Exploring Iodide and Hydrogen Sulfide as ROS Scavengers to Delay Acute Rejection in MHC-Defined Vascularized Composite Allografts.

Vascularized composite allografts (VCA) face ischemic challenges due to their limited availability. Reperfusion following ischemia triggers oxidative stress and immune reactions, and scavenger molecules could mitigate ischemia-reperfusion injuries and, therefore, immune rejection. We compared two scavengers in a myocutaneous flap VCA model. In total, 18 myocutaneous flap transplants were performed in Major histocompatibility complex (MHC)-defined miniature swine. In the MATCH group (n = 9), donors and recipients had minor antigen mismatch, while the animals were fully mismatched in the MISMATCH group (n = 9). Grafts were pretreated with saline, sodium iodide (NaI), or hydrogen sulfide (H2S), stored at 4 °C for 3 h, and then transplanted. Flaps were monitored until clinical rejection without immunosuppression. In the MATCH group, flap survival did not significantly differ between the saline and hydrogen sulfide treatments (p = 0.483) but was reduced with the sodium iodide treatment (p = 0.007). In the MISMATCH group, survival was similar between the saline and hydrogen sulfide treatments (p = 0.483) but decreased with the sodium iodide treatment (p = 0.007). Rhabdomyolysis markers showed lower but non-significant levels in the experimental subgroups for both the MATCH and MISMATCH animals. This study provides insightful data for the field of antioxidant-based approaches in VCA and transplantation.

Synthesis,Antidiabetic and Antitubercular Evaluation of Quinoline-pyrazolopyrimidine hybrids and Quinoline-4-Arylamines.

Two libraries of quinoline-based hybrids 1-(7-chloroquinolin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 7-chloro-N-phenylquinolin-4-amine were synthesized and evaluated for their α-glucosidase inhibitory and antioxidant properties. Compounds with 4-methylpiperidine and para-trifluoromethoxy groups, respectively, showed the most promising α-glucosidase inhibition activity with IC50=46.70 and 40.84 µM, compared to the reference inhibitor, acarbose (IC50=51.73 µM). Structure-activity relationship analysis suggested that the cyclic secondary amine pendants and para-phenyl substituents account for the variable enzyme inhibition. Antioxidant profiling further revealed that compounds with an N-methylpiperazine and N-ethylpiperazine ring, respectively, have good DPPH scavenging abilities with IC50=0.18, 0.58 and 0.93 mM, as compared to ascorbic acid (IC50=0.05 mM), while the best DPPH scavenger is NO2-substituted compound (IC50=0.08 mM). Also, compound with N-(2-hydroxyethyl)piperazine moiety emerged as the best NO radical scavenger with IC50=0.28 mM. Molecular docking studies showed that the present compounds are orthosteric inhibitors with their quinoline, pyrimidine, and 4-amino units as crucial pharmacophores furnishing α-glucosidase binding at the catalytic site. Taken together, these compounds exhibit dual potentials; i. e., potent α-glucosidase inhibitors and excellent free radical scavengers. Hence, they may serve as structural templates in the search for agents to manage Type 2 diabetes mellitus. Finally, in preliminary assays investigating the anti-tubercular potential of these compounds, two pyrazolopyrimidine series compounds and a 7-chloro-N-phenylquinolin-4-amine hybrid showed sub-10 µM whole-cell activities against Mycobacterium tuberculosis.

Dextran coated iron oxide nanoparticles loaded with protocatechuic acid as multifunctional therapeutic agents.

Nowadays, there is a growing interest in multifunctional therapeutic agents as valuable tools to improve and expand the applicability field of traditional bioactive compounds. In this context, the synthesis and main characteristics of dextran-coated iron oxide nanoparticles (IONP-Dex) loaded with both an antioxidant, protocatechuic acid (PCA), and an antibiotic, ceftazidime (CAZ) or levofloxacin (LEV) are herein reported for the first time, with emphasis on the potentiation effect of PCA on drugs activity. All nanoparticles were characterized by transmission electron microscopy, X-ray diffraction, vibrating sample magnetometry, differential scanning calorimetry and dynamic light scattering. As evidenced by DPPH method, IONP-Dex loaded with PCA and LEV had similar antioxidant activity like those with PCA only, but higher than PCA and CAZ loaded ones. A synergy of action between PCA and each antibiotic co-loaded on IONP-Dex has been highlighted by an enhanced activity against reference bacterial strains, such as S. aureus and E. coli after 40 min of incubation. It was concluded that PCA, which is the main cause of the antioxidative properties of loaded nanoparticles, further improves the antimicrobial activity of IONP-Dex nanoparticles when was co-loaded with CAZ or LEV antibiotics. All constructs also showed a good biocompatibility with normal human dermal fibroblasts.

Antioxidant activity of lidocaine, bupivacaine, and ropivacaine in aqueous and lipophilic environments: an experimental and computational study.

Introduction: Local anesthetics are widely recognized pharmaceutical compounds with various clinical effects. Recent research indicates that they positively impact the antioxidant system and they may function as free radical scavengers. We hypothesize that their scavenging activity is influenced by the lipophilicity of the environment. Methods: We assessed the free radical scavenging capacity of three local anesthetics (lidocaine, bupivacaine, and ropivacaine) using ABTS, DPPH, and FRAP antioxidant assays. We also employed quantum chemistry methods to find the most probable reaction mechanism. The experiments were conducted in an aqueous environment simulating extracellular fluid or cytosol, and in a lipophilic environment (n-octanol) simulating cellular membranes or myelin sheets. Results: All local anesthetics demonstrated ABTS˙+ radical scavenging activity, with lidocaine being the most effective. Compared to Vitamin C, lidocaine exhibited a 200-fold higher half-maximal inhibitory concentration. The most thermodynamically favorable and only possible reaction mechanism involved hydrogen atom transfer between the free radical and the -C-H vicinal to the carbonyl group. We found that the antioxidant activity of all tested local anesthetics was negligible in lipophilic environments, which was further confirmed by quantum chemical calculations. Conclusion: Local anesthetics exhibit modest free radical scavenging activity in aqueous environments, with lidocaine demonstrating the highest activity. However, their antioxidant activity in lipophilic environments, such as cellular membranes, myelin sheets, and adipose tissue, appears to be negligible. Our results thus show that free radical scavenging activity is influenced by the lipophilicity of the environment.

Six-month follow-up of salivary antioxidant defense outcomes of individuals using medicated toothpaste.

Objective: The objective of this study was to study the effect of medicated toothpaste on oral health, a 6-month follow-up. Methods: Four hundred and twenty-seven participants were screened and followed up for 6 months. The intraoral examination was performed to record caries, gingival bleeding, and plaque index. Saliva collected was evaluated for pH, total antioxidant capacity (TAC), malondialdehyde (MDA), and Vitamin C level for 6 months, and data were analyzed. Results: On the usage of medicated toothpaste with herbal extract for 6 months, the salivary pH levels were increased, the interquartile range for plaque, and the gingival bleeding index decreased. The percentage change in salivary TAC, MDA, and Vitamin C levels in the caries-free group of subgroup I was 174.8, 58.06, and 59.98, respectively, in subgroup II was 133.3, 52.08, and 58.51, and in subgroup III was 63.77, 45.11, and 47.77. The percentage change in salivary TAC, MDA, and Vitamin C levels in the caries-active group of subgroup I was 136.62, 57.27, and 72.83, subgroup II was 108.59, 37.50, and 61.55, and in subgroup III was 35.62, 30.82, and 54.10, respectively. Conclusion: The salivary pH levels increased on the usage of medicated toothpaste with herbal extract; plaque and the gingival bleeding index scores were decreased. The salivary antioxidant defense was increased in individuals using medicated toothpaste with herbal extracts which signifies an improvement in overall oral health in the 6-month follow-up.

Polyfunctionalized α-Phenyl-tert-butyl(benzyl)nitrones: Multifunctional Antioxidants for Stroke Treatment.

