Oxidative Damage as a Fundament of Systemic Toxicities Induced by Cisplatin-The Crucial Limitation or Potential Therapeutic Target?

Cisplatin, an inorganic complex of platinum, is a chemotherapeutic drug that has been used for 45 years. Despite the progress of pharmaceutical sciences and medicine and the successful application of other platinum complexes for the same purpose, cisplatin is still the therapy of choice in many cancers. Treatment for testicular, ovarian, head and neck, urothelial, cervical, esophageal, breast, and pulmonary malignancies is still unthinkable without the use of this drug. However, cisplatin is also known for many side effects, of which the most pronounced are nephrotoxicity leading to acute renal failure, neurotoxicity, and ototoxicity. Mechanistic studies have proven that one of the conditions that plays a major role in the development of cisplatin-induced toxicities is oxidative stress. Knowing the fact that numerous antioxidants can be used to reduce oxidative stress, thereby reducing tissue lesions, organ failure, and apoptosis at the cellular level, many studies have defined antioxidants as a priority for investigation as a cotreatment. To investigate the mechanism of antioxidant action in vivo, many animal models have been employed. In the last few years, studies have mostly used rodents and zebrafish models. In this article, some of the most recent investigations that used animal models are listed, and the advantages and disadvantages of such experimental studies are pointed out.

Simultaneous Administration of Hyperbaric Oxygen Therapy and Antioxidant Supplementation with Filipendula ulmaria Extract in the Treatment of Thermal Skin Injuries Alters Nociceptive Signalling and Wound Healing.

Background and Objectives: Thermal skin injuries are a prevalent cause of skin damage, potentially leading to severe morbidity and significant mortality. In this study, we intended to estimate the effects of HBO (hyperbaric oxygen treatment) and antioxidant supplementation with Filipendula ulmaria extract, individually and simultaneously, in the treatment of thermal skin injuries. Materials and Methods: As a thermal skin injury experimental model, we used two-month-old male Wistar albino rats. Thermal injuries were made with a solid aluminium bar at a constant temperature of 75 °C for 15 s. Hyperbaric oxygen treatment was performed in a specially constructed hyperbaric chamber for rats (HYB-C 300) for seven consecutive days (100% O2 at 2.5 ATA for 60 min). Antioxidant supplementation was performed with oral administration of Filipendula ulmaria extract dissolved in tap water to reach a final concentration of 100 mg/kg b.w. for seven consecutive days. Results: Simultaneous administration of hyperbaric oxygen therapy and antioxidant supplementation with Filipendula ulmaria extract significantly ameliorated the macroscopic and histopathological characteristics of the wound area and healing. Also, this therapeutic approach decreased the local expression of genes for proinflammatory mediators and increased the expression of the µ-opioid receptor and the MT1 and MT2 receptors in the wound area and spinal cord, with a consequent increase in reaction times in behavioural testing. Conclusions: In conclusion, the presented results of our study allow evidence for the advantages of the simultaneous employment of HBO and antioxidant supplementation in the treatment of thermal skin injuries, with special reference to the attenuation of painful sensations accompanied by this type of trauma.

The Investigation of the Chemical Composition and Applicability of Gold Nanoparticles Synthesized with Amygdalus communis (Almond) Leaf Aqueous Extract as Antimicrobial and Anticancer Agents.

The current work's main objective was to determine the chemical composition of Amygdalus communis (AC) leaf extract and examine the antibacterial and cytotoxic properties of biosynthesized gold nanoparticles (AuNPs). The chemical composition of AC leaf extract was determined using LC-ESI/MS/MS to detect compounds that may be responsible for the reducing, stabilizing, and capping steps in the synthesis of nanoparticles and their biological activities. The AC-AuNPs were spherical, with a particle size lower than 100 nm and a face-centered cubic structure. The EDX spectrum confirmed the formation of AuNPs and a negative zeta potential value (-27.7 mV) suggested their physicochemical stability. The in vitro cytotoxic efficacy of the AC-AuNPs against colorectal adenocarcinoma (Caco-2), glioma (U118), and ovarian (Skov-3) cancer cell lines and human dermal fibroblasts (HDFs) was evaluated by MTT assay. CaCo-2 cell proliferation was effectively inhibited by the AC-AuNPs at concentrations between 25 and 100 g mL-1. The AC-AuNPs exerted preeminent antimicrobial activity against Bacillus subtilis with an MIC of 0.02 µg/mL, whilst good activity was shown against Staphylococcus aureus bacteria and Candida albicans yeast with an MIC of 0.12 µg/mL. Ultimately, the results support the high antibacterial and anticancer potential of biosynthesized AuNPs from AC leaf extract.

Green Synthesis of Silver Nanoparticles Using Salvia verticillata and Filipendula ulmaria Extracts: Optimization of Synthesis, Biological Activities, and Catalytic Properties.

The study's objective was to obtain silver nanoparticles (SVAgNP and FUAgNP) using aqueous extracts of Salvia verticillata and Filipendula ulmaria. The optimal conditions for nanoparticle synthesis were determined and obtained; nanoparticles were then characterized using UV-Vis, Fