Induction Of Peroxidation Research Articles

The study of primary DNA damage in the bone marrow of mice under the combined action of pesticides

Introduction. The study of the potential negative effects of combinations of several pesticide active ingredients is an important and understudied area of toxicological and hygienic research. The initial phase of the genotoxicant action on the genetic structures in cells is the primary DNA damage, the identification of which makes it possible to assess the early stages of the genotoxic effect of xenobiotics and their mixtures. The DNA comet assay is widely used for these purposes. The aim of the research is to assess the primary DNA damage under the combined action of pesticides. Materials and methods. To assess DNA damage the experiments on CD-1 mice of both sexes were performed using alkaline comet analysis. The concentration of active products reacting with thiobarbituric acid (TBA) in the blood serum of white outbred rats was assessed as a marker of lipid peroxidation. Results. It was found that mixtures of 2,4-D-acid + glyphosate and thiram + carbendazim did not cause the formation of breaks and alkali-labile sites in the DNA of mice bone marrow cells. Exposure to the combination of the technical grade active ingredients captan and fludioxonil induced the breaks and alkali-labile sites in the DNA of animal bone marrow cells. The comparison of the genotoxicity assessment results obtained by the comet assay and results of analysis of the TBA-active product concentrations in the rat blood serum suggests that the observed primary DNA damage upon exposure to the captan and fludioxonil combination can be mediated by the induction of lipid peroxidation and subsequent interaction of the resulting products with nucleic acids. Conclusion. The results indicate that some pesticides in combination can damage hereditary material in mammalian cells. Therefore, in order to ensure the safe use of pesticides for public health it is necessary to take into account the data on the genotoxicity not only of individual pesticide technical grade active ingredients but also their combinations.

The photodynamic and intrinsic effects of Azure B on mitochondrial bioenergetics and the consequences of its intrinsic effects on hepatic energy metabolism

BackgroundThe present study aimed to characterize the intrinsic and photodynamic effects of azure B (AB) on mitochondrial bioenergetics, as well as the consequences of its intrinsic effects on hepatic energy metabolism. MethodsTwo experimental systems were utilized: (a) isolated rat liver mitochondria and (b) isolated perfused rat liver. ResultsAB interacted with mitochondria regardless of photostimulation, but its binding degree was reduced by mitochondrial energization. Under photostimulation, AB caused lipid peroxidation and protein carbonylation and decreased the content of reduced glutathione (GSH) in mitochondria. AB impaired mitochondrial bioenergetics in at least three distinct ways: (1) uncoupling of oxidative phosphorylation; (2) photoinactivation of complexes I and II; and (3) photoinactivation of the FoF1–ATP synthase complex. Without photostimulation, AB also demonstrated mitochondrial toxicity, which was characterized by the induction of lipid peroxidation, loss of inner mitochondrial membrane integrity, and uncoupling of oxidative phosphorylation. The perfused rat liver experiments showed that mitochondria were one of the major targets of AB, even in intact cells. AB inhibited gluconeogenesis and ureagenesis, two biosynthetic pathways strictly dependent on intramitochondrially generated ATP. Contrariwise, AB stimulated glycogenolysis and glycolysis, which are required compensatory pathways for the inhibited oxidative phosphorylation. Similarly, AB reduced the cellular ATP content and the ATP/ADP and ATP/AMP ratios. ConclusionsAlthough the properties and severe photodynamic effects of AB on rat liver mitochondria might suggest its usefulness in PDT treatment of liver tumors, this possibility should be considered with precaution given the toxic intrinsic effects of AB on mitochondrial bioenergetics and energy-linked hepatic metabolism.

Intracerebral Injection of Heme Induces Lipid Peroxidation, Neuroinflammation, and Sensorimotor Deficits.

Heme is a red blood cell component released in the brain parenchyma following intracerebral hemorrhage. However, the study of the pathophysiological mechanisms triggered by heme in the brain is hampered by the lack of well-established in vivo models of intracerebral heme injection. This study aims to optimize and characterize a protocol of intrastriatal heme injection in mice, with a focus on the induction of lipid peroxidation, neuroinflammation and, ultimately, sensorimotor deficits. We also evaluated the involvement of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome sensor, in the behavior deficits induced by heme in this model. Mice were injected with heme in the striatum for the evaluation of neuroinflammation and brain damage through histological and biochemical techniques. Immunoblot was used to evaluate the expression of proteins involved in heme/iron metabolism and antioxidant responses and the activation of the MAPK (mitogen-activated protein kinase) signaling pathway. For the assessment of neurological function, we followed-up heme-injected mice for 2 weeks using the rotarod, elevated body swing, and cylinder tests. Mice injected with the vehicle (sham), or autologous blood were used as controls. Heme induced lipid peroxidation and inflammation in the brain. Moreover, heme increased the expression of HO-1 (heme oxygenase-1), ferritin, p62, and superoxide dismutase 2, and activated the MAPK signaling pathway promoting pro-IL (interleukin)-1β production and its cleavage to the active form. Heme-injected mice exhibited signs of brain damage and reactive astrogliosis around the injection site. Behavior deficits were observed after heme or autologous blood injection in comparison to sham-operated controls. In addition, behavior deficits and IL-1β production were reduced in Nlrp3 knockout mice in comparison to wild-type mice. Our results show that intracerebral heme injection induces neuroinflammation, and neurological deficits, in an NLRP3-dependent manner, suggesting that this is a feasible model to evaluate the role of heme in neurological disorders.

Short overview on the relevance of microRNA-reactive oxygen species (ROS) interactions and lipid peroxidation for modulation of oxidative stress-mediated signalling pathways in cancer treatment.

Modulation of oxidative stress-mediated signalling pathways is constantly getting more attention as a valuable therapeutic strategy in cancer treatment. Although complexity of redox signalling pathways might represent a major hurdle, the development of advanced -omics technologies allow thorough studies on cancer-specific biology, which is essential to elucidate the impact of these signalling pathways in cancer cells. The scope of our review is to provide updated information about recent developments in cancer treatment. In recent years identifying oxidative stress-mediated signalling pathways is a major goal of cancer research assuming it may provide novel therapeutic approaches through the development of agents that may have better tissue penetration and therefore affect specific redox signalling pathways. In this review, we discuss some recent studies focussed on the modulation of oxidative stress-related signalling pathways as a novel anti-cancer treatment, with a particular emphasis on the induction of lipid peroxidation. Characterization and modulation of oxidative stress-mediated signalling pathways and lipid peroxidation products will continue to foster novel interest and further investigations, which may pave the way for more effective, selective, and personalized integrative biomedicine treatment strategies.

Acceleration Breaks the Cells Defense Mechanisms against Vibration in Anthemis gilanica Calli

Vibration is a mechanical stress which happens in nature and affects many biological aspects of plants. In this research, the effect of acceleration and vibration was investigated on some physiological and biochemical responses of Anthemis gilanica in vitro. Calli were induced from leaf (LS) and root segments (RS) and were applied to different frequencies of vibrations (0, 50, and 100 Hz) and accelerations (1, 2, and 4 g) on the A. gilanica calli for 30 min. Results showed that vibration significantly increased relative water content (RWC), growth parameters, protein and proline contents, ascorbate peroxidase (APX), peroxidase (POX), and superoxide dismutase (SOD) activities and decreased total carbohydrate, malondialdehyde (MDA), H2O2 contents, and polyphenol oxidase (PPO) activity in both LS and RS calli. Inversely, increase of acceleration in vibrated calli decreased growth parameters, RWC, protein content, and POX activity and induced proline and carbohydrate accumulations, SOD, APX, and PPO activities as compared to vibration alone. Different responses of two callus types were observed, and the highest growth, protein content, and membrane stability were observed in LS calli as compared to RS calli. It found that high acceleration amplitude intensified the resonance effect of vibration by induction of lipid peroxidation and oxidative stress damage in A. gilanica.

Auranofin reveals therapeutic anticancer potential by triggering distinct molecular cell death mechanisms and innate immunity in mutant p53 non-small cell lung cancer

Auranofin (AF) is an FDA-approved antirheumatic drug with anticancer properties that acts as a thioredoxin reductase 1 (TrxR) inhibitor. The exact mechanisms through which AF targets cancer cells remain elusive. To shed light on the mode of action, this study provides an in-depth analysis on the molecular mechanisms and immunogenicity of AF-mediated cytotoxicity in the non-small cell lung cancer (NSCLC) cell line NCI–H1299 (p53 Null) and its two isogenic derivates with mutant p53 R175H or R273H accumulation.TrxR is highly expressed in a panel of 72 NSCLC patients, making it a valid druggable target in NSCLC for AF. The presence of mutant p53 overexpression was identified as an important sensitizer for AF in (isogenic) NSCLC cells as it was correlated with reduced thioredoxin (Trx) levels in vitro. Transcriptome analysis revealed dysregulation of genes involved in oxidative stress response, DNA damage, granzyme A (GZMA) signaling and ferroptosis. Although functionally AF appeared a potent inhibitor of GPX4 in all NCI–H1299 cell lines, the induction of lipid peroxidation and consequently ferroptosis was limited to the p53 R273H expressing cells. In the p53 R175H cells, AF mainly induced large-scale DNA damage and replication stress, leading to the induction of apoptotic cell death rather than ferroptosis. Importantly, all cell death types were immunogenic since the release of danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation occurred irrespective of (mutant) p53 expression. Finally, we show that AF sensitized cancer cells to caspase-independent natural killer cell-mediated killing by downregulation of several key targets of GZMA.Our data provides novel insights on AF as a potent, clinically available, off-patent cancer drug by targeting mutant p53 cancer cells through distinct cell death mechanisms (apoptosis and ferroptosis). In addition, AF improves the innate immune response at both cytostatic (natural killer cell-mediated killing) and cytotoxic concentrations (dendritic cell maturation).

Tebuconazole induced cytotoxic and genotoxic effects in HCT116 cells through ROS generation

Tebuconazole (TEB) is a common triazole fungicide that has been widely used for the control of plant pathogenic fungi, suggesting that mammal exposure occurs regularly. Several studies demonstrated that TEB exposure has been linked to a variety of toxic effects, including neurotoxicity, immunotoxicity, reprotoxicity and carcinogenicity. However, there is a few available data regarding the molecular mechanism involved in TEB-induced toxicity. The current study was undertaken to investigate the toxic effects of TEB in HCT116 cells. Our results showed that TEB caused cytotoxicity by inhibiting cell viability as assessed by the MTT assay. Furthermore, we have demonstrated that TEB induced a significant increase in the reactive oxygen species (ROS) production leading to the induction of lipid peroxidation and DNA fragmentation and increased superoxide dismutase (SOD) and catalase (CAT) activities. Moreover, TEB exposure induced mitochondrial membrane potential loss and caspase-9/-3 activation. Treatment with general caspases inhibitor (Z-VAD-fmk) significantly prevented the TEB-induced cell death, indicating that TEB induced caspases-dependent cell death. These findings suggest the involvement of oxidative stress and apoptosis in TEB-induced toxicity in HCT116.

Eco-Friendly Preparation of Epoxy-Rich Graphene Oxide for Wound Healing.

Despite the ever-growing endangerment caused by the multidrug resistance (MDR) of bacteria, the development of effective antibacterial materials still remains a global challenge. Current antibiotic therapies cannot simultaneously inactivate bacteria and accelerate wound healing. This study aimed to originally separate the intercalation of MnO3+ and the oxidation processes to synthesize epoxy-rich graphene oxide (erGO) nanofilms via an eco-friendly synthetic route, which possessed low density and large lamellar distribution and was rich in epoxide. Importantly, the MnO3+ could be separated from the product and recycled for preparing the next generation of erGO nanofilms, which was quite economical and eco-friendly. The erGO nanofilm was capable of successfully inhibiting Gram-negative bacteria and even had excellent growth-inhibitory effects on Gram-positive bacteria including multidrug resistance (MDR) bacteria, as evidenced by antibacterial phenomena. Additionally, the erGO nanofilm with high •C density formed from epoxide exerted excellent antibacterial effects through tight membrane wrapping and induction of lipid peroxidation. The wound-healing property of the erGO nanofilm was evaluated via treatments of wounds infected by Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), which not only killed bacteria but also accelerated wound healing in mice with a skin infection. The novel erGO nanofilm with dual antimicrobial mechanisms might serve as a promising multifunctional antimicrobial agent for medical wound dressing with high biocompatibility.

Oxidative Stress Mediated Cytotoxicity, Cell Cycle Arrest, and Apoptosis Induced by Rosa damascena in Human Cervical Cancer HeLa Cells.

Rosa damascena Mill (Damask rose), belonging to the Rosaceae family, is known for medicinal purposes in traditional medicine system. However, its anticancer activity has not been studied yet in detail. Herein, we aimed to investigate the cytotoxic effects of R. damascena hexane (RA-HE) and methanolic (RA-ME) extracts against human breast (MCF-7), lung epithelial (A-549), and cervical (HeLa) cancer cells. The RA-HE and RA-ME showed more potent cytotoxic effects against HeLa cells with an IC50 of 819.6 and 198.4 μg/ml, respectively. Further, cytotoxic concentrations of most effective extract (RA-ME) were used to evaluate the mechanism of cytotoxicity involved in HeLa cells. A concentration-dependent induction of lipid peroxidation (LPO) and reduction of glutathione (GSH) in HeLa cells treated with 250-1000 μg/ml of RA-ME confirms the association of oxidative stress. We also detected a noteworthy increase in reactive oxygen species (ROS) production and a decline in mitochondrial membrane potential (MMP) level in RA-ME-exposed HeLa cells. Flow cytometric data showed a strong dose-response relationship in cell cycle analysis between subG1 phase in HeLa cells and RA-ME treatment. Similarly, a concentration-dependent increase was recorded with Annexin V assay in HeLa cells going to late apoptosis. In conclusion, our findings suggest that RA-ME-induced cytotoxicity and apoptosis in HeLa cells are mediated by oxidative stress.

Cytotoxic effects of dental prosthesis grinding dust on RAW264.7 cells

Respiratory diseases, including pulmonary fibrosis, silicosis, and allergic pneumonia, can be caused by long-term exposure to dental prosthesis grinding dust. The extent of the toxicity and pathogenicity of exposure to PMMA dust, Vitallium dust, and dentin porcelain dust differs. The dust from grinding dental prosthesis made of these three materials was characterized in terms of morphology, particle size, and elemental composition. The adverse effects of different concentrations of grinding dust (50, 150, 300, 450, and 600 μg ml−l) on RAW264.7 macrophages were evaluated, including changes in cell morphology and the production of lactate dehydrogenase (LDH) and reactive oxygen species (ROS). The dust particles released by grinding dental prosthesis made of these materials had different morphologies, particle sizes, and elemental compositions. They also induced varying degrees of cytotoxicity in RAW264.7 macrophages. A possible cytotoxicity mechanism is the induction of lipid peroxidation and plasma membrane damage as the dust particles penetrate cells. Therefore, clinicians who regularly work with these materials should wear the appropriate personal protection equipment to minimize exposure and reduce the health risks caused by these particulates.

Abstract 237: DECR1: The rate limiting enzyme of polyunsaturated fatty acid metabolism and a novel therapeutic target in prostate cancer

Abstract Introduction: Fatty acid oxidation (FAO) is the dominant bioenergetic pathway in prostate cancer (PCa). Previous studies have demonstrated efficacy in targeting key FAO enzymes using in vitro and in vivo models of PCa. However, clinical evidence supporting FAO targeting in PCa is lacking. A recent study reported that FAO is upregulated in PCa cells and is essential for cell viability. Here, we demonstrated therapeutic efficacy of targeting FAO in clinical prostate tumors and identified DECR1 as a potential FAO-related survival factor. Methods and Results: To examine the therapeutic efficacy of targeting FAO in a more clinically-relevant setting, patient-derived prostate explants (PDE) were treated with etomoxir (FAO inhibitor). Results showed significant inhibition of cell proliferation (evaluated using Ki67 immunohistochemistry staining) in drug-treated PDE by a mean of 48% (n=13, p<0.05). To identify key targets of FAO in PCa, a meta-analysis was performed using four clinical RNA-sequencing datasets comprising of malignant and matched normal PCa patient tissues. DECR1 – the rate limiting enzyme of polyunsaturated fatty acid (PUFA) oxidation was identified as a robustly overexpressed FAO gene in PCa tissues; its expression is significantly associated with shorter biochemical recurrence-free survival and overall PCa patient survival. Consistent with the vital role of DECR1 in PUFA oxidation, knockdown of DECR1 impaired the cell's capacity to metabolize PUFAs; furthermore, FAO inhibition via DECR1 knockdown is specific to PUFA oxidation. Notably, DECR1 knockdown significantly inhibited PCa cell proliferation, migration, and invasion, and significantly reduced cellular proliferation in tumors. Mechanistically, DECR1 knockdown results in the induction of lipid peroxidation and cell death via ferroptosis in PCa cells. In contrast, overexpression of DECR1 significantly decreased mitochondrial oxidative stress and reduced levels of malondialdehyde. Treatment of PCa cells with ferrostatin successfully rescued PCa cells from death by DECR1 inhibition. Taken together, these data suggest that overexpression of DECR1 may offer PCa cells a survival advantage by protecting the cells from ferroptosis. Conclusion: This study demonstrated for the first time clinically-relevant evidence that targeting FAO is efficacious and provides evidence for the importance of FAO, and specifically PUFA oxidation, in PCa progression. Importantly, this study identified DECR1 as a promising and novel therapeutic target for PCa. Citation Format: Chui Yan Mah, Zeyad D. Nassar, Ingrid J. Burvenich, Swati Irani, Margaret M. Centenera, Max Moldovan, David J. Lynn, Andrew J. Hoy, Johannes V. Swinnen, Lisa M. Butler. DECR1: The rate limiting enzyme of polyunsaturated fatty acid metabolism and a novel therapeutic target in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 237.

UVB photoirradiation of aloe vera - Formation of free radicals, singlet oxygen, superoxide, and induction of lipid peroxidation

Aloe vera whole leaf extracts are incorporated into a wide variety of topically applied commercial products. Aloe vera whole leaf extracts contain anthraquinones, which can generate reactive oxygen species (ROS) upon UVA light irradiation. In this study, the phototoxicity of two Aloe vera whole leaf extracts, Aloe A and Aloe B, were examined. The Aloe B extract was prepared by treating the Aloe A extract with activated carbon (1%, wt/wt) and filtration to remove the Aloe latex components, including the anthraquinones. UVB irradiation of the Aloe vera whole leaf extracts induced lipid peroxidation in the presence of a lipid, methyl linoleate. The amounts of lipid peroxides formed were higher in the Aloe B, which contained lower amounts of anthraquinones than Aloe A. Sodium azide inhibited and deuterium oxide enhanced the formation of lipid peroxides by Aloe B, suggesting that singlet oxygen was involved in the mechanism. When superoxide dismutase was incorporated prior to irradiation, lipid peroxidation was inhibited, indicating that superoxide was produced during the photoirradiation of Aloe B. In addition, electron spin resonance (ESR) spectroscopy was also used to investigate the generation of free radicals by the UVB photoirradiated Aloe B. ESR measurements indicated that the UVB photoirradiation of Aloe B produced carbon-centered free radicals. These results suggested that, as with the exposure to UVA light, the exposure of Aloe vera whole leaf extracts to UVB light can also generate ROS and induce lipid peroxidation.

Risk assessment of heavy metal(loid)s via Spinacia oleracea ingestion after sewage water irrigation practices in Vehari District.

The use of sewage water as an irrigation source can be beneficial in agricultural practices, however, it may result in human health risks due to the consumption of heavy metal(loid)-contaminated food. This study evaluated the suitability of using sewage water (SW), freshwater (FW), and groundwater (GW) for vegetable irrigation in District Vehari. Spinach (Spinacia oleracea) plants were grown in pots irrigated with FW, GW, and SW in different proportions and combinations. The results indicated the substantial lesser buildup of heavy metal(loid)s (As (- 0.8%), Cd (- 38%), Cr (- 6.2%), Cu (- 20%), Fe (- 9.2%), Mn (- 13%), Ni (- 16%), Pb (- 19%), and Zn (-15%)) in soil after S. oleracea cultivation compared to unirrigated soil possibly due to high metal(loid) uptake by S. oleracea. Irrigation with all types of waters resulted in metal(loid) accumulation in S. oleracea predominantly in roots. The combinations of FW, GW, and SW resulted in high metal(loid) accumulation (As, Cd, Cr, Cu, Fe, Mn, Ni, Pb, and Zn) in the edible S. oleracea leaves than their alone application. Owing to high metal(loid) buildup, plants showed a linear trend in physiological imbalance in terms of reduced pigment content, induction of peroxidation, and oxidation of lipids. The severe oxidative stress was observed in S. oleracea plants under FW and GW irrigation due to high metal(loid) accumulation. The risk indices showed possible carcinogenic risk (CR > 0.0001) and non-carcinogenic risk (HI > 1) from the consumption of metal(loid)-contaminated S. oleracea leaves. Results revealed unsuitability of all waters and their combinations for S. oleracea irrigation. Moreover, this study does not encourage the use of mixed water for vegetable irrigation in Vehari District. Therefore, it is of utmost importance to monitor the quality of irrigation waters to ensure food safety and prevent chronic health risks to the exposed population.

Effect of di(2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney.

Environmental toxicants such as phthalate have been involved in multiple health disorders including renal diseases. Oxidative damage is implicated in many alterations caused by phthalate especially the di(2-ethylhexyl) phthalate (DEHP), which is the most useful phthalate. However, information regarding its mechanism of renal damage is lacking. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates gene expression implicated in free radical scavenging and cytoprotection including the antioxidant glutathione (GSH) pathway. The aim of this study was to assess whether DEHP affects the Nrf2 pathway and the GSH concentration. Mice were divided into four groups: a control group and three groups treated with DEHP at different concentrations (5, 50, and 200 mg/kg body weight) for 30 days. Our results showed that DEHP altered the normal levels of serum biochemical parameters creatinine (CREA), urea, and lactate dehydrogenase (LDH). This phthalate caused oxidative damage through the induction of lipid peroxidation and protein oxidation as marked by increase of protein carbonyl (PC) and loss of protein-bound sulfhydryls (PSH). Simultaneously, DEHP treatment decreased the protein level of Nrf-2, HO-1, and GCLC (responsible of GSH synthesis) and decreased the GSH level. Inhibition of the Nrf2 pathway is related to the activation of the mitochondrial pathway of apoptosis. This apoptotic process is evidenced by an upregulation of p53 and Bax protein levels in addition to a downregulation of Bcl-2. Collectively, our data demonstrated that depletion of Nrf2 and GSH was associated with the elevation of oxidative stress and the activation of intrinsic apoptosis in mouse kidney treated with DEHP.

Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction

Conditions of impaired adrenal function and tissue destruction, such as in Addison’s disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate improved understanding of the pathophysiology of adrenal cell death. Due to relevant oxidative processes in the adrenal cortex, our study investigated the role of ferroptosis, an iron-dependent cell death mechanism and found high adrenocortical expression of glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4) genes, key factors in the initiation of ferroptosis. By applying MALDI mass spectrometry imaging to normal and neoplastic adrenocortical tissue, we detected high abundance of arachidonic and adrenic acid, two long chain polyunsaturated fatty acids which undergo peroxidation during ferroptosis. In three available adrenal cortex cell models (H295R, CU-ACC1 and CU-ACC-2) a high susceptibility to GPX4 inhibition with RSL3 was documented with EC50 values of 5.7 × 10−8, 8.1 × 10−7 and 2.1 × 10−8 M, respectively, while all non-steroidogenic cells were significantly less sensitive. Complete block of GPX4 activity by RSL3 led to ferroptosis which was completely reversed in adrenal cortex cells by inhibition of steroidogenesis with ketoconazole but not by blocking the final step of cortisol synthesis with metyrapone. Mitotane, the only approved drug for ACC did not induce ferroptosis, despite strong induction of lipid peroxidation in ACC cells. Together, this report is the first to demonstrate extraordinary sensitivity of adrenal cortex cells to ferroptosis dependent on their active steroid synthetic pathways. Mitotane does not induce this form of cell death in ACC cells.

The Anticancer Properties of Artemisia aucheri Boiss Extract on HT29 Colon Cancer Cells

Colon cancer is one of the most common cancers in the world, and efforts toward its treatment have not been completely successful. In recent years, more attention has been focused on herbal medicine (HM) due to their anticancer and cytotoxic properties. This study investigated the anticancer and antioxidant effects of Artemisia aucheri (A. aucheri) Boiss extract against HT29 colon cancer cells compared with HEK239 natural cells. This study was performed on human HT29 colon cancer cells. Various doses of 0, 10, 100, 500, and 1000μg/ml of A. aucheri extract were subjected to cells at specified time intervals. After treatment, the trypan blue test was employed to determine the viability of the cells. MTT and annexin tests were used to determine cell viability and the apoptosis induced by the extract. Malondialdehyde (MDA) testing was applied to investigate the antioxidant properties of the extract on fatty acids. Data analysis was performed using SPSS version 22. One-way ANOVA and paired comparison tests were employed for data analysis. The highest cytotoxicity effect of A. aucheri extract was observed at 1000μg/ml (80.63 ± 3.66) being dose-dependent compared with the control in both cell lines (p < 0.001). Additionally, the survival rate of HT29 (IC50 = 57.88μg/ml) and HEK (IC50 = 295μg/ml) cancer cells decreased with increasing concentration of A. aucheri (the lowest cell viability was at 1000μg/ml). Furthermore, the induction of membrane lipid peroxidation was significantly higher in HT29 compared with the control (p < 0.001). Another cytotoxic mechanism for the extract was the induction of apoptosis being significantly higher in HT29 colon cancer cells compared with the control group (p < 0.001). Cytotoxic effects of A. aucheri extract were dose-dependent. This HM exerted cytotoxic effects against HT29 cells through the induction of membrane lipid peroxidation and apoptosis.

Di(2-ethylhexyl) phthalate inhibits glutathione regeneration and dehydrogenases of the pentose phosphate pathway on human colon carcinoma cells.

Phthalates, particularly di(2-ethylhexyl) phthalate (DEHP), are compounds widely used as plasticizers and have become serious global contaminants. Because of the bioaccumulation of such substances, the food chain is at risk. The food contamination by some phthalates has been linked to different side effects in experimental animals. That is why we have chosen the intestinal system's cells which represent the primary targets of these compounds to test their toxic effects. Human colon carcinoma cells (HCT 116) were chosen to elucidate whether DEHP triggers oxidative stress and apoptosis. Our results indicated that DEHP is cytotoxic; it induces the overexpression of Hsp70 protein and causes oxidative damage through the generation of free radicals leading to lipid peroxidation induction and the increase of superoxide dismutase (SOD) and catalase (CAT) activities. In addition, cell treatment with DEHP resulted in a glutathione (GSH) content decrease and a decrease in the glutathione reductase (GR) activity. As new evidence provided in this study, we demonstrated that the DEHP affected the two enzymes' activities of the oxidative phase of the pentose phosphate pathway: Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD). This leads to a decrease in the level of NADPH used by the GR to maintain the regeneration of the reduced GSH. We also demonstrated that such effects can be responsible for DEHP-induced apoptosis.

Antimalarial plants with potential male-factor antifertility properties.

Malaria, caused mainly by Plasmodium falciparum among other Plasmodium species, is one of the main causes of death from parasitic diseases. Malaria is still a health problem mainly because of the cost of effective antimalarial drugs and the growing parasite resistance to conventional antimalarial drugs, making a great proportion of the people in malaria endemic countries dependent on plants for its treatment. Corollary, a large number of the rural populations consume antimalarial herbal preparations in large or excessive quantities despite the fact that it has been reported that some of them could cause male-factor infertility, a growing global health concern. Few studies have compiled information on the scientifically validated male-factor antifertility effects of these antimalarial plant remedies. The aim of this review therefore is to compile information on commonly used antimalarial plant remedies that have been experimentally validated as having male-factor antifertility effects. Thus, antimalarial plant remedies with experimentally confirmed male-factor antifertility potentials and compounds isolated from them are identified and discussed. The male-factor antifertility effects of these plants include reduction of sperm quality, regulation of reproductive hormone levels and induction of lipid peroxidation. Indiscriminate use of such antimalarial plants is discouraged when male contraception is not desired.