Nowadays, most stroke patients are treated exclusively with recombinant tissue plasminogen activator, a drug with serious side effects and limited therapeutic window. For this reason, and because of the known effects of oxidative stress on stroke, a more tolerable and efficient therapy for stroke is being sought that focuses on the control and scavenging of highly toxic reactive oxygen species by appropriate small molecules, such as nitrones with antioxidant properties. In this context, herein we report here the synthesis, antioxidant, and neuroprotective properties of twelve novel polyfunctionalized α-phenyl-tert-butyl(benzyl)nitrones. The antioxidant capacity of these nitrones was investigated by various assays, including the inhibition of lipid peroxidation induced by AAPH, hydroxyl radical scavenging assay, ABTS+-decoloration assay, DPPH scavenging assay, and inhibition of soybean lipoxygenase. The inhibitory effect on monoamine oxidases and cholinesterases and inhibition of ß-amyloid aggregation were also investigated. As a result, (Z)-N-benzyl-1-(2-(3-(piperidin-1-yl)propoxy)phenyl)methanimine oxide (5) was found to be one of the most potent antioxidants, with high ABTS+ scavenging activity (19%), and potent lipoxygenase inhibitory capacity (IC50 = 10 µM), selectively inhibiting butyrylcholinesterase (IC50 = 3.46 ± 0.27 µM), and exhibited neuroprotective profile against the neurotoxicant okadaic acid in a neuronal damage model. Overall, these results pave the way for the further in-depth analysis of the neuroprotection of nitrone 5 in in vitro and in vivo models of stroke and possibly other neurodegenerative diseases in which oxidative stress is identified as a critical player.

Polyphenolic Contents, Free Radical Scavenging and Cholinesterase Inhibitory Activities of Dalbergiella welwitschii Leaf Extracts.

A decoction of Dalbergiella welwitschii leaves has been used ethnomedicinally for the treatment of mental illness and inflammatory diseases amongst other diseases. In this study, the leaf methanol extract of D. welwitschii and its partition fractions: n-hexane, ethyl acetate and aqueous, were tested and evaluated for their polyphenolic contents, free radical scavenging and cholinesterase inhibitory activities. The total phenolic (TPC), flavonoid (TFC) and proanthocyanidin (TPA) contents were determined using standard colorimetric methods. The anti-radical activity of the extracts against the 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric ion and nitric oxide (NO) radicals as well as their effects on lipid peroxidation were monitored spectrophotometrically. The cholinesterase enzyme (AChE and BuChE) inhibitions by the extracts were determined by a modified method of Ellman. The result showed a concentration-dependent increase in inhibition of the free radicals and the cholinesterase enzymes, except for that of lipid peroxidation. The ethyl acetate (EtOAc) fraction exhibited the highest polyphenolic contents among the fractions, with a TPC of 1.08 mgGAE/g, TFC of 0.38 mgQuE/g and TPA of 0.21 mgGAE/g. It also demonstrated the highest free radical scavenging activities with 72.63% and 65.43% inhibitions of DPPH and NO, respectively. The EtOAc fraction inhibited AChE and BuChE enzymes with IC50 values of 0.94 and 8.49 mg/mL, respectively. Our findings show that the plant may have polyphenol contents, in particular in the methanol extract and EtOAc fraction. These extracts showed considerable free radical scavenging and cholinesterase inhibitory properties. Thus, the observed bioactivities may serve as a justification for its folkloric use as a remedy for mental illness. The study also provides relevant information that could help in the search for lead cholinesterase inhibitors from medicinal plants that can be exploited against neurodegenerative disorders.

Synthesis and Antioxidant Properties of HeteroBisNitrones Derived from Benzene Dicarbaldehydes.

