Upregulation Of Antioxidant System Research Articles

Diindolylmethane Inhibits Cadmium-Induced Autophagic Cell Death via Regulation of Oxidative Stress in HEL299 Human Lung Fibroblasts.

Cadmium (Cd), a harmful heavy metal, can lead to various pulmonary diseases, including chronic obstructive pulmonary disease (COPD), by inducing cytotoxicity and disturbing redox homeostasis. The aim of the present study was to investigate Cd-mediated cytotoxicity using human lung fibroblasts and the therapeutic potential of 3,3′-diindolylmethane (DIM). Cadmium significantly reduced the cell viability of human embryonic lung (HEL299) cells accompanied by enhanced oxidative stress as evidenced by the increased expression of autophagy-related proteins such as LC3B and p62. However, treatment with DIM significantly suppressed autophagic cell death in Cd-induced HEL299 fibroblasts. In addition, DIM induced antioxidant enzyme activity and decreased intracellular reactive oxygen species (ROS) levels in Cd-damaged HEL299 cells. This study suggests that DIM effectively suppressed Cd-induced lung fibroblast cell death through the upregulation of antioxidant systems and represents a potential agent for the prevention of various diseases related to Cd exposure.

64Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity

Simple SummaryCarbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. Here we show that the carbon ion RBE in human cancer cells correlates with the cellular uptake of 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. High RBE/64Cu-ATSM cells show greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts. These data suggest that the cellular antioxidant activity is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake.Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with 64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake. These new findings highlight the potential clinical utility of 64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.

Hepatoprotective Plants from Bangladesh: A Biophytochemical Review and Future Prospect.

Liver diseases are quite prevalant in many densely populated countries, including Bangladesh. The liver and its hepatocytes are targeted by virus and microbes, as well as by chemical environmental toxicants, causing wide-spread disruption of metabolic fuctions of the human body, leading to death from end-stage liver diseases. The aim of this review is to systematically explore and record the potential of Bangladeshi ethnopharmacological plants to treat liver diseases with focus on their sources, constituents, and therapeutic uses, including mechanisms of actions (MoA). A literature survey was carried out using Pubmed, Google Scholar, ScienceDirect, and Scopus databases with articles reported until July, 2020. A total of 88 Bangladeshi hepatoprotective plants (BHPs) belonging to 47 families were listed in this review, including Euphorbiaceae, Cucurbitaceae, and Compositae families contained 20% of plants, while herbs were the most cited (51%) and leaves were the most consumed parts (23%) as surveyed. The effect of BHPs against different hepatotoxins was observed via upregulation of antioxidant systems and inhibition of lipid peroxidation which subsequently reduced the elevated liver biomarkers. Different active constituents, including phenolics, curcuminoids, cucurbitanes, terpenoids, fatty acids, carotenoids, and polysaccharides, have been reported from these plants. The hepatoameliorative effect of these constituents was mainly involved in the reduction of hepatic oxidative stress and inflammation through activation of Nrf2/HO-1 and inhibition of NF-κB signaling pathways. In summary, BHPs represent a valuable resource for hepatoprotective lead therapeutics which may offer new alternatives to treat liver diseases.

Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas.

Simple SummaryPrimary aldosteronism is a common form of endocrine hypertension often caused by a hyper-secreting tumor of the adrenal cortex called an aldosterone-producing adenoma. Metabolic reprogramming plays a role in tumor progression and influences the tumor immune microenvironment by limiting immune-cell infiltration and suppressing its anti-tumor function. We hypothesized that the development of aldosterone-producing adenomas involves metabolic adaptations of its component tumor cells and intrinsically influences tumor pathogenesis. Herein, we use state-of-the-art computational tools for the comprehensive analysis of array-based gene expression profiles to demonstrate metabolic reprogramming and remodeling of the immune microenvironment in aldosterone-producing adenomas compared with paired adjacent adrenal cortical tissue. Our findings suggest metabolic alterations may function in the pathogenesis of aldosterone-producing adenomas by conferring survival advantages to their component tumor cells.Aldosterone-producing adenomas (APAs) are characterized by aldosterone hypersecretion and deregulated adrenocortical cell growth. Increased energy consumption required to maintain cellular tumorigenic properties triggers metabolic alterations that shape the tumor microenvironment to acquire necessary nutrients, yet our knowledge of this adaptation in APAs is limited. Here, we investigated adrenocortical cell-intrinsic metabolism and the tumor immune microenvironment of APAs and their potential roles in mediating aldosterone production and growth of adrenocortical cells. Using multiple advanced bioinformatics methods, we analyzed gene expression datasets to generate distinct metabolic and immune cell profiles of APAs versus paired adjacent cortex. APAs displayed activation of lipid metabolism, especially fatty acid β-oxidation regulated by PPARα, and glycolysis. We identified an immunosuppressive microenvironment in APAs, with reduced infiltration of CD45+ immune cells compared with adjacent cortex, validated by CD45 immunohistochemistry (3.45-fold, p < 0.001). APAs also displayed an association of lipid metabolism with ferroptosis and upregulation of antioxidant systems. In conclusion, APAs exhibit metabolic reprogramming towards fatty acid β-oxidation and glycolysis. Increased lipid metabolism via PPARα may serve as a key mechanism to modulate lipid peroxidation, a hallmark of regulated cell death by ferroptosis. These findings highlight survival advantages for APA tumor cells with metabolic reprogramming properties.

Contribution of Rhizobium–Legume Symbiosis in Salt Stress Tolerance in Medicago truncatula Evaluated through Photosynthesis, Antioxidant Enzymes, and Compatible Solutes Accumulation

The effects of salt stress on the growth, nodulation, and nitrogen (N) fixation of legumes are well known, but the relationship between symbiotic nitrogen fixation (SNF) driven by rhizobium–legume symbiosis and salt tolerance in Medicago truncatula is not well studied. The effects of the active nodulation process on salt stress tolerance of Medicago truncatula were evaluated by quantifying the compatible solutes, soluble sugars, and antioxidants enzymes, as well as growth and survival rate of plants. Eight weeks old plants, divided in three groups: (i) no nodules (NN), (ii) inactive nodules (IN), and (iii) active nodules (AN), were exposed to 150 mM of NaCl salt stress for 0, 8, 16, 24, 32, 40, and 48 h in hydroponic system. AN plants showed a higher survival rate (30.83% and 38.35%), chlorophyll contents (37.18% and 44.51%), and photosynthesis compared to IN and NN plants, respectively. Improved salt tolerance in AN plants was linked with higher activities of enzymatic and nonenzymatic antioxidants and higher K+ (20.45% and 39.21%) and lower Na+ accumulations (17.54% and 24.51%) when compared with IN and NN plants, respectively. Additionally, higher generation of reactive oxygen species (ROS) was indicative of salt stress, causing membrane damage as revealed by higher electrolyte leakage and lipid peroxidation. All such effects were significantly ameliorated in AN plants, showing higher compatible solutes (proline, free amino acids, glycine betaine, soluble sugars, and proteins) and maintaining higher relative water contents (61.34%). This study advocates positive role of Rhizobium meliloti inoculation against salt stress through upregulation of antioxidant system and a higher concentration of compatible solutes.

The effects of quercetin on antioxidant and cytokine levels in rat hippocampus exposed to acute cadmium toxicity

&amp;nbsp;The aim of this study was to determine cadmium neurotoxicity (Branca et al.&amp;nbsp; 2018) and beneficial effect of quercetin (QE) (Kanter et al.&amp;nbsp; 2016) against on neuronal damage in hippocampus exposed with acute cadmium (Cd). Adult male Wistar-Albino rats (n = 30) were used and divided into four groups as Control (C, n = 6), Cadmium (Cd, n = 8), Quercetin (Q, n = 8) and Cadmium + Quercetin (Cd + Q, n = 8). Cadmium (CdCl2, 4 mg kg-1 daily, s.c) were administrated to Cd and Cd+Q groups, and Quercetin (Q, 50 mg kg-1 daily, i.p) were administrated to Q and Cd + Q groups for 3 days, respectively. At 4th day after the treatments, hippocampal samples were taken from the four groups. Cadmium decreased superoxide dismutase (SOD) and reduced glutathione (GSH) levels and the SOD activity and GSH level were markedly (p&amp;lt; 0.05) lower in Cd group than in the Q and C groups. Lipid peroxidation (MDA) levels were higher in Cd group when compared to the control, Q and Cd+Q groups. IL1 levels were found statistically higher in Cd group than in the control, Q and Cd+Q groups. IL-6 and TNF-alfa levels were significantly (p&amp;lt; 0.05) higher in Cd and&amp;nbsp;Cd+Q groups than the Q and C groups.&amp;nbsp; In addition, IL10 levels were detected the lowest in Cd group when compared to other groups.&amp;nbsp; &amp;nbsp; &amp;nbsp; In conclusion, our results show that quercetin can be beneficial against to neurotoxic effects of acute cadmium toxicity in the rat hippocampus through upregulation of antioxidant system but down regulation of cytokine levels.&amp;nbsp;

