The iron and nitroprusside induced lipid peroxidation was also significantly inhibited by leaf extracts of Cannabis sativa and Morus nigra in liver homogenates such as 230.63±0.52 and 326.91±0.01 µg/mL (iron-induced) while 300.47±0.07 and 300.47±0.07 µg/mL (nitroprusside induced), respectively. The extracts of Cannabis sativa extract showed promising activity (96.04±0.060%) against DPPH radicals while Morus nigra showed a moderate activity (34.11±0.120%). The results suggest that different accessions ofCannabis sativa and Morus nigra are a potential source of antioxidants and have a therapeutic effect against disease induced by oxidative stress and hence can be used for novel drug discovery and development.

Isorhapontigenin Attenuates Cardiac Microvascular Injury in Diabetes via the Inhibition of Mitochondria-Associated Ferroptosis Through PRDX2-MFN2-ACSL4 Pathways.

Ferroptosis is a newly identified form of regulated cell death that is driven by iron overload and uncontrolled lipid peroxidation, but the role of ferroptosis in cardiac microvascular dysfunction remains unclear. Isorhapontigenin (ISO) is an analog of resveratrol and possesses strong antioxidant capacity and cardiovascular-protective effects. Moreover, ISO has been shown to alleviate iron-induced oxidative damage and lipid peroxidation in mitochondria. Therefore, the current study aimed to explore the benefits of ISO treatment on cardiac microvascular dysfunction in diabetes and the possible mechanisms involved, with a focus on ferroptosis and mitochondria. Our data revealed that ISO treatment improved microvascular density and perfusion in db/db mice by mitigating vascular structural damage, normalizing nitric oxide (NO) production via endothelial NO synthase activation, and enhancing angiogenetic ability via vascular endothelial growth factor receptor 2 phosphorylation. PRDX2 was identified as a downstream target of ISO, and endothelial-specific overexpression of PRDX2 exerted effects on the cardiac microvascular function that were similar to those of ISO treatment. In addition, PRDX2 mediated the inhibitive effects of ISO treatment on ferroptosis by suppressing oxidative stress, iron overload, and lipid peroxidation. Further study suggested that mitochondrial dynamics and dysfunction contributed to ferroptosis, and ISO treatment or PRDX2 overexpression attenuated mitochondrial dysfunction via MFN2-dependent mitochondrial dynamics. Moreover, MFN2 overexpression suppressed the mitochondrial translocation of ACSL4, ultimately inhibiting mitochondria-associated ferroptosis. In contrast, enhancing mitochondria-associated ferroptosis via ACSL4 abolished the protective effects of ISO treatment on cardiac microcirculation. Taken together, the results of the present work demonstrated the beneficial effects of ISO treatment on cardiac microvascular protection in diabetes by suppressing mitochondria-associated ferroptosis through PRDX2-MFN2-ACSL4 pathways.

ВЛИЯНИЕ ЭКСТРАКТА RUMEX CONFERTUS НА МЕТАБОЛИЧЕСКИЕ ПРОЦЕССЫ В ОРГАНИЗМЕ

Vital physiological and metabolic processes occurring in the human body are associated with free radical oxidation, which affects the structure, permeability and physico-chemical properties of biological membranes. Horse sorrel is used for scurvy, gout, diabetes, jaundice, hypertension, rheumatism, skin diseases – scabies, lichen, eczema, burns, as well as diseases of the digestive and cardiovascular systems. The purpose of the research: to study the technology of obtaining liquid extract of horse sorrel roots and to study its antioxidant activity on the body. Liquid extract of horse sorrel roots and auxiliary substances were used as the object of the study: dimethyl sulfoxide DMSO, ethyl alcohol 96%, quercetin, lecithin. When performing the work, equipment was used: liquid chromatograph "Color Yauza-01-AA", SF-LEKISS 1207UV. The object of the study of the total antioxidant activity were extracts of horse sorrel roots obtained using ethyl alcohol in concentration: 30%, 40%, 50%, 60%, 70%, 80%. The total content of antioxidants in the studied liquid extracts of horse sorrel roots was determined by two methods: using a liquid chromatograph "Color Yauza-01-AA" with an amperometric detector. The quantitative content of antioxidants was determined according to the calibration schedule. The conversion was carried out for gallic acid and quercetin. Using a model of iron-induced lipid peroxidation in the system of lecithin (phosphotidylcholine) liposomes, the studied liquid extracts were evaluated by reducing the accumulation of peroxide compounds. The study was carried out at a concentration of 200 mcg/ml to 500 mcg/ml of horse sorrel extract and increasing the dose.

Studies on antioxidant activities of grape pomace using in vitro, ex vivo, and in vivo models

Grape pomace (GP) is a by-product resulting from the wine industry and can be considered raw material for animal nutrition, mainly due to its richness in polyphenolic substances. The present study, determined the antioxidant activity of GP by different in vitro assays including 1,1-Diphenyl-2-picrylhydrazyl (DPPH), superoxide anion, and hydroxyl radical and hydrogen peroxide scavenging activity and the inhibitory effect on iron-induced lipid peroxidation system. The estimated IC50 value (the concentration required to scavenge 50% of the radicals) of GP methanolic extract was 53.49 mg/L for DPPH; 57.37 mg/L for hydroxyl radical; 29.06 mg/L for superoxide radical and 102.15 mg/L for hydrogen peroxide. The effect of grape pomace supplements in broiler diets on oxidative stability of meat was tested in an experiment on 80 broiler chicks, 1-day-old Cobb 500, divided into 2 groups (C and E) reared on permanent wood shaves litter (10–12 cm thick). Compared to the control diet C, during the grower (14–28 days) and finisher (29–42 days) stages, the experimental diet (E) was supplemented with 6% GP. At the end of the experiment, 6 chicks aged 42 days from each group were slaughtered and samples of thigh meat were collected for further analysis. When the iron-induced lipid peroxidation system was applied, no significant differences were noticed between ex vivo groups’ lipid peroxidation inhibition percentage (24.71% inhibition when GP was added to meat samples and 24.10% inhibition when GP was ingested by animals) and in vivo data (26.92% inhibition) obtained.

Study on the Neuroprotective, Radical-Scavenging and MAO-B Inhibiting Properties of New Benzimidazole Arylhydrazones as Potential Multi-Target Drugs for the Treatment of Parkinson's Disease.

Oxidative stress is a key contributing factor in the complex degenerating cascade in Parkinson’s disease. The inhibition of MAO-B affords higher dopamine bioavailability and stops ROS formation. The incorporation of hydroxy and methoxy groups in the arylhydrazone moiety of a new series of 1,3-disubstituted benzimidazole-2-thiones could increase the neuroprotective activity. In vitro safety evaluation on SH-SY5Y cells and rat brain synaptosomes showed a strong safety profile. Antioxidant and neuroprotective effects were evaluated in H2O2-induced oxidative stress on SH-SY5Y cells and in a model of 6-OHDA-induced neurotoxicity in rat brain synaptosomes, where the dihydroxy compounds 3h and 3i demonstrated the most robust neuroprotective and antioxidant activity, more pronounced than the reference melatonin and rasagiline. Statistically significant MAO-B inhibitory effects were exerted by some of the compounds where again the catecholic compound 3h was the most potent inhibitor similar to selegiline and rasagiline. The most potent antioxidant effect in the ferrous iron induced lipid peroxidation assay was observed for the three catechols—3h and 3j, 3q. The catecholic compound 3h showed scavenging capability against superoxide radicals and antioxidant effect in the iron/deoxyribose system. The study outlines a perspective multifunctional compound with the best safety profile, neuroprotective, antioxidant and MAO-B inhibiting properties.

Acetylcholinesterase inhibitory activity and iron-induced lipid peroxidation reducing potential of Pimpinella stewartii leaves in male wistar rats

This study was aimed to determine the potentialities of Pimpinella stewartii leaves extracts fractions towards the inhibition of acetylcholinesterase (AChE) activity as well as reduction of iron-induced lipid peroxidation in male Wistar rats (age – 50 days; weight – 280–300 g). Initially, animals were divided into 17 groups with 7 rats in each group. Gallic acid and quercetin were used as standards. The AChE activities of aqueous and ethanolic extract fractions of P. stewartii leaves were determined using standard protocol. Results showed that ethyl acetate extract fractions significantly (P = 0.01) inhibited the enzyme in a concentration dependent manner when compared to the aqueous extract fractions and the control group. Gallic acid and quercetin depicted higher inhibition of AChE activities than ethyl acetate extract fractions. Additionally, the IC50 values for aqueous extract fractions, ethyl acetate extract fractions, gallic acid, and quercetin were estimated as 72.6 ± 2.72, 30.41 ± 0.56, 8.4 ± 0.22, and 6.82 ± 0.2 µg/mL, respectively. Furthermore, the lipid peroxidation activities of extracts fractions were assessed by estimating thiobarbituric acid reactive substances (TBARS) production. Both the extracts fractions showed significant protection against lipid peroxidation but the ethyl acetate extract fractions exhibited comparatively higher reductions in TBARS levels (P = 0.001). However, gallic acid and quercetin revealed higher reductions of pro-oxidants than the extracts fractions. In conclusion, findings of this study demonstrated pronounced AChE inhibitory activity and reduced lipid peroxidation trait of ethyl acetate extract fractions of P. stewartii leaves, and thus, suggested its paramount role as therapeutics against Alzheimer disease.

PHARMACOLOGICAL ACTIVITY OF EXTRACTS FROM PLANTS OF COSMOS BIPINNATUS CAV. SPECIES

The aim of the study is to determine antioxidant, anti-inflammatory and hypolipidemic activities of the extracts from Cosmos bipinnatus Cav. three varieties, obtained by the extraction with 70% ethyl alcohol.Materials and methods. The antioxidant effect was studied in vitro using a model of iron-induced lipid peroxidation in the lecithin liposome system. The study of the anti-inflammatory activity was carried out on 30 male rats of the “Wistar” line. Diclofenac was used as a reference drug (p. o., the dose of 13 mg/kg in terms of the weight of an adult). The substances were administered to animals in the form of an aqueous suspension stabilized with Tween-80. To simulate the inflammatory process, a model of “cotton granuloma” was created. A hypolipidemic activity of the extracts was studied on 36 white male rats of the “Wistar” line. To study the hypolipidemic activity of the studied extracts, a tween model was used to create a hyperlipidemic state in rats, the concentrations of total cholesterol and triglycerides was determined in the serum of the experimental animals.Results. The conducted model experiments made it possible to conclude that the alcohol extracts obtained from the dried inflorescences of the “Dazzler”, “Rosea” and “Purity” varieties of Cosmos bipinnatus Cav. have antioxidant, anti-inflammatory and hypolipidemic kinds of activities. It has been established that the extracts from the “Dazzler” and “Rosea” varieties (Cosmos bipinnatus Cav.) contribute to a better reduction in the accumulation of peroxide compounds, compared to the extract obtained from the “Purity” variety. The data analysis on the anti-inflammatory activity shows that all the studied objects significantly (p = 0.05) reduce the stage of exudation compared with the control group animals by 50% (the «Purity» variety), by 52% (the «Rosea» variety) and by 40% (the “Dazzler” variety).An experiment on the study of a hypolipidemic activity in the control group of the animals revealed a significant, in relation to the values of the intact group, increase in the cholesterol level of the blood serum by 78%, and in the level of triglycerides (TGCs) – by 64%.The administration of the extracts obtained from Cosmos bipinnatus Cav. “Purity”, “Rosea”, “Dazzler” varieties to the animals, led to a decrease in cholesterol in blood serum by 44%, 47%, 50%, and triglycerides by 52%, 52% and 57%, respectively. Both indicators reached the normal level and did not differ significantly from the values in healthy (intact) animals.Conclusion. According to the conducted studies, it can be concluded that alcohol extracts obtained from Cоsmos bipinnatus Cav., have pronounced antioxidant, anti-inflammatory and hypolipidemic kinds of effect.

Role of Sulphur and Heavier Chalcogens on the Antioxidant Power and Bioactivity of Natural Phenolic Compounds.

The activity of natural phenols is primarily associated to their antioxidant potential, but is ultimately expressed in a variety of biological effects. Molecular scaffold manipulation of this large variety of compounds is a currently pursued approach to boost or modulate their properties. Insertion of S/Se/Te containing substituents on phenols may increase/decrease their H-donor/acceptor ability by electronic and stereo-electronic effects related to the site of substitution and geometrical constrains. Oxygen to sulphur/selenium isosteric replacement in resveratrol or ferulic acid leads to an increase in the radical scavenging activity with respect to the parent phenol. Several chalcogen-substituted phenols inspired by Vitamin E and flavonoids have been prepared, which in some cases prove to be chain-breaking antioxidants, far better than the natural counterparts. Conjugation of catechols with biological thiols (cysteine, glutathione, dihydrolipoic acid) is easily achieved by addition to the corresponding ortho-quinones. Noticeable examples of compounds with potentiated antioxidant activities are the human metabolite 5-S-cysteinyldopa, with high iron-induced lipid peroxidation inhibitory activity, due to strong iron (III) binding, 5-S-glutathionylpiceatannol a most effective inhibitor of nitrosation processes, and 5-S-lipoylhydroxytyrosol, and its polysulfides that proved valuable oxidative-stress protective agents in various cellular models. Different methodologies have been used for evaluation of the antioxidant power of these compounds against the parent compounds. These include kinetics of inhibition of lipid peroxidation alkylperoxyl radicals, common chemical assays of radical scavenging, inhibition of the OH• mediated hydroxylation/oxidation of model systems, ferric- or copper-reducing power, scavenging of nitrosating species. In addition, computational methods allowed researchers to determine the Bond Dissociation Enthalpy values of the OH groups of chalcogen modified phenolics and predict the best performing derivative. Finally, the activity of Se and Te containing compounds as mimic of glutathione peroxidase has been evaluated, together with other biological activities including anticancer action and (neuro)protective effects in various cellular models. These and other achievements are discussed and rationalized to guide future development in the field.

Multimodal polymer encapsulated CdSe/Fe3O4 nanoplatform with improved biocompatibility for two-photon and temperature stimulated bioapplications

Multimodal polymer encapsulated CdSe/Fe3O4 nanoplatforms with dual optical and magnetic properties have been fabricated. We demonstrate that CdSe/Fe3O4 nanocapsules (NCs) upon excitation with UV radiation or NIR fs-laser excitation exhibit intense one- or two-photon emission at 535 nm, whereas the combination of an alternating magnetic field and 808 nm IR laser excitation results in heat generation. Since anticancer therapies require relatively high doses of Fe3O4 nanoparticles (NPs) to induce biologically relevant temperature jumps, the therapeutic effects of 0.1 and 1 mg/mL Fe3O4 NCs and CdSe/Fe3O4 NCs were investigated using breast cancer cell lines, ER-positive MCF-7, and triple-negative MDA-MB-231 cells. Improved biocompatibility of CdSe/Fe3O4 NCs compared to Fe3O4 NCs was revealed at higher NCs concentration suggesting safe potential medical applications of CdSe/Fe3O4 NCs. In contrast, 1 mg/mL Fe3O4 NCs were found to be more cytotoxic to MDA-MB-231 than MCF-7 cells through iron-induced oxidative stress, lipid peroxidation, and concomitant ferroptotic cell death. We believe that Fe3O4 NCs-mediated cellular response may be heterogeneous that reflects, at least in part, cancer cell genotype, molecular phenotype, and pathological classification.

Xanthine Oxidase and Lipid Peroxidation Inhibition of Taiwan Folkloric Medicine Factors Affecting Rhus semialata var. Roxburghiana Activities against Xanthine Oxidase and Ferrous Iron-induced Lipid Peroxidation on Mice Liver Mitochondria

Abstract: Background: Gout, a disease characterized by recurrent inflammatory for urate deposit from overactive xanthine oxidase, is common among Taiwanese. Rhus semialata var. roxburghiana (RSR) grows wildly in Central Mountain of Taiwan and used by aboriginal Taiwanese as traditional medicine for gout and hepatitis. Methods: In this study, the factors such as variations in RSR extracts in terms of geographical sources, aerial parts and extraction solvents were investigated for antioxidant capabilities, phytochemical analysis and inhibitory effects against xanthine oxidase and lipid peroxidation using ferrous ion as ROS inducer on mice liver mitochondria. Results: The results showed that ML-n-hexane and NS-acetone gave the maximum XO inhibitions (IC50=16.74±0.74 μg/mL) and LPO inhibitions (IC50=8.40±0.35 μg/mL) in the liver mitochondria of mice, respectively. And ML-n-hexane and NS-acetone contained phenolic and flavonoids compounds for its potential target components against XO and LPO in this study. Conclusion: Overall, RSR could lead to a medicinal potential as a suitable candidate for the development of a natural anti-gout and liver damage protective agent that have yet to be conducted. Key words: Rhus semialata var. Roxburghiana extracts, Geographical source, Xanthine oxidase inhibitor, Free radical scavenging, Liver mitochondria LPO inhibitor.

Gallic Acid Attenuated LPS-Induced Neuroinflammation: Protein Aggregation and Necroptosis.

Gallic acid (3,4,5-trihydroxybenzoic acid, GA), a phenolic acid, is ubiquitous in almost all parts of the plant. In the present study, a neuroinflammatory rat model using intranigral infusion of lipopolysaccharides (LPS, 4μg/μL) was employed to study the neuroprotective effect of GA which was orally administered daily. Compared with the vehicle-treated rats, systemic administration of GA (100mg/kg) significantly attenuated LPS-induced increases in glial fibrillary acidic protein (a biomarker of activated astrocytes) and ED-1 (a biomarker of activated microglia), as well as inducible nitric oxide synthase (iNOS, a proinflammatory enzyme) and interleukin-1β (a proinflammatory cytokine), in the LPS-infused substantia nigra (SN) of rat brain. At the same time, GA attenuated LPS-induced elevation in heme oxygenase-1 level (a redox-regulated protein) and α-synuclein aggregation (a hallmark of CNS neurodegeneration), suggesting that GA is capable of inhibiting LPS-induced oxidative stress and protein conjugation. Furthermore, GA prevented LPS-induced caspase 3 activation (a biomarker of programmed cell death) and LPS-induced increases in receptor-interacting protein kinase (RIPK)-1 and RIPK-3 levels (biomarkers of necroptosis), indicating that GA inhibited LPS-induced apoptosis and necroptosis in the nigrostriatal dopaminergic system of rat brain. Moreover, an in vitro study was employed to investigate the anti-inflammatory effect of GA on BV2 microglial cells which were subjected to LPS (1μg/mL) treatment. Consistently, co-incubation of GA diminished LPS-induced increases in iNOS mRNA and iNOS protein expression in the treated BV-2 cells as well as NO production in the culture medium. The anti-oxidative activity of GA was evaluated using iron-induced lipid peroxidation of brain homogenates. After 3-h incubation at 37°C, GA was more potent than glutathione and less potent than trolox in inhibiting iron-induced lipid peroxidation. Conclusively, the present study suggests that GA is anti-inflammatory via attenuating LPS-induced neuroinflammation, oxidative stress, and protein conjugation. Furthermore, GA prevented LPS-induced programmed cell deaths of nigrostriatal dopaminergic neurons of the rat brain, suggesting that GA may be neuroprotective by attenuating neuroinflammation in CNS neurodegenerative diseases.