We report herein the synthesis and antioxidant profile of nine novel heterobisnitrones (hBNs) as new α-phenyl-tert-butylnitrone (PBN) analogues. The synthesized hBNs 1-9 were evaluated for their antioxidant activity using different in vitro techniques, while they were also tested as inhibitors of soybean LOX, as an indication of their anti-inflammatory effect. Nitrone hBN9 is the most potent antioxidant presenting higher anti-lipid peroxidation and hydroxyl radicals scavenging activities as well as higher lipoxygenase inhibition. In silico calculations reveal that hBN9 follows Lipinski's rule of five and that the molecule is able to penetrate theoretically the brain. All these results led us to propose hBN9 as a new potent antioxidant nitrone.

Plant cell cultures of Nordic berry species: Phenolic and carotenoid profiling and biological assessments.

Plant cell cultures from cloudberry (CL), lingonberry (LI), stone berry (ST), arctic bramble (AB), and strawberry (SB) were studied in terms of their polyphenol and carotenoid composition, antioxidant activity, antihemolytic activity and cytotoxicity effects on cancerous cells. High-resolution mass spectrometry data showed that LI, presented the highest antioxidant activity, contained the highest contents of flavones, phenolic acids, lignans, and total carotenoids, while CL, ST and SB presented the opposite behavior. AB and SB presented the lowest FRAP and CUPRAC values, while AB and CL presented the lowest reducing power. SB presented the lowest antioxidant activity measured by single electron transfer assays and the lowest content of lignans, phenolic acids, and flavones. CL and LI decreased the viability of in vitro mammary gland adenocarcinoma while only LI decreased the viability of in vitro lung carcinoma and showed protective effects of human erythrocytes against mechanical hemolysis.

Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders.

Although melatonin is an astonishing molecule, it is possible that chemistry will help in the discovery of new compounds derived from it that may exceed our expectations regarding antioxidant protection and perhaps even neuroprotection. This review briefly summarizes the significant amount of data gathered to date regarding the multiple health benefits of melatonin and related compounds. This review also highlights some of the most recent directions in the discovery of multifunctional pharmaceuticals intended to act as one-molecule multiple-target drugs with potential use in multifactorial diseases, including neurodegenerative disorders. Herein, we discuss the beneficial activities of melatonin derivatives reported to date, in addition to computational strategies to rationally design new derivatives by functionalization of the melatonin molecular framework. It is hoped that this review will promote more investigations on the subject from both experimental and theoretical perspectives.

Phytochemical Profile, Free Radical Scavenging and Anti-Inflammatory Properties of Acalypha Indica Root Extract: Evidence from In Vitro and In Vivo Studies.

In our in vitro and in vivo studies, we used Acalypha indica root methanolic extract (AIRME), and investigated their free radical scavenging/antioxidant and anti-inflammatory properties. Primarily, phytochemical analysis showed rich content of phenols (70.92 mg of gallic acid/g) and flavonoids (16.01 mg of rutin/g) in AIRME. We then performed HR-LC-MS and GC-MS analyses, and identified 101 and 14 phytochemical compounds, respectively. Among them, ramipril glucuronide (1.563%), antimycin A (1.324%), swietenine (1.134%), quinone (1.152%), oxprenolol (1.118%), choline (0.847%), bumetanide (0.847%) and fenofibrate (0.711%) are the predominant phytomolecules. Evidence from in vitro studies revealed that AIRME scavenges DPPH and hydroxyl radicals in a concentration dependent manner (10-50 µg/mL). Similarly, hydrogen peroxide and lipid peroxidation were also remarkably inhibited by AIRME as concentration increases (20-100 µg/mL). In vitro antioxidant activity of AIRME was comparable to ascorbic acid treatment. For in vivo studies, carrageenan (1%, sub-plantar) was injected to rats to induce localized inflammation. Acute inflammation was represented by paw-edema, and significantly elevated (p < 0.05) WBC, platelets and C-reactive protein (CRP). However, AIRME pretreatment (150/300 mg/kg bodyweight) significantly (p < 0.05) decreased edema volume. This was accompanied by a significant (p < 0.05) reduction of WBC, platelets and CRP with both doses of AIRME. The decreased activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase in paw tissue were restored (p < 0.05 / p < 0.01) with AIRME in a dose-dependent manner. Furthermore, AIRME attenuated carrageenan-induced neutrophil infiltrations and vascular dilation in paw tissue. For the first time, our findings demonstrated the potent antioxidant and anti-inflammatory properties of AIRME, which could be considered to develop novel anti-inflammatory drugs.

Edaravone attenuates sustained pial arteriolar vasoconstriction independently of endothelial function after unclamping of the abdominal aorta in rabbits.

BACKGROUND: Cerebral blood flow (CBF) has direct effects on neuronal function and neurocognitive disorders. Oxidative stress from abdominal aortic surgery is important in the pathophysiology of CBF impairment. We investigated the effect of edaravone on the pial arteriolar diameter changes induced by abdominal aortic surgery and the involvement of the endothelium in the changes. METHODS: The closed cranial window technique was used in rabbits to measure changes in pial arteriolar diameter after the unclamping of abdominal aortic cross-clamping with an intravenous free radical scavenger, edaravone (control group [n = 6], edaravone 10 µg/kg/min [n = 6], 100 µg/kg/min [n = 6]). Pial vasodilatory responses to topical application of acetylcholine (ACh) into the cranial window were investigated before abdominal aortic cross-clamping and after unclamping with intravenous administration of edaravone (control group [n = 6], edaravone 100 µg/kg/min [n = 6]). RESULTS: Aortic unclamping-induced vasoconstriction was significantly attenuated by continuous infusion of edaravone at 100 µg/kg/min. Topical ACh after unclamping did not produce any changes in pial arteriolar responses in comparison to before aortic cross-clamping in the control or edaravone groups. The changes in the response to topical ACh after unclamping in the saline and edaravone groups did not differ significantly. CONCLUSIONS: Free radicals during abdominal aortic surgery might have contracted cerebral blood vessels independently of endothelial function in rabbits. Suppression of free radicals attenuated the sustained pial arteriolar vasoconstriction after aortic unclamping. Thus, the free radical scavenger might have some brain protective effect that maintains CBF independently of endothelial function.

Synthesis, Neuroprotection, and Antioxidant Activity of 1,1'-Biphenylnitrones as α-Phenyl-N-tert-butylnitrone Analogues in In Vitro Ischemia Models.

Herein, we report the neuroprotective and antioxidant activity of 1,1'-biphenyl nitrones (BPNs) 1-5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1'-biphenyl]-4-carbaldehyde and [1,1'-biphenyl]-4,4'-dicarbaldehyde. The neuroprotection of BPNs1-5 has been measured against oligomycin A/rotenone and in an oxygen-glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that BPNs 1-5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC50 = 13.16 ± 1.65 and 25.5 ± 3.93 µM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen-glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC50 = 11.2 ± 3.94 µM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs1-5 has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 µM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 µM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.

Protective Effects of Hydrogen against Irradiation.

Radiation-induced lung injury is characterized by an acute pneumonia phase followed by a fibrotic phase. At the time of irradiation, a rapid, short-lived burst of reactive oxygen species (ROS) such as hydroxyl radicals (•OH) occurs, but chronic radiation-induced lung injury may occur due to excess ROS such as H2O2, O2•-, ONOO-, and •OH. Molecular hydrogen (H2) is an efficient antioxidant that quickly diffuses cell membranes, reduces ROS such as •OH and ONOO-, and suppresses damage caused by oxidative stress in various organs. In 2011, through the evaluation of electron-spin resonance and fluorescent indicator signals, we had reported that H2 can eliminate •OH and can protect against oxidative stress-related apoptotic damage induced by irradiation of cultured lung epithelial cells. We had explored for the first time the radioprotective effects of H2 treatment on acute and chronic radiation-induced lung damage in mice by inhaled H2 gas (for acute) and imbibed H2-enriched water (for chronic). Thus, we had proposed that H2 be considered a potential radioprotective agent. Recent publications have shown that H2 directly neutralizes highly reactive oxidants and indirectly reduces oxidative stress by regulating the expression of various genes. By regulating gene expression, H2 functions as an anti-inflammatory and anti-apoptotic molecule and promotes energy metabolism. The increased evidence obtained from cultured cells or animal experiments reveal a putative place for H2 treatment and its radioprotective effect clinically. This review focuses on major scientific advances in the treatment of H2 as a new class of radioprotective agents.

Homo-Tris-Nitrones Derived from α-Phenyl-N-tert-butylnitrone: Synthesis, Neuroprotection and Antioxidant Properties.

Herein we report the synthesis, antioxidant and neuroprotective power of homo-tris-nitrones (HTN) 1-3, designed on the hypothesis that the incorporation of a third nitrone motif into our previously identified homo-bis-nitrone 6 (HBN6) would result in an improved and stronger neuroprotection. The neuroprotection of HTNs1-3, measured against oligomycin A/rotenone, showed that HTN2 was the best neuroprotective agent at a lower dose (EC50 = 51.63 ± 4.32 µM), being similar in EC50 and maximal activity to α-phenyl-N-tert-butylnitrone (PBN) and less potent than any of HBNs 4-6. The results of neuroprotection in an in vitro oxygen glucose deprivation model showed that HTN2 was the most powerful (EC50 = 87.57 ± 3.87 µM), at lower dose, but 50-fold higher than its analogous HBN5, and ≈1.7-fold less potent than PBN. HTN3 had a very good antinecrotic (IC50 = 3.47 ± 0.57 µM), antiapoptotic, and antioxidant (EC50 = 6.77 ± 1.35 µM) profile, very similar to that of its analogous HBN6. In spite of these results, and still being attractive neuroprotective agents, HTNs 2 and 3 do not have better neuroprotective properties than HBN6, but clearly exceed that of PBN.

Application of electron beam water radiolysis for sewage sludge treatment-a review.

A review of the applicability of electron beam water radiolysis for sewage sludge treatment is presented. Electron beam treatment has been proven to be a successful approach to the disinfection of both wastewater and sewage sludge. Nevertheless, before 2000, there were concerns about the perceived high capital costs of the accelerator and with public acceptance of the usage of radiation for water treatment purposes. Nowadays, with increased knowledge and technological development, it may be not only possible but also desirable to use electron beam technology for risk-free sewage sludge treatment, disposal and bio-friendly fertiliser production. Despite the developing interest in this method, there has been no attempt to perform a review of the pertinent literature relating to this technology. It appears that understanding of the mechanism and primary parameters of disinfection is key to optimising the process. This paper aims to reliably characterise the sewage sludge electron beam treatment process to elucidate its major issues and make recommendations for further development and research. Graphical abstract.

Radioprotectors.org: an open database of known and predicted radioprotectors.

The search for radioprotectors is an ambitious goal with many practical applications. Particularly, the improvement of human radioresistance for space is an important task, which comes into view with the recent successes in the space industry. Currently, all radioprotective drugs can be divided into two large groups differing in their effectiveness depending on the type of exposure. The first of these is radioprotectors, highly effective for pulsed, and some types of relatively short exposure to irradiation. The second group consists of long-acting radioprotectors. These drugs are effective for prolonged and fractionated irradiation. They also protect against impulse exposure to ionizing radiation, but to a lesser extent than short-acting radioprotectors. Creating a database on radioprotectors is a necessity dictated by the modern development of science and technology. We have created an open database, Radioprotectors.org, containing an up-to-date list of substances with proven radioprotective properties. All radioprotectors are annotated with relevant chemical and biological information, including transcriptomic data, and can be filtered according to their properties. Additionally, the performed transcriptomics analysis has revealed specific transcriptomic profiles of radioprotectors, which should facilitate the search for potent radioprotectors.

Dual aspect of radioenhancers and free radical scavengers.

Combining an external beam of ionizing particles with agents to augment the dose effects of cell damages for therapeutic purpose is an important goal of radiotherapy. This last decade intensive works have focused on metal compounds or metal nanoparticles as radiosensitizers to increase the oxidative damages under irradiation. In principle the nanoparticles can be coated with a functionalized shell, to achieve a specific targeting of the tissues, making such approach attractive. The functionalized coating is made of polymers. These molecules are able to scavenge the free radicals, thus, the coating can decrease the overall efficacy of the radiation. The purpose of the present model is to analyse the role of free hydroxyl radicals in the dual behaviour of the added agent. Consideration of the efficiency of the added agents versus the Linear Energy Transfer - LET - of the ionizing particles is made. It is shown that an efficient agent combined with a low-LET particle beams might become less efficient when high-LET particles like heavy-ions are used. These general considerations should be useful to optimize the design of the nanoparticles to be combined with the different kind of ionizing particles.

Randomized placebo-controlled clinical trial investigating the effect of antioxidants and a vasodilator on overall safety and residual hearing preservation in cochlear implant patients.

BACKGROUND: The standard therapy for patients suffering from sensorineural hearing loss is cochlear implantation. The insertion of the electrode array into the cochlea, with potential mechanical trauma and the presence of this foreign body inside the cochlea, may lead to free radical formation and reduced blood perfusion of the cochlea which can result in a loss of residual hearing. Studies have suggested that a particular combination of the antioxidants vitamins A, C and E as well as the vasodilator magnesium (together: ACEMg) may protect the residual hearing. METHODS: The potential protective effect of ACEMg on residual hearing preservation in cochlear implant (CI) patients was investigated in a single-centre, randomized, placebo-controlled, double-blind phase II clinical trial. CI candidates with some residual hearing in low frequencies receiving MED-EL implants of different FLEX electrode array lengths were treated with ACEMg tablets or placebo respectively 2 days preoperatively and up to 3 months postoperatively. The study objective was to demonstrate that ACEMg is more efficacious than placebo in preserving residual hearing during cochlear implantation by comparing the hearing loss (change in hearing thresholds at 500 Hz from baseline) 3 months after the first fitting between the two treatment groups and to investigate the treatments' safety. RESULTS: Fifty-one patients were included in the study, which had to be terminated before the recruitment goal was reached because of IMP-resupply mismanagement of one partner. In the intention-to-treat population, 25 patients were treated with ACEMg and 24 patients with placebo. The mean hearing loss at 500 Hz was (± 15.84) 30.21 dB (placebo) or (± 17.56) 26.00 dB (ACEMg) 3 months after the initial fitting. Adjusting the postoperative hearing loss for the baseline residual hearing, planned electrode length and surgeon results in 8.01 dB reduced hearing loss in ACEMg-treated patients compared to placebo-treated ones. The safety analysis revealed that ACEMg was generally well-tolerated with adverse event frequencies below the placebo level. CONCLUSION: This is the first clinical trial investigating a drug effect on residual hearing in CI patients. These first-in-man data may suggest that a perioperative oral administration of ACEMg is safe and may provide protection of residual hearing in CI patients. TRIAL REGISTRATION: EU Clinical Trial Register No. 2012-005002-22 . Registered on 6 December 2013. FUNDING: European Commission FP7-HEALTH-2012-INNOVATION-2.

Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis.

Cytoglobin (Cygb), a stellate cell-specific globin, has recently drawn attention due to its association with liver fibrosis. In the livers of both humans and rodents, Cygb is expressed only in stellate cells and can be utilized as a marker to distinguish stellate cells from hepatic fibroblast-derived myofibroblasts. Loss of Cygb accelerates liver fibrosis and cancer development in mouse models of chronic liver injury including diethylnitrosamine-induced hepatocellular carcinoma, bile duct ligation-induced cholestasis, thioacetamide-induced hepatic fibrosis, and choline-deficient L-amino acid-defined diet-induced non-alcoholic steatohepatitis. This review focuses on the history of research into the role of reactive oxygen species and nitrogen species in liver fibrosis and discusses the current perception of Cygb as a novel radical scavenger with an emphasis on its role in hepatic stellate cell activation and fibrosis.