Protective Effect of Angelica sinensis Extract and Origanum majorana Oil on Hepatic and Renal Toxicities Induced by Nickel Chloride in Male Albino Rats

The present study was accomplished to evaluate the efficacy of Angelica sinensis root extract and Origanum majorana oil on subchronic toxicity of nickel chloride (NiCl2) in albino rats by studying the changes in the biochemical parameters, lipid peroxidation and antioxidant status related to the liver and kidneys. This study was carried out on sixty male albino rats with average body weight (120 ± 10 g), which were divided into 6 equal groups. Gp.(1): were kept as control on distilled water, rats in Gp. (2) received NiCl2 (0.75 mg/kg BW), Gp. (3) received A. sinensis root extract (300 mg/kg BW) and Gp. (4) received O. majorana oil (0.5 ml/kg BW). NiCl2 intoxicated rats in Gp. (5) and Gp. (6) were administered A. sinensis root extract and O. majorana oil at the same former doses, respectively. The treatments were daily and orally for 4 weeks. Blood and tissue samples were collected for performing the different experimental analysis after 4 weeks from starting the treatments. Comparing with the control group, results showed that NiCl2 significantly increased serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities and serum bilirubin, triglycerides, total cholesterol, urea and creatinine concentrations, besides hepatic and renal malondialdehyde concentration, while serum total proteins, albumin and hepatic and renal glutathione, glutathione peroxidase, superoxide dismutase and catalase levels were significantly decreased. A. sinensis root extract and O. majorana oil has no adverse effects and worked on amelioration the various alterations in estimated analytes in combined treated groups. In conclusion, NiCl2 caused hepatic and renal injuries besides the induction of lipid peroxidation and reducing the antioxidant enzymes activities in these organs. Moreover, both of A. sinensis root extract and O. majorana oil provided significant protection against harmful effects of NiCl2 with superiorty of A. sinensis root extract

Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases.

Oxidative stress is a consequence of the use of oxygen in aerobic respiration by living organisms and is denoted as a persistent condition of an imbalance between the generation of reactive oxygen species (ROS) and the ability of the endogenous antioxidant system (AOS) to detoxify them. The oxidative stress theory has been confirmed in many animal studies, which demonstrated that the maintenance of cellular homeostasis and biomolecular stability and integrity is crucial for cellular longevity and successful aging. Mitochondrial dysfunction, impaired protein homeostasis (proteostasis) network, alteration in the activities of transcription factors such as Nrf2 and NF-κB, and disturbances in the protein quality control machinery that includes molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy/lysosome pathway have been observed during aging and age-related chronic diseases. The accumulation of ROS under oxidative stress conditions results in the induction of lipid peroxidation and glycoxidation reactions, which leads to the elevated endogenous production of reactive aldehydes and their derivatives such as glyoxal, methylglyoxal (MG), malonic dialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE) giving rise to advanced lipoxidation and glycation end products (ALEs and AGEs, respectively). Both ALEs and AGEs play key roles in cellular response to oxidative stress stimuli through the regulation of a variety of cell signaling pathways. However, elevated ALE and AGE production leads to protein cross-linking and aggregation resulting in an alteration in cell signaling and functioning which causes cell damage and death. This is implicated in aging and various age-related chronic pathologies such as inflammation, neurodegenerative diseases, atherosclerosis, and vascular complications of diabetes mellitus. In the present review, we discuss experimental data evidencing the impairment in cellular functions caused by AGE/ALE accumulation under oxidative stress conditions. We focused on the implications of ALEs/AGEs in aging and age-related diseases to demonstrate that the identification of cellular dysfunctions involved in disease initiation and progression can serve as a basis for the discovery of relevant therapeutic agents.