Nitric oxide reverses glucose-mediated photosynthetic repression in wheat (Triticum aestivum L.) under salt stress

The involvement of nitric oxide (as sodium nitroprusside, SNP) in the reversal of glucose (Glu)-inhibited photosynthetic characteristics in the presence or absence of salt stress (100 mM NaCl) was studied in wheat (Triticum aestivum L.). The plants treated with either NaCl or 6% Glu exhibited reduced photosynthesis due to higher oxidative stress. The increased content of Na+ and Cl−, and lipid peroxidation in plants grown under salt stress were reduced with the application of 50μM SNP. The SNP- treated plants with or without 6% Glu exhibited reduced Glu and ethylene sensitivity and oxidative stress, resulting in improved photosynthesis under salt stress through upregulation of antioxidant system, proline accumulation and N assimilation. The results show that SNP improves photosynthetic performance of plants in the absence of salt stress, and also reduces glucose-mediated repression of photosynthesis under salt stress.

Differential proteomic analysis reveals the mechanism of Musa paradisiaca responding to salt stress

Salinity is one of the most important abiotic stresses, which affects the yield and quality of banana (Musa paradisiaca). To understand the salinity tolerance mechanisms of banana, the iTRAQ technique is employed to reveal the proteomic response of Brazil banana under different durations of 60 mmol/L NaCl stress. We have identified 77 DEPs and classified them into nine functional categories, compared with control (0 mmol/L NaCl treatment). The four major categories involve protein synthesis and degradation, photosynthesis, defense response, and energy and carbohydrate metabolism. The results indicate that photosynthesis, protein synthesis and degradation, lipid metabolism and secondary metabolism are promoted to limit damage to a repairable level. The accumulation of ROS under salt stress is harmful to cells and causes up-regulation of antioxidant systems. Furthermore, to cope with cells injured by salt stress, PCD is used to remove the damaged. Additionally, the cytoskeleton can play an important role in maintaining cellular and redox homeostasis. Different categories of functional proteins by changing the abundance ratio shows that plants have different mechanisms of response to salinity. Conclusively, Function of the observed changes in protein expression objective is to establish a new metabolic process of steady-state balance. To my knowledge, this is the first report that investigates responses of M. paradisiaca to salt stress by proteomic analysis.

Immunoglobulins G from Sera of Amyotrophic Lateral Sclerosis Patients Induce Oxidative Stress and Upregulation of Antioxidative System in BV-2 Microglial Cell Line.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with a very fast progression, no diagnostic tool for the presymptomatic phase, and still no effective treatment of the disease. Although ALS affects motor neurons, the overall pathophysiological condition points out to the non-cell autonomous mechanisms, where astrocytes and microglia play crucial roles in the disease progression. We have already shown that IgG from sera of ALS patients (ALS IgG) induce calcium transients and an increase in the mobility of acidic vesicles in cultured rat astrocytes. Having in mind the role of microglia in neurodegeneration, and a well-documented fact that oxidative stress is one of the many components contributing to the disease, we decided to examine the effect of ALS IgG on activation, oxidative stress and antioxidative system of BV-2 microglia, and to evaluate their acute effect on cytosolic peroxide, pH, and on reactive oxygen species (ROS) generation. All tested ALS IgGs (compared to control IgG) induced oxidative stress (rise in nitric oxide and the index of lipid peroxidation) followed by release of TNF-α and higher antioxidative defense (elevation of Mn- and CuZn-superoxide dismutase, catalase, and glutathione reductase with a decrease of glutathione peroxidase and glutathione) after 24 h treatment. Both ALS IgG and control IgG showed same localization on the membrane of BV-2 cells following 24 h treatment. Cytosolic peroxide and pH alteration were evaluated with fluorescent probes HyPer and SypHer, respectively, having in mind that HyPer also reacts to pH changes. Out of 11 tested IgGs from ALS patients, 4 induced slow exponential rise of HyPer signal, with maximal normalized fluorescence in the range 0.2–0.5, also inducing similar increase of SypHer intensity, but of a lower amplitude. None of the control IgGs induced changes with neither of the indicators. Acute ROS generation was detected in one out of three tested ALS samples with carboxy-H2DCFDA. The observed phenomena demonstrate the potential role of inflammatory humoral factors, IgGs, as potential triggers of the activation in microglia, known to occur in later stages of ALS. Therefore, revealing the ALS IgG signaling cascade in microglial cells could offer a valuable molecular biomarker and/or a potential therapeutic target.

Protective effects of Nymphaea lotus Linn (Nymphaeaceae) on L-NAME-induced tissular oxidative damages and erectile dysfunction in hypertensive male rat

To investigate Nymphaea lotus aqueous extract on L-NAME-mediated sexual dysfunction and tissular oxidative stress in male Wistar rats. Methods: Fifty adult male Wistar rats were randomly classified into 5 groups; Control, L-NAME (10 mg/kg), L-NAME + losartan (10 mg/kg), L-NAME + N. lotus at the dose of 75 mg/kg and 200 mg/kg. L-NAME was administered during 8 weeks, but others treatments started from the 4th week and were administered continuously with L-NAME (10 mg/kg) during 4 additional weeks. Results: L-NAME administration caused marked hit of sexual behaviour, specifically failure of penile insertion or difficulty to ejaculate during the test interval. Further L-NAME causes a significant decrease in antioxidant products as reduced gluthatione (GSH) and nitrites (NO) in aorta and penile tissues, as compared to control group. N. lotus co-treatment for 4 weeks increased markedly the erectile index and the ejaculation rates contrarily to losartan in comparison to negative control receiving only L-NAME. N. lotus, but not the positive drug losartan, induced a significant increase in the anti-oxidant enzymes activities and GSH and NO levels, as well as a significant decrease in MDA levels compared to L-NAME group. These results suggests N. lotus may provide significant protection against L-NAME-induced tissular oxidative damages by up-regulation of antioxidant systems and promotion of the vasodilator factors in chronic NO-deficient rats. These alleviating effects of Nymphaea lotus denote a pro-sexual, antioxidant and vasodilatatory properties that was more appreciated after histological examination where remodeling of aorta were visibly reduced. Conclusion: N. lotus may be considered as a potentially useful strategy to limit erectile dysfunction and toxicity associated with hypertension.

Thymoquinone treatment against acetaminophen-induced hepatotoxicity in rats

AimIn this study, we aimed to examine the efficacy of thymoquinone (TQ) treatment in acetaminophen-induced liver toxicity in rats. MethodsForty Wistar Albino rats were used for the study (four groups, with 10 rats for each group). Animals in the control group were not given any medication. In the thymoquinone (TQ) group, animals were given three times 5 mg/kg oral thymoquinone for every six hours, which equals to a total dose of 15 mg/kg. In the acetaminophen (APAP) group, animals were given APAP at a single dose of 500 mg/kg orally. In the APAP + TQ group, animals were given 500 mg/kg APAP orally followed by three doses of TQ at a 15 mg/kg total dose in an 18-h time interval. All animals were sacrificed at the 24th hour. Alanine amino transferase (ALT), aspartat amino transferase (AST), superoxide dismutase (SOD), oxidized glutathione (GSSG), glutathione peroxides (GSH-Px), and malondialdehyde (MDA) activities were measured in rat blood. Histopathological examination was also performed. ResultsSerum ALT, AST levels, GSSG, and SOD activity as well as the serum and tissue MDA levels were found to be higher in the APAP group than in the control group (p ≤ 0.001). Likewise, serum GSH-Px activity was found to be lower in the APAP group (p ≤ 0.001). In contrast, in the APAP + TQ group, serum ALT, AST levels, GSSG, SOD activity and the serum and tissue MDA levels were found to be lower compared to that of the APAP group. This difference was statistically significant (p ≤ 0.001). In the APAP + TQ group, the GSH-Px activity was found to be significantly higher compared to the APAP group (p < 0.05). In contrast to this finding, the GSH-Px activity in the APAP + TQ group was found to be lower than that of the control group (p ≤ 0.001). Histopathological analysis revealed significant liver necrosis and toxicity with a high dose of APAP where TQ treatment was related with significantly lower liver injury scores. ConclusionTQ treatment may have an important therapeuthic effect via the upregulation of antioxidant systems in the APAP-induced liver hepatotoxicity in rats.

Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation

ObjectiveNLRP12 mutations have been described in patients affected with peculiar autoinflammatory symptoms. This study was undertaken to characterize NLRP12 mutations in patients with autoinflammatory syndromes, particularly a novel missense mutation, p.D294E, affecting a protein sequence crucial for ATP binding, which was identified in a Caucasian family with familial cold-induced autoinflammatory syndrome in some family members.MethodsFifty patients were tested for NLRP12 mutations. A Caucasian family with the p.D294E missense mutation of NLRP12 in some family members was clinically characterized. In vitro analysis of the effects of the mutation on NF-κB activity was performed in HEK 293 cells after cotransfection of the cells with a luciferase NF-κB–responsive element and mutant or wild-type (WT) NLRP12 expression plasmids. NF-κB activity was also evaluated 24 hours after stimulation with tumor necrosis factor α in monocytes from individual family members carrying the mutation. Furthermore, secretion of interleukin-1β (IL-1β), production of reactive oxygen species (ROS), and activation of antioxidant systems in patient and healthy donor monocytes, under resting conditions and after stimulation with pathogen-associated molecular patterns (PAMPs), were also assessed.ResultsIn the family assessed, the p.D294E mutation segregated in association with a particular sensitivity to cold exposure (especially arthralgias and myalgia), but not always with an inflammatory phenotype (e.g., urticarial rash or fever). In vitro, the mutant protein maintained the same inhibitory activity as that shown by WT NLRP12. Consistently, NLRP12-mutated monocytes showed neither increased levels of p65-induced NF-κB activity nor higher secretion of IL-1β. However, the kinetics of PAMP-induced IL-1β secretion were significantly accelerated, and high production of ROS and up-regulation of antioxidant systems were demonstrated.ConclusionEven with a variable range of associated manifestations, the extreme sensitivity to cold represents the main clinical hallmark in an individual carrying the p.D294E mutation of the NLRP12 gene. Although regulation of NF-κB activity is not affected in patients, redox alterations and accelerated secretion of IL-1β are associated with this mild autoinflammatory phenotype.

Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice

Although inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke-induced (CS-induced) emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases. Susceptibility of the lung to oxidative injury, such as that originating from inhalation of CS, depends largely on its upregulation of antioxidant systems. Nuclear factor, erythroid-derived 2, like 2 (Nrf2) is a redox-sensitive basic leucine zipper protein transcription factor that is involved in the regulation of many detoxification and antioxidant genes. Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive CS-induced emphysema than was found in wild-type littermates. Emphysema in Nrf2-deficient mice exposed to CS for 6 months was associated with more pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of oxidative stress; and with an increased number of apoptotic alveolar septal cells--predominantly endothelial and type II epithelial cells--as compared with wild-type mice. Microarray analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract CS-induced oxidative stress and inflammation. The responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco smoke-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis.

Direct placental effects of cigarette smoke protect women from pre-eclampsia: the specific roles of carbon monoxide and antioxidant systems in the placenta

Pre-eclampsia is a hypertensive disorder of pregnancy characterized by shallow placentation, inadequate placental perfusion, localized placental oxidative stress, a heightened maternal inflammatory response and subsequent maternal endothelial dysfunction. This pathophysiology leads to an increase in maternal blood pressure, edema and proteinurea. Interestingly, women who smoke cigarettes throughout pregnancy are at a 33% reduced risk of developing this disorder. The exact mechanisms through which cigarette smoke reduces the risk of pre-eclampsia are not yet understood. We propose that cigarette smoke reduces the risk of developing pre-eclampsia via direct placental effects. In this review we will address, and provide evidence for, our specific hypotheses that: (a) CO increases trophoblast invasion and spiral arteriole remodeling; (b) CO decreases a localized inflammatory response at the level of the decidua; (c) CO increases utero-placental, intra-placental and feto-placental blood flow; (d) CO decreases hypoxia-induced apoptosis of the syncitiotrophoblast layer; (e) CO activates hemoproteins involved in normal endothelial functioning normally acted upon by NO; (f) compound(s) within cigarette smoke result in upregulation of antioxidant systems within the placenta. These various mechanisms of action must be further examined as they may provide valuable keys to novel therapeutic design in the realm of pre-eclampsia research.