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Anti-inflamatory activity of fullerenol C60(OH)24 nano-particles in a model of acute inflammation in rats
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Water soluble fullerene (C60) derivative fullerenol C60(OH)24 nano-particles (FNP) are a promising candidate for many biomedical applications due to, besides other properties, strong free-radical scavenging and antioxidative potential. Using the carrageenan-induced rat footpad oedema test, the anti-inflammatory effect of FNP have been estimated in comparison with those of amifostine (AMI) and indomethacin (IND). FNP and IND, dissolved in dimethylsulfoxide, and AMI, dissolved in saline, were intraperitoneally injected to rats in a dose range 12.5 - 75 mg/kg, 3 - 10 mg/kg, and 50 - 300 mg/kg, respectively. The control groups were given corresponding vehicles. The drugs or vehicles were given 30 min before carrageenan injection. Footpad swelling was measured 3 hours after carrageenan application. Calculation of a per cent of inhibition derived through comparison with the control groups was done. Histopathological examination of the inflamed foot skin biopsies was also performed. FNP dose-dependently and significantly reduced the extent of footpad oedema, comparable to that of IND and significantly better than AMI; their ED50 values (in μmol/kg) were: 35.36, 32.12 and 871.0, respectively. Histopathological examination confirmed these results. The largest therapeutic index of FNP suggests their safety for potential use in humans. Our results support the hypothesis that FNP produce a strong acute anti-inflammatory activity.
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... Our first study on the influence of FRL C 60 (OH) 24 on DOX-induced cardiotoxicity in rats was published in 2006, followed by 16 additional papers related to the idea of protecting (as antioxidants) different organs in vivo after the administration of DOX. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] In this review, we summarized the developments made over the past 2 decades, regarding the use of FRLs for medical purposes, with a focus on their applicability in oncology treatments, both as a co-treatment drug in chemotherapy and radiation owing to the antioxidant properties and as a cytostatic drug for major cancer treatment. The available data were reviewed and presented objectively, with all benefits and limitations related to future medical use, providing guidance and recommendations for future investigations. ...
... In both cases (with Tween and DMSO), FRL created a solution that was stable over a longer period and could be easily reconstituted by placing it on a vortex mixer for a few minutes. [14][15][16][17][18][19][20][21][22][23][24][25][26][27] Using this approach, FRL was found to be highly soluble (still below the value published by Mohan et al 35 ), creating a dark brown solution that could be used for in-vivo administration. In one of our papers, 19 the differences across powder, saline water solution, and solution with co-solvent in water base were reported at the microscopic level. ...
... The most significant research investigations related to the potential applicability of FRL as organ-protectors in oncology treatments are listed in Table 2. [11][12][13][14][15]19,20,22,24,[75][76][77][78][79][80][81][82][83][84][85] Our extended research team has been publishing several papers focusing on the applicability of FRLs as antioxidants to protect organs from the side effects of chemotherapy 12-27 and radiotherapy. 11,77,82 Most of the tests were performed with intraperitoneal injection of FRL, [11][12][13][14][15][16][18][19][20][21][22][23][24][25][26][27] whereas only 2 were administered orally. 17,83 In all in-vivo investigations, mice and rats were used as animal models [11][12][13][14][15][16][17][18][19][20][21][23][24][25][26][27][77][78][79][80][81][82]84 ; however, only one study used a swine model. ...
Fullerenes are carbon molecules that are found in nature in various forms. They are composed of hexagonal and pentagonal rings that create closed structures. Almost 4 decades ago, fullerenes were identified in the form of C 60 and C 70 , and following the award of the Nobel Prize in Chemistry for this discovery in 1996, many laboratories started working on their water-soluble derivatives that could be used in different industries, including pharmaceutical industries. One of the first fullerene forms that was the focus of different research groups was fullerenol, C 60 (OH) n ( n = 2-44). Both in-vitro and in-vivo studies have shown that polyhydroxylate fullerene derivatives can potentially be used as either antioxidative agents or cytostatics (depending on their co-administration, forms, and concentration/dose) in biological systems. The current review aimed to present a critical view of the potential applications and limitations of fullerenols in oncology, as understood from the past 2 decades of research.
... • a mean lethal dose (LD 50 ) [178,179], • pharmacological-toxicological profile (i.e., absorption, distribution, metabolism, and excretion (ADME)) [180][181][182][183], as well as • pathohistological alterations in tissues in which they primarily accumulate [176,180]. In these studies, the acute toxicity of FNPs was directly dependent on the dose administered, the exposure conditions, and the duration of exposure. ...
... The relatively lower toxicity has been confirmed in our previous in vivo studies when FNPs were applied in an increasing-dose regimen. The calculated medial lethal dose (LD 50 ) [178,179], however, has reached similar values, as can be seen in Figure 6a,b. Nanomaterials 2020, 10, 1508 19 of 30 ...
... In addition, due to the possible different routes of exposure, assessment of acute FNP toxicity is the first step in considering their general toxic effects [17]. Namely, FNP toxicity studies performed mainly in mice and rats [177] were based on the determination of: a mean lethal dose (LD50) [178,179], pharmacological-toxicological profile (i.e., absorption, distribution, metabolism, and excretion (ADME)) [180][181][182][183], as well as pathohistological alterations in tissues in which they primarily accumulate [176,180]. In these studies, the acute toxicity of FNPs was directly dependent on the dose administered, the exposure conditions, and the duration of exposure. ...
Being a member of the nanofamily, carbon nanomaterials exhibit specific properties that mostly arise from their small size. They have proved to be very promising for application in the technical and biomedical field. A wide spectrum of use implies the inevitable presence of carbon nanomaterials in the environment, thus potentially endangering their whole nature. Although scientists worldwide have conducted research investigating the impact of these materials, it is evident that there are still significant gaps concerning the knowledge of their mechanisms, as well as the prolonged and chronic exposure and effects. This manuscript summarizes the most prominent representatives of carbon nanomaterial groups, giving a brief review of their general physico-chemical properties, the most common use, and toxicity profiles. Toxicity was presented through genotoxicity and the activation of the cell signaling pathways, both including in vitro and in vivo models, mechanisms, and the consequential outcomes. Moreover, the acute toxicity of fullerenol, as one of the most commonly investigated members, was briefly presented in the final part of this review. Thinking small can greatly help us improve our lives, but also obliges us to deeply and comprehensively investigate all the possible consequences that could arise from our pure-hearted scientific ambitions and work.
... Wang et al., 1999, reported that C 60 and some of its derivatives efficiently prevented peroxidation and membrane breakdown triggered by free radical species and were more effective in inhibiting lipid peroxidation compared to vitamin E, a natural antioxidant. They weakened certain inflammatory processes (e.g., arthritis and acute inflammation in rats) and possibly facilitate the recovery of damaged tissue (Dragojevic-Simic et al., 2011;Kuznietsova et al., 2020;Yudoh et al., 2009). The water-soluble derivatives of C 60 with potent antioxidant properties demonstrated robust neuroprotection against excitotoxic, apoptotic, and metabolic insults in cortical cell cultures (Dugan et al., 2001). ...
... A combination of C 60 antioxidant potential (Dragojevic-Simic et al., 2011;Dugan et al., 2001;Eswaran, 2018;Gharbi et al., 2005;Kuznietsova et al., 2020;Wang et al., 1999;Yudoh et al., 2009) and its ability for drug delivery (Kumar & Raza, 2017) make that nanostructure very attractive for anticancer therapy. A coupling of cargo molecules of C 60 for passive targeting of cancer cells was achieved through the noncovalent interactions (Prylutska, Panchuk, et al., 2017;Skivka et al., 2018). ...
Noncovalent water-soluble nanocomplexes of C60 fullerene (C60) with chemotherapeutic drugs (Doxorubicin (Dox), Cisplatin (Cis), and herbal alkaloid Berberine (Ber)) were created. Their anticancer action toward various tumor cells was studied in vitro, addressing specifically their biological synergy, compared with the action of these drugs in the non-immobilized form. Different theoretical and experimental (SEM and AFM microscopy, UV-Vis, DLS, NMR and SANS spectroscopy, ITC calorimetry) methods were applied for getting insight into the nature of the nanocomplexes with drug molecules, as well as into the physical forces enabling stabilization of these complexes. Physicochemical mechanisms were proposed for drug interaction with C60.
... Water-soluble polyhydroxylated derivatives of C60 fullerene, such as C60(OH)24 fullereneol, are nanoparticulate molecules capable of self-assembly in biological media, forming stable polyanionic nanoparticles ranging in size from 5 to 90 nm with a charge ranging from -20 to -55 mV, depending on the conditions Vraneš et al., 2017). Fullerene-based nanoparticle (FNP) has shown low cytotoxicity in in vitro studies and low acute, subacute, and chronic toxicity in in vivo models using mice and rats (Dragojevic-Simic et al., 2011). FNP exhibits high antioxidant properties in both chemical and biological models (Mirkov et al., 2004;Bogdanović et al., 2004;Trajković et al., 2007;Bogdanović et al., 2008;Milic et al., 2009;Stankov et al., 2013Vesna et al., 2016Kojić et al., 2020. ...
Nanoinformatics emerged in the early 21st century as a response to the need for computer applications at the nano level. While nanomaterials offer the potential for developing new devices in various industrial and scientific fields, they also provide revolutionary perspectives in disease prevention, diagnosis, and treatment in humans. This review paper analyzes different aspects of nanoinformatics with a special focus on nanomedicine. Another important aspect is the use of informatics in further advancing the biological and clinical applications of basic research in nanoscience and nanotechnology. Nanoinformatics can accelerate the development of the emerging field of nanomedicine, similar to what happened with the Human Genome and other -omics projects, through the exchange of modeling and simulation methods and tools, linking toxicity information with clinical and personal databases, or developing new approaches for scientific studies.
... They could weaken certain inflammatory processes (e.g. arthritis and acute inflammation in rats) and possibly facilitate the recovery of damaged tissue [28,29]. ...
Biochemical indices of blood and tissue of the gastrocnemius muscle chronically alcoholized (for 3, 6 and 9 months) rats were studied. С60 fullerene aqueous solution (C60FAS) was administered orally as a pharmacological agent at a dose of 1 mg/kg daily throughout the experiment in a three routes: 1 h before alcohol intake (preventive regimen), together with alcohol (therapeutic regimen I) and 1 h after alcohol intake (therapeutic regimen II). Creatine phosphokinase (CPK), lactate dehydrogenase (LDH), catalase, superoxide dismutase, glutathione peroxidase (GPx) activity and the level of creatinine, lactate, hydrogen peroxide, reduced glutathione were estimated with clinical diagnostic kits. A pronounced upward trend in creatinine and lactate content, CPK and LDH activity with increasing degree of alcoholic myopathy during experiment was detected. Administration of C60FAS was shown to reduce the biochemical indices of muscle injury and to reduce oxidative processes by maintaining the balance between pro-oxidant and antioxidant systems. The maximum positive effect was observed when C60FAS was administered together with alcohol (therapeutic regimen I). The results indicate on C60 fullerene ability to correct the pathological condition of the muscular system arising from alcohol intoxication. Keywords: alcohol intoxication, antioxidant system, C60 fullerene, creatine phosphokinase, gastrocnemius muscle, lactate dehydrogenase
... They could weaken certain inflammatory processes (e.g. arthritis and acute inflammation in rats) and possibly facilitate the recovery of damaged tissue (Yudoh et al., 2009;Dragojevic-Simic et al., 2011) However, it can form aggregates in aqueous solutions and make stable colloid solutions which contain both individual C 60 fullerene and its nanoclusters (Skamrova et al., 2014;Ritter et al., 2015). As is known, C 60 fullerene is active only in a soluble form when its carbon double bounds are freely accessible (Gharbi et al., 2005). ...
Oxidative stress is thought to be one of the mechanisms that leads to the dysfunction and degeneration of dopaminergic neurons in Parkinson’s disease pathogenesis and presumed to be underway during the prodromal phase. Therefore, therapy, which is effective against pre-motor symptoms, might be effective in preventing or delaying the development and progression of Parkinson’s disease. The aim of our study was to investigate the therapeutic efficiency of pristine C60 fullerene aqueous solution (C60FAS) during Parkinson’s disease in rats. The unilateral dopamine deficiency was induced in male Wistar rats (220–250 g) by stereotaxic microinjection of neurotoxin 6-hydroxydopamine (6-OHDA, 12 μg). C60FAS was injected to rats intraperitoneally daily for 10 days (0.65 mg/kg per day). The percentage of destroyed dopaminergic neurons was determined by the apomorphine test and by IHC staining of tyrosine hydroxylase-positive neurons in substantia nigra. We evaluated the rat body weight, the water and food intake, Open Field behavioural test, the level of biochemical antioxidant system, the activity of peritoneal macrophages. Levels of spontaneous and carbachol-stimulated colon motility were estimated by ballonographic method in vivo. C60FAS showed a positive tendency to increase the number of tyrosine hydroxylase-positive cells in the midbrain, which was associated with more profound improvement in apomorphine-rotation behaviour and slight relief of the anxiety level in Open Field test. Furthermore, C60FAS treatment increased the index of stimulated distal colon motor activity while it did not have a significant effect on water content in feces and total gastrointestinal transit time. C60FAS treatment did not affect water intake behaviour or body weight changes while it induced an increase of glutathione level and decrease activity of glutathione peroxidase in the brain as well as an increase in activity of peritoneal macrophages in 6-OHDA-Parkinson’s disease rats. These findings confirmed the potential therapeutic effectiveness of water-soluble pristine C60 fullerene in Parkinson’s disease pathogenesis, though there is ground for caution because of its systemic mild toxic effect.
... For example, Chedid et al. demonstrated the ability of vasoactive intestinal peptide (VIP) to reduce cellular ROS production in vitro and ameliorate footpad edema in vivo when administered 1 day and 1 h prior to carrageenan injection. 73 Similarly, antioxidant fullerenol nanoparticles 74 and Ficus exasperata bark extract 75 significantly reduced edema as a prophylactic treatment. These results support systemic antioxidant treatment for aggressively inflammatory conditions. ...
Oxidative stress is broadly implicated in chronic, inflammatory diseases because it causes protein and lipid damage, cell death, and stimulation of inflammatory signaling. Supplementation of innate antioxidant mechanisms with drugs such as the superoxide dismutase (SOD) mimetic compound 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) is a promising strategy for reducing oxidative stress-driven pathologies. TEMPO is inexpensive to produce and has strong antioxidant activity, but it is limited as a drug due to rapid clearance from the body. It is also challenging to encapsulate into micellar nanoparticles or polymer microparticles, because it is a small, water soluble molecule that does not efficiently load into hydrophobic carrier systems. In this work, we pursued a polymeric form of TEMPO [poly(TEMPO)] to increase its molecular weight with the goal of improving in vivo bioavailability. High density of TEMPO on the poly(TEMPO) backbone limited water solubility and bioactivity of the product, a challenge that was overcome by tuning the density of TEMPO in the polymer by copolymerization with the hydrophilic monomer dimethylacrylamide (DMA). Using this strategy, we formed a series of poly(DMA-co-TEMPO) random copolymers. An optimal composition of 40 mol % TEMPO/60 mol % DMA was identified for water solubility and O2•- scavenging in vitro. In an air pouch model of acute local inflammation, the optimized copolymer outperformed both the free drug and a 100% poly(TEMPO) formulation in O2•- scavenging, retention, and reduction of TNFα levels. Additionally, the optimized copolymer reduced ROS levels after systemic injection in a footpad model of inflammation. These results demonstrate the benefit of polymerizing TEMPO for in vivo efficacy and could lead to a useful antioxidant polymer formulation for next-generation anti-inflammatory treatments.
... Additionally, Injac et al. confirmed that polyhydroxylated fullerene derivatives could be as potential antioxidant agents in biological systems (Injac et al., 2013). Moreover, it has been reported that fullerene nanoparticles have anti-inflammatory activity (Dragojevic-Simic et al., 2011). According to mentioned studies, oxygen free radicals (ROS) play a crucial role in pathogenesis of reperfusion injury after ischemic stroke. ...
Overproduction of oxygen free radicals (ROS) and oxidative stress during reperfusion period plays a critical role in pathophysiology of cerebral ischemia-reperfusion injury. Since the an-tioxidant properties of fullerene nanoparticles have been extensively demonstrated, we as-sessed the possible protective effects of water-soluble fullerene derivatives (C60(OH)18-22) on infarct volume and edema after middle cerebral artery occlusion in rats. Twenty four rats were randomly divided into three groups (each group; n=8): sham, control ischemia (IR) and ischemic treatment groups. Cerebral ischemia was induced by 90 min middle cerebral artery occlusion (MCAO) followed by 24 hours reperfusion. Fullerene nanoparticles were given orally at a dose of 1mg/kg immediately after termination of MCAO and the beginning of the reperfusion period. The brains were processed for histopathological assessment and quantitation of the infarct volume (TTC staining method). Finally, the brain hemispheres were weighted as an index of brain edema. There was no infarction and edema in right hemispheres of sham rats. MCAO induced brain infarction both in cortex (261±23 mm3) and subcortex (138±23 mm3) and also increased the right hemispheres weights (23%) of control ischemic rats. Administration of fullerene reduced the infarction both in cortex (49±26 mm3) and subcortex (43±21 mm3) and also the value of right hemisphere weight (20%) of ischemic treatment rats. Additionally, in histopathological assessment, the perivascular areas decreased in ischemic treatment rats. The findings of the present study revealed the protective effects of water-soluble fullerene derivatives against reperfusion-induced injury such as infarction and edema after middle cerebral artery occlusion in rats.
... The carrageenan-induced rat footpad edema test performed by Dragojevic Simic et al. showed that when all the formulations were intraperitoneally injected to rats in different doses, the fullerol nanoparticles significantly reduced the extent of footpad edema in a dosedependent manner as compared with amifostine and indomethacin. The results were confirmed by the following histopathological examination (Dragojevic Simic et al., 2011). ...
Selection of a suitable nanocarrier with an ability to sense and respond to the biological
signals is the most essential and challenging step toward the development of a promising
targeted drug delivery system. The distinct and integrated physicochemical behavior of
carbon nanomaterial presents it as a potential carrier system for site-specific delivery of
various therapeutically active moieties including anticancer agents, anti-Alzheimer drugs,
neuroprotective agents, antiinflammatory agents, and gene delivery. In addition, these are
potentially used in tissue engineering and regenerative medicines. Surface functionaliza-
tion of carbon nanomaterial is one of the indispensable prerequisites to facilitate drug
loading, site-specificity, and safety of the carrier system. Recent investigations are evident
that surface functionalization with various bioactives, proteins, peptides, and drug sub-
stances improve the therapeutic potency and reduce the toxicity of carbon nanomaterials.
The current review article highlights carbon nanomaterial and its biomedical application,
including surface functionalization via the covalent and noncovalent coupling. In addition,
we have also briefly explained the toxicity profile of carbon nanomaterial.
... Off-white powder, Yield = 54%, m.p. (11) Albino rats of both sexes weighing (190 ± 10 g) were delivered by the animal house of the College of Pharmacy, University of Baghdad, and are kept in the same place under consistent conditions. Animals were fed commercial chaw and had access to water freely. ...
Three new hydrazone derivatives of Etodolac were synthesized and evaluated for their anti-inflammatory activity by using egg white induced paw edema method. All the synthesized target compounds were characterized by CHN- microanalysis, FT-IR spectroscopy, and 1HNMR analysis. The synthesis of the target (P1-P3) compounds was accomplished following multistep reaction procedures. The synthesized target compounds were found to be active in reducing paw edema thickness and their anti-inflammatory effect was comparable to that of the standard (Etodolac).
The antioxidant properties of open cage water-soluble fullerenol C 60(OH)24 were tested by measuring their ability to scavenge stable 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and reactive hydroxyl radical (•OH) during the Fenton reaction using electron spin resonance (ESR) spectroscopy. The fullerenol, obtained by newly developed method in our laboratory, scavenged both types of investigated radicals in dose-dependent manner in concentration range of 0.18-0.88 mmol/l. Generally, higher concentrations (0.71-0.88 mmol/l) of fullerenol possessed better inhibition of hydroxyl radical (50-82%) than of DPPH radical (28-50%). Fullerenol can exhibit its antioxidative properties by simultaneous hydrogen atom donation to investigated free radicals (DPPH and •OH). This reaction also gave rise to the generation of the fullerenol radical C 60(OH)23 which presence was confirmed by ESR. The interaction between hydroxyl radical and fullerenol is also based on radical-addition reaction of 2n •OH radicals to remaining olefinic double bonds of fullerenol core to yield C60(OH) 24 + 2n•OH (n = 1-12).
Polyhydroxylated fullerenes, named fullerenols (C60(OH)n; n = 12–26) are excellent antioxidants. Harmful effects of ionizing radiation on living organism are mainly mediated by free radical species and fullerenols attract an attention as a potential radioprotectors. Our preliminary investigations on mice and rats subjected to radiation injury show that fullerenol C60(OH)24 provides high survival rate of irradiated small rodents. Radioprotective effect was comparable to that of the standard radioprotector amifostine.
In this paper the procedure for catalytical bromination of C 60 with elementary bromine with FeBr 3 as a catalyst is described In this procedures only one reaction product - C 60 Br 24 is obtained. The twenty four bromine atoms are symmetrically distributed over the C 60 sphere, which was confirmed by thermogravi metric analysis. The yield of bromine derivative in this reaction is 98%.
Aminothiol amifostine (AMI) protects against toxic effects of both ionizing radiation and numerous anticancer drugs. The aim of this study was to investigate the potential protective effects of AMI against doxorubicin (DOX)induced cardiotoxicity in rats. Male Wistar rats were treated with AMI (75 mg/kg i.p.) and/or DOX (1.25 mg/kg i.p.), 4 times per week, for 4 weeks. Mortality, general condition and body weight of the animals were observed during the whole treatment, and for a further 4 weeks, until the end of experiment. Evaluation of cardioprotective efficacy of AMI was performed by analyzing the electrocardiographic parameters and response to the pro-arrhythmic agent aconitine, as well as activity registration of the in situ rat heart preparations. Necropsy was also performed at the end of the experiment, and heart excision, weight and macroscopic examination were done before histological evaluation. Doxorubicin caused rat heart disturbances manifested by prominent electrocardiographic changes (Salpha-T prolongation and T-wave flattening), significantly enhanced response to aconitine, decrease of the heart rate and contractility, as well as histopathologically verified myocardial lesions. The heart changes were accompanied by 40% mortality rate, significant decline in body mass and severe effusion intensity score in 66.6% of the animals. Application of AMI before each dose of DOX significantly reduced or completely prevented its toxic effects. Therefore, since AMI had very good protective effects against a high dose of DOX given as a multiple, low, unitary dose regimen, not only on the heart but on the whole rat as well, it could be recommended for further investigation in this potentially new indication for clinical application.
Water-soluble polyhydroxylated fullerene derivatives (fullerenols) show excellent efficiency in eliminating superoxide radicals (O2–˙), generated by xanthine and xanthine oxidase, thus revealing the potential use of these compounds as novel potent free radical scavengers in biological systems.
Contents: Military Radiobiology: A Perspective; Physical Principles of Nuclear Weapons; Nuclear Weapons Fallout; Ionizing Radiations and Their Interactions with Matter; Cellular Radiation Biology; Radiation Effects on the Lymphohematopoietic System: A Compromise in Immune Competency; Effect of Ionizing Radiation on Gastrointestinal Physiology; Postirradiation Cardiovascular Dysfunction; Acute Radiation Syndrome; The Combined Injury Syndrome; Mechanisms and Management of Infectious Complications of Combined Injury; Diagnosis, Triage, and Treatment of Casualties; Internal Contamination with Medically Significant Radionuclides; Radioprotectants; Psychological Effects of Nuclear Warfare; Effects of Ionizing Radiation on Behavior and the Brain; Nuclear Weapons Accident Response Procedure; Management of Radiation Accidents; Medical Operations in Nuclear War; Low-Level Effects. (Reprints).