Assessing the Anti-Inflammatory and Antioxidant Activity of Mangiferin in Murine Model for Myocarditis: Perspectives and Challenges.

Myocarditis is a major cause of heart failure and death, particularly in young individuals. Current treatments are mainly symptomatic, but emerging therapies focus on targeting inflammation and fibrosis pathways. Natural bioactive compounds like flavonoids and phenolic acids show promising anti-inflammatory and antioxidant properties. Corticosteroids are frequently employed in the treatment of autoimmune myocarditis and appear to lower mortality rates compared to conventional therapies for heart failure. This study aims to explore the effects of Mangiferin on pro-inflammatory cytokine levels, nitro-oxidative stress markers, histopathological alterations, and cardiac function in experimental myosin-induced autoimmune myocarditis. The effects were compared to Prednisone, used as a reference anti-inflammatory compound, and Trolox, used as a reference antioxidant. The study involved 30 male Wistar-Bratislava rats, which were randomly divided into five groups: a negative control group (C-), a positive control group with induced myocarditis using a porcine myosin solution (C+), three groups with induced myocarditis receiving Mangiferin (M), Prednisone (P), or Trolox (T) as treatment. Cardiac function was evaluated using echocardiography. Biochemical measurements of nitro-oxidative stress and inflammatory markers were conducted. Finally, histopathological changes were assessed. At echocardiography, the evaluation of the untreated myocarditis group showed a trend toward decreased left ventricular ejection fraction (LVEF) but was not statistically significant, while all treated groups showed some improvement in LVEF and left ventricular fraction shortening (LVFS). Significant changes were seen in the Mangiferin group, with lower end-diastolic left ventricular posterior wall (LVPWd) by day 21 compared to the Trolox group (p < 0.001). In the first week of the experiment, levels of interleukins (IL)-1ß, IL-6, and tumour necrosis factor (TNF)-α were significantly higher in the myosin group compared to the negative control group (p < 0.001, p < 0.001, p < 0.01), indicating the progression of inflammation in this group. Treatment with Mangiferin, Prednisone, and Trolox caused a significant reduction in IL-1ß compared to the positive control group (p < 0.001). Notably, Mangiferin resulted in a superior reduction in IL-1ß compared to Prednisone (p < 0.05) and Trolox (p < 0.05). Furthermore, Mangiferin treatment led to a statistically significant increase in total oxidative capacity (TAC) (p < 0.001) and a significant reduction in nitric oxide (NOx) levels (p < 0.001) compared to the negative control group. Furthermore, when compared to the Prednisone-treated group, Mangiferin significantly reduced NOx levels (p < 0.001) and increased TAC levels (p < 0.001). Mangiferin treatment significantly lowered creatine kinase (CK) and aspartate aminotransferase (AST) levels on day 7 (p < 0.001 and p < 0.01, respectively) and reduced CK levels on day 21 (p < 0.01) compared to the untreated group. In the nontreated group, the histological findings at the end of the experiment were consistent with myocarditis. In the group treated with Mangiferin, only one case exhibited mild inflammatory infiltrates, represented by mononucleated leukocytes admixed with few neutrophils, with the severity graded as mild. Statistically significant correlations between the grades (0 vs. 1-2) and the study groups have been highlighted (p < 0.005). This study demonstrated Mangiferin's cardioprotective effects in autoimmune myocarditis, showing reduced oxidative stress and inflammation. Mangiferin appears promising as a treatment for acute myocarditis, but further research is needed to compare its efficacy with other treatments like Trolox and Prednisone.

Nitro-oxidative response to internalized multi-walled carbon nanotubes in Brassica napus and Solanum lycopersicum.

In addition to their beneficial effects on plant physiology, multi-walled carbon nanotubes (MWCNTs) are harmful to plants in elevated concentrations. This study compared the effects of two doses of MWCNT (10 and 80 mg/L) in Brassica napus and Solanum lycopersicum seedlings focusing on nitro-oxidative processes. The presence of MWCNTs was detectable in the root and hypocotyl of both species. Additionally, transmission electron microscopy analysis revealed that MWCNTs are heavily transformed within the root cells forming large aggregates. The uptake of MWCNTs negatively affected root viability and root cell proliferation of both species, but more intense toxicity was observed in S. lycopersicum compared to B. napus. The presence of MWCNT triggered more intense protein carbonylation in the relative sensitive S. lycopersicum, where increased hydrogen peroxide levels were observed. Moreover, MWCNT exposure increased the level of physiological protein tyrosine nitration which was more intense in S. lycopersicum where notable peroxynitrite accumulation occurred. These suggest for the first time that MWCNT triggers secondary nitro-oxidative stress which contributes to its toxicity. Moreover, the results indicate that the extent of the nitro-oxidative processes is associated with the extent of MWCNT toxicity.

Influence of rosuvastatin treatment on cerebral inflammation and nitro-oxidative stress in experimental lung injury in pigs.

BACKGROUND: Many patients with acute respiratory distress syndrome (ARDS) suffer from cognitive impairment after hospital discharge. Different mechanisms have been implicated as potential causes for this impairment, inter alia cerebral inflammation. A class of drugs with antioxidant and anti-inflammatory properties are ß-HMG-CoA-reductase inhibitors ("statins"). We hypothesized that treatment with rosuvastatin attenuates cerebral cytokine mRNA expression and nitro-oxidative stress in an animal model of acute lung injury. METHODS: After approval of the institutional and state animal care committee, we performed this prospective randomized controlled animal study in accordance with the international guidelines for the care and use of laboratory animals. Thirty-two healthy male pigs were randomized to one of four groups: lung injury by central venous injection of oleic acid (n = 8), statin treatment before and directly after lung injury (n = 8), statin treatment after lung injury (n = 8), or ventilation-only controls (n = 8). About 18 h after lung injury and standardized treatment, the animals were euthanised, and the brains and lungs were collected for further examinations. We determined histologic lung injury and cerebral and pulmonal cytokine and 3-nitrotyrosine production. RESULTS: We found a significant increase in hippocampal IL-6 mRNA after lung injury (p < 0.05). Treatment with rosuvastatin before and after induction of lung injury led to a significant reduction of hippocampal IL-6 mRNA (p < 0.05). Cerebral 3-nitrotyrosine was significantly higher in lung-injured animals compared with all other groups (p < 0.05 vs. animals treated with rosuvastatin after lung injury induction; p < 0.001 vs. all other groups). 3-Nitrotyrosine was also increased in the lungs of the lung-injured pigs compared to all other groups (p < 0.05 each). CONCLUSIONS: Our findings highlight cerebral cytokine production and nitro-oxidative stress within the first day after induction of lung injury. The treatment with rosuvastatin reduced IL-6 mRNA and 3-nitrotyrosine concentration in the brains of the animals. In earlier trials, statin treatment did not reduce mortality in ARDS patients but seemed to improve quality of life in ARDS survivors. Whether this is attributable to better cognitive function because of reduced nitro-oxidative stress and inflammation remains to be elucidated.

The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it?

Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.

Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy.

Epileptogenesis is the process of developing an epileptic condition and/or its progression once it is established. The molecules that initiate, promote, and propagate remarkable changes in the brain during epileptogenesis are emerging as targets for prevention/treatment of epilepsy. Epileptogenesis is a continuous process that follows immediately after status epilepticus (SE) in animal models of acquired temporal lobe epilepsy (TLE). Both SE and epileptogenesis are potential therapeutic targets for the discovery of anticonvulsants and antiepileptogenic or disease-modifying agents. For translational studies, SE targets are appropriate for screening anticonvulsive drugs prior to their advancement as therapeutic agents, while targets of epileptogenesis are relevant for identification and development of therapeutic agents that can either prevent or modify the disease or its onset. The acute seizure models do not reveal antiepileptogenic properties of anticonvulsive drugs. This review highlights the important components of epileptogenesis and the long-term impact of intervening one of these components, nitric oxide (NO), in rat and mouse kainate models of TLE. NO is a putative pleotropic gaseous neurotransmitter and an important contributor of nitro-oxidative stress that coexists with neuroinflammation and epileptogenesis. The long-term impact of inhibiting the glial source of NO during early epileptogenesis in the rat model of TLE is reviewed. The importance of sex as a biological variable in disease modification strategies in epilepsy is also briefly discussed.

Zinc-induced root architectural changes of rhizotron-grown B. napus correlate with a differential nitro-oxidative response.

Roots have a noteworthy plasticity: due to different stress conditions their architecture can change to favour seedling vigour and yield stability. The development of the root system is regulated by a complex and diverse signalling network, which besides hormonal factors, includes reactive oxygen (ROS) - and nitrogen species (RNS). The delicate balance of the endogenous signal system can be affected by various environmental stimuli, such as the excess of essential heavy metals, like zinc (Zn). Zn at low concentration, is able to induce the morphological and physiological adaptation of the root system, but in excess it exerts toxic effects on plants. In this study the effect of a low, growth-inducing, and a high, growth inhibiting Zn concentrations on the early development of Brassica napus (L.) root architecture and the underlying nitro-oxidative mechanisms were studied in a soil-filled rhizotron system. The growth-inhibiting Zn treatment resulted in elevated protein tyrosine nitration due to the imbalance in ROS and RNS homeostasis, however its pattern was not changed compared to the control. This nitro-oxidative stress was accompanied by serious changes in the cell wall composition and decrease in the cell proliferation and viability, due to the high Zn uptake and disturbed microelement homeostasis in the root tips. During the positive root growth response, a tyrosine nitration-pattern reorganisation was observed; there were no substantial changes in ROS and RNS balance and the viability and proliferation of the root tips' meristematic zone decreased to a lesser extent, as a result of a lower Zn uptake. The obtained results suggest that Zn in different amounts triggers different root growth responses accompanied by distinct changes in the pattern and strength of tyrosine nitration, proposing that nitrosative processes have an important role in the stress-induced root growth responses.

Correlation of adenosine deaminase operating under nitro-oxidative stress with tumor and vascularization in patients with advanced gallbladder carcinoma.

This study investigates serum redox status and adenosine catabolism markers in relation to tumor and angiogenesis, in patients with gallbladder carcinoma (GBC). The level of adenosine deaminase (ADA) and xanthine oxidase (XO) activities, nitrites (NO2-), glutathione (GSH) and malondialdehyde (MDA) were measured in sera of 40 GBC patients and 40 healthy donors. In parallel, 15 tumors at TNM stage IV were scored for CD34 expression and microvessel density (MVD). The results showed that XO and ADA activities, nitrites and MDA levels enhanced by 1.26 (p < 0.01), 2.69, 2.0, and 3.2-fold (p < 0.001), respectively, while those of GSH decreased by 44.6% (p < 0.001). According to receiver operating characteristic (ROC) curve, the optimal cut-off for XO, ADA, MDA, GSH and nitrites were 5.41U/l, 17.02 U/l, 3.72 µM, 36.91 µM and 21.21 µM, respectively. Spearman correlation revealed that ADA activity correlated to nitrites levels (r = 0.3419, p < 0.05) and XO activity (r = 0.5487, p < 0.001). Multivariate binary logistic regression analysis revealed that MDA (OR = 5.78, p < 0.05), ADA (OR = 1.28, p < 0.001) and XO (OR = 2.81, p < 0.05) correlated positively to GBC. CD34 was up expressed in 73.3% of tumors at intermediate to high levels. Multiple regression analysis showed that ADA affected MVD (r = 0.604, p < 0.01). The results suggest that high MDA/GSH ratio is a potential biomarker of GBC. In addition, the oxidative adenosine catabolism indicated that active purine salvage pathway could support tumor progression by sustaining angiogenesis.

Pro-oxidant versus anti-oxidant effects of seeds aglycone extracts of Lepidium sativum and Eruca vesicaria Linn., in vitro, and on neutrophil nitro-oxidative functions.

This study evaluated the anti-inflammatory and antioxidant properties of seeds aglycone extracts from Lepidium sativum (LS) and Eruca vesicaria (EV) Linn., on oxidative damages in vitro and on neutrophil nitro-oxidative functions. The results showed that LS and EV aglycone extracts attenuated liver microsomal lipids and proteins oxidation through a potent antioxidant effect as attested by the dose dependent quenching of DPPH radical scavenging activity. LS and EV aglycone extracts inhibited dose dependently the production of superoxide anion by BALB/c mice-derived peritoneal neutrophils, whereas they slightly enhanced exocytosis of myeloperoxidase (MPO), a marker of azurophilic granules. Interestingly, only LS replenished glutathione (GSH) and nitric oxide levels, indicating a fine differential effect. This study highlighted the subtle oxidative and antioxidant capacity of LS and EV seeds aglycone extracts. These health promoting compounds could be used to finely modulate critical events involved in microbial infection, inflammation and nitro-oxidative stress.

Role of the Fyn-PKCδ signaling in SE-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy.

Status epilepticus (SE) induces neuroinflammation and epileptogenesis, but the mechanisms are not yet fully delineated. The Fyn, a non-receptor Src family tyrosine kinase (SFK), and its immediate downstream target, PKCδ are emerging as potential mediators of neuroinflammation. In order to first determine the role of Fyn kinase signaling in SE, we tested the efficacy of a SFK inhibitor, saracatinib (25mg/kg, oral) in C57BL/6J mouse kainate model of acute seizures. Saracatinib pretreatment dampened SE severity and completely prevented mortality. We further utilized fyn-/- and fyn+/+ mice (wildtype control for the fyn-/- mice on same genetic background), and the rat kainate model, treated with saracatinib post-SE, to validate the role of Fyn/SFK in SE and epileptogenesis. We observed significant reduction in SE severity, epileptiform spikes, and electrographic non-convulsive seizures in fyn-/- mice when compared to fyn+/+ mice. Interestingly, significant reductions in phosphorylated pSrc-416 and PKCδ (pPKCδ-507) and naive PKCδ were observed in fyn-/- mice as compared to fyn+/+ mice suggesting that PKCδ signaling is a downstream mediator of Fyn in SE and epileptogenesis. Notably, fyn-/- mice also showed a reduction in key proinflammatory mediators TNF-α, IL-1ß, and iNOS mRNA expression; serum IL-6 and IL-12 levels; and nitro-oxidative stress markers such as 4-HNE, gp91phox, and 3-NT in the hippocampus. Immunohistochemistry revealed a significant increase in reactive microgliosis and neurodegeneration in the hippocampus and hilus of dentate gyrus in fyn+/+ mice in contrast to fyn-/- mice. Interestingly, we did not observe upregulation of Fyn in pyramidal neurons of the hippocampus during post-SE in fyn+/+ mice, but it was upregulated in hilar neurons of the dentate gyrus when compared to naïve control. In reactive microglia, both Fyn and PKCδ were persistently upregulated during post-SE suggesting that Fyn-PKCδ may drive neuroinflammation during epileptogenesis. Since disabling the Fyn kinase prior to SE, either by treating with saracatinib or fyn gene knockout, suppressed seizures and the subsequent epileptogenic events, we further tested whether Fyn/SFK inhibition during post-SE modifies epileptogenesis. Telemetry-implanted, SE-induced, rats were treated with saracatinib and continuously monitored for a month. At 2h post-diazepam, the saracatinib (25mg/kg) or the vehicle was administered orally and repeated twice daily for first three days followed by a single dose/day for the next four days. The saracatinib post-treatment prevented epileptogenesis in >50% of the rats and significantly reduced spontaneous seizures and epileptiform spikes in the rest (one animal did not respond) when compared to the vehicle treated group, which had >24 seizures in a month. Collectively, the findings suggest that Fyn/SFK is a potential mediator of epileptogenesis and a therapeutic target to prevent/treat seizures and epileptogenesis.

Nitro-Oxidative Stress Correlates with Se Tolerance of Astragalus Species.

At high concentrations, selenium (Se) exerts phytotoxic effects in non-tolerant plant species partly due to the induction of nitro-oxidative stress; however, these processes are not fully understood. In order to obtain a more accurate view of the involvement of nitro-oxidative processes in plant Se sensitivity, this study aims to characterize and compare Se-triggered changes in reactive oxygen (ROS) and nitrogen species (RNS) metabolism and the consequent protein tyrosine nitration as a marker of nitrosative stress in the non-accumulator Astragalus membranaceus and the Se hyperaccumulator Astragalus bisulcatus. The observed parameters (Se accumulation, microelement homeostasis, tissue-level changes in the roots, germination, biomass production, root growth and cell viability) supported that A. membranaceus is Se sensitive while the hyperaccumulator A. bisulcatus tolerates high Se doses. We first revealed that in A. membranaceus, Se sensitivity coincides with the Se-induced disturbance of superoxide metabolism, leading to its accumulation. Furthermore, Se increased the production or disturbed the metabolism of RNS (nitric oxide, peroxynitrite and S-nitrosoglutathione), consequently resulting in intensified protein tyrosine nitration in sensitive A. membranaceus. In the (hyper)tolerant and hyperaccumulator A. bisulcatus, Se-induced ROS/RNS accumulation and tyrosine nitration proved to be negligible, suggesting that this species is able to prevent Se-induced nitro-oxidative stress.

Selenite-induced nitro-oxidative stress processes in Arabidopsis thaliana and Brassica juncea.

Extremes of selenium (Se) exert toxic effects on plants' physiological processes; although plant species tolerate Se differently. This study focuses on the effect of Se (0, 20, 50 or 100µM sodium selenite) on secondary nitro-oxidative stress processes mainly using in situ microscopic methods in non-accumulator Arabidopsis thaliana and secondary Se accumulator Brassica juncea. Relative Se tolerance or sensitivity of the species was evaluated based on growth parameters (fresh and dry weight, root growth) and cell viability. Besides, selenite-triggered cell wall modifications (pectin, callose) and stomatal regulations were determined for the first time. In case of Arabidopsis, relative selenite sensitivity was accompanied by decreased stomatal density and induced stomatal opening, callose accumulation, pronounced oxidative stress and moderate nitrosative modifications. In contrast, the selenite-treated, relatively tolerant Brassica juncea showed larger number of more opened stomata, pectin accumulation, moderate oxidative and intense nitrosative stress. These suggest that selenite tolerance or sensitivity is rather associated with oxidative processes than secondary nitrosative modifications in higher plants.

In vitro nitro-fatty acid release from Cys-NO2-fatty acid adducts under nitro-oxidative conditions.

Stress situations are characterized by a rise in reactive oxygen (ROS) and nitrogen (RNS) species levels. Nitro-fatty acids (NO2-FAs), or nitroalkenes, are produced by the interaction of RNS and unsaturated fatty acids, stored in cells, mostly as part of protein-adducted NO2-FAs, and are esterified in complex lipids. These molecules, which have been shown to play a pivotal role as anti-inflammatory and pro-survival players, have been widely characterized in animal systems. Recently, it has been reported that NO2-FAs play an important role in plant defense against several stress conditions. Furthermore, a significant increase in NO2-FA levels has been observed under various inflammatory and stressful conditions in both animal and plant systems. In this study, we describe the in vitro release of NO2-FAs from protein-adducts under nitro-oxidative stress conditions. The findings of this study highlight the ability of hydrogen peroxide and peroxynitrite, as representative ROS and RNS molecules induced under stress conditions, to oxidize cysteine-adducted NO2-FAs, which is followed by the release of free nitroalkenes. This release may be partly responsible for the increase in NO2-FA content observed under different stressful conditions in both animal and plant systems as well as the activation of antioxidant and anti-inflammatory properties attributed to these molecules.

Sensitivity to anti-Fas is independent of increased cathepsin D activity and adrenodoxin reductase expression occurring in NOS-3 overexpressing HepG2 cells.

Stable overexpression of endothelial nitric oxide synthase (NOS-3) in HepG2 cells (4TO-NOS) leads to increased nitro-oxidative stress and upregulation of the cell death mediators p53 and Fas. Thus, NOS-3 overexpression has been suggested as a useful antiproliferative mechanism in hepatocarcinoma cells. We aimed to identify the underlying mechanism of cell death induced by NOS-3 overexpression at basal conditions and with anti-Fas treatment. The intracellular localization of NOS-3, the nitro-oxidative stress and the mitochondrial activity were analysed. In addition, the protein expression profile in 4TO-NOS was screened for differentially expressed proteins potentially involved in the induction of apoptosis. NOS-3 localization in the mitochondrial outer membrane was not associated with changes in the respiratory cellular capacity, but was related to the mitochondrial biogenesis increase and with a higher protein expression of mitochondrial complex IV. Nitro-oxidative stress and cell death in NOS-3 overexpressing cells occurred with the expression increase of pro-apoptotic genes and a higher expression/activity of the enzymes adrenodoxin reductase mitochondrial (AR) and cathepsin D (CatD). CatD overexpression in 4TO-NOS was related to the apoptosis induction independently of its catalytic activity. In addition, CatD activity inhibition by pepstatin A was not effective in blocking apoptosis induced by anti-Fas. In summary, NOS-3 overexpression resulted in an increased sensitivity to anti-Fas induced cell death, independently of AR expression and CatD activity.

Defective Human Sperm Cells Are Associated with Mitochondrial Dysfunction and Oxidant Production.

Infertility affects about 15% of couples of reproductive age. The male factor is involved in nearly 50% of infertility cases. Defective human sperm function has been associated with evidence of high levels of reactive oxygen species (ROS) and a resultant loss of fertilizing potential in vivo and in vitro. Analogous to what has been observed in somatic cells, mitochondria are likely the major sources of ROS in sperm cells. In this study, we analyzed mitochondrial function using high-resolution respirometry, ROS production, and footprints of oxidative and nitrative stress processes in intact human sperm cells. We showed that mitochondrial dysfunction (measured through the respiratory control ratio) was correlated with a decrease in human sperm motility. The samples analyzed presented nitro-oxidative modifications of proteins, such as protein 3-nitrotyrosine, that were observed mainly in the mid-piece (where mitochondria are localized) and in the sperm head. Semen samples presenting lower percentage of motile sperm showed higher amounts of nitro-oxidative protein modifications than those with larger quantities of motile sperm. When spermatozoa were exposed to inhibitors of the respiratory mitochondrial function, in the presence of a nitric oxide flux, sperm produced potent nitro-oxidative species (i.e., peroxynitrite). This effect was observed in more than 90% of intact living sperm cells and in sperm mitochondrial fractions. These data suggest that dysfunctional mitochondria in sperm cells produce oxidants that may contribute to male infertility. These data provide the rationale for testing the potential of compounds that improve sperm mitochondrial function to treat male infertility.

Serum lipids and cardiac function correlate with nitrotyrosine and MMP activity in coronary artery disease patients.

AIMS: Peroxynitrite-matrix metalloproteinase (MMP) signalling has been shown to contribute to myocardial ischaemia/reperfusion injury and heart failure and to be influenced by hyperlipidaemia in preclinical models. Therefore, here we investigated the correlation between the markers of peroxynitrite-MMP signalling and hyperlipidaemia in patients with significant coronary stenosis. METHODS: Five minutes before percutaneous coronary intervention (PCI), arterial blood samples were collected from 36 consecutive patients with coronary artery disease (CAD) selected for elective PCI. RESULTS: Serum nitrotyrosine positively correlated with MMP-9 activity (r = 0·54, P = 0·01), but not with MMP-2 activity. Nitrotyrosine positively correlated with total (r = 0·58; P < 0·01) and LDL cholesterol (r = 0·55; P < 0·01), serum triglyceride (r = 0·47; P < 0·05), and creatinine (r = 0·42; P < 0·05) and negatively correlated with HDL cholesterol (r = -0·46; P < 0·05) and with left ventricular ejection fraction (LVEF; r = -0·55; P < 0·05), respectively. MMP-2 activity correlated positively with total (r = 0·55; P < 0·05) and LDL cholesterol (r = 0·45; P < 0·05). In statin-treated patients, a significantly reduced serum nitrotyrosine was found as compared to statin naives; however, MMP activities and serum cholesterol levels were not different. MMP-9 activity correlated with urea nitrogen (r = 0·42; P < 0·05) and LVEF (r = -0·73; P < 0·01). Serum creatinine correlated negatively with LVEF (r = -0·50, P < 0·01). CONCLUSIONS: This is the first demonstration that (i) serum nitrotyrosine correlates with MMP-9 activity, (ii) lipid parameters correlate with nitrotyrosine and MMP-2 activity, (iii) myocardial function correlates with creatinine, nitrotyrosine and MMP-9 activity, and (iv) creatinine correlates with nitrotyrosine and urea nitrogen with MMP-9 activity in patients with CAD. Studying the biomarkers of peroxynitrite-MMP pathway in large prospective trials may reveal their diagnostic avails.

The Dual Role of Amyloid Beta-Peptide in Oxidative Stress and Inflammation: Unveiling Their Connections in Alzheimer's Disease Etiopathology.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and it is currently the seventh leading cause of death worldwide. It is characterized by the extracellular aggregation of the amyloid ß-peptide (Aß) into oligomers and fibrils that cause synaptotoxicity and neuronal death. Aß exhibits a dual role in promoting oxidative stress and inflammation. This review aims to unravel the intricate connection between these processes and their contribution to AD progression. The review delves into oxidative stress in AD, focusing on the involvement of metals, mitochondrial dysfunction, and biomolecule oxidation. The distinct yet overlapping concept of nitro-oxidative stress is also discussed, detailing the roles of nitric oxide, mitochondrial perturbations, and their cumulative impact on Aß production and neurotoxicity. Inflammation is examined through astroglia and microglia function, elucidating their response to Aß and their contribution to oxidative stress within the AD brain. The blood-brain barrier and oligodendrocytes are also considered in the context of AD pathophysiology. We also review current diagnostic methodologies and emerging therapeutic strategies aimed at mitigating oxidative stress and inflammation, thereby offering potential treatments for halting or slowing AD progression. This comprehensive synthesis underscores the pivotal role of Aß in bridging oxidative stress and inflammation, advancing our understanding of AD and informing future research and treatment paradigms.

Herniarin ameliorates acrylamide-induced neurotoxicity in rat: involvement of neuro-inflammation and acetylcholinesterase.

This study aimed to investigate the protective effects of herniarin against acrylamide neuro-toxicity. Rats were administered 50 mg/kg of acrylamide (Acr) along with oral doses of herniarin at 50, 100, and 200 mg/kg for 11 days. After treatment, the animals were sacrificed and biochemical markers including superoxide dismutase (SOD), catalase activity, malondialdehyde (MDA), nitric oxide (NO), thiols and acetylcholine esterase (AChE) level were evaluated. Moreover, mRNA expression of neuro-inflammatory cytokines including TNF-α, IL-1ß, and IL-6 were measured using qRT-PCR method. As results, Acr increased MDA with subsequent reduction in SOD, catalase, and thiols content. In contrast, administration of herniarin remarkably normalised the antioxidants and decreased lipid peroxidation. Furthermore, it downregulated mRNA expression of TNF-α, IL-1ß, and IL-6 (p < 0.001) as well as decreased NO (p < 0.01) and AchE levels (p < 0.001) in the Acr-injured brains. Herniarin ameliorated Acr-induced brain injury via modulating redox hemostasis, cholinergic function, as well as inhibiting neuro-inflammation in rats.

Neuroprotective effects of naltrexone in a mouse model of post-traumatic seizures.

Traumatic Brain Injury (TBI) induces neuroinflammatory response that can initiate epileptogenesis, which develops into epilepsy. Recently, we identified anti-convulsive effects of naltrexone, a mu-opioid receptor (MOR) antagonist, used to treat drug addiction. While blocking opioid receptors can reduce inflammation, it is unclear if post-TBI seizures can be prevented by blocking MORs. Here, we tested if naltrexone prevents neuroinflammation and/or seizures post-TBI. TBI was induced by a modified Marmarou Weight-Drop (WD) method on 4-week-old C57BL/6J male mice. Mice were placed in two groups: non-telemetry assessing the acute effects or in telemetry monitoring for interictal events and spontaneous seizures both following TBI and naltrexone. Molecular, histological and neuroimaging techniques were used to evaluate neuroinflammation, neurodegeneration and fiber track integrity at 8 days and 3 months post-TBI. Peripheral immune responses were assessed through serum chemokine/cytokine measurements. Our results show an increase in MOR expression, nitro-oxidative stress, mRNA expression of inflammatory cytokines, microgliosis, neurodegeneration, and white matter damage in the neocortex of TBI mice. Video-EEG revealed increased interictal events in TBI mice, with 71% mice developing post-traumatic seizures (PTS). Naltrexone treatment ameliorated neuroinflammation, neurodegeneration, reduced interictal events and prevented seizures in all TBI mice, which makes naltrexone a promising candidate against PTS, TBI-associated neuroinflammation and epileptogenesis in a WD model of TBI.

Histone (de)acetylation in epigenetic regulation of Phytophthora pathobiology.

Phytophthora species are oomycetes that have evolved a broad spectrum of biological processes and improved strategies to cope with host and environmental challenges. A growing body of evidence indicates that the high pathogen plasticity is based on epigenetic regulation of gene expression linked to Phytophthora's rapid adjustment to endogenous cues and various stresses. As 5mC DNA methylation has not yet been identified in Phytophthora, the reversible processes of acetylation/deacetylation of histone proteins seem to play a pivotal role in the epigenetic control of gene expression in oomycetes. To explore this issue, we review the structure, diversity, and phylogeny of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in six plant-damaging Phytophthora species: P. capsici, P. cinnamomi, P. infestans, P. parasitica, P. ramorum, and P. sojae. To further integrate and improve our understanding of the phylogenetic classification, evolutionary relationship, and functional characteristics, we supplement this review with a comprehensive view of HATs and HDACs using recent genome- and proteome-level databases. Finally, the potential functional role of transcriptional reprogramming mediated by epigenetic changes during Phytophthora species saprophytic and parasitic phases under nitro-oxidative stress is also briefly discussed.

LP342, a novel histone deacetylase inhibitor, decreases nitro-oxidative stress, mitochondrial dysfunction and hepatic ischaemia/reperfusion injury in mice.

Objectives: Some histone deacetylase (HDAC) isoforms contribute to ischaemia/reperfusion (IR) injury (IRI). Here, we examined whether LP342, the lead candidate of a new generation of hydrazide-based HDAC inhibitors (HDACi), decreases hepatic IRI. Methods: IR was induced by clamping blood vessels to ~70% of the livers of mice for 1 h. Key findings: At 6 h after reperfusion, ALT markedly increased, and wide-spread necrosis, leukocyte infiltration, and apoptosis occurred. LP342 treatment (1 mg/kg, ip) at 20 h or 1 h before ischaemia markedly decreased IRI whereas LP342 treatment upon reperfusion was marginally protective. Nitro-oxidative stress, c-Jun-N-terminal kinase (JNK) activation, and mitochondrial dysfunction contribute to IRI. 4-Hydroxynonenal, 3-nitrotyrosine, inducible nitric oxide synthase (iNOS), JNK activation and Sab binding increased markedly after IR, which LP342 blunted. LP342 also induced thioredoxin-1 expression before and after IR. LP342 also decreased mitochondrial depolarisation as detected by intravital microscopy at 2 h after IR. Lastly, LP342 increased acetylation of both histone-3 (class I HDAC substrate) and NFκB p65 but not tubulin (class II HDAC substrate) before and after IR. Conclusions: This novel HDACi protects against IRI most likely by epigenetic upregulation of antioxidant proteins and post-translational modifications of NFκB thus inhibiting iNOS expression and inflammatory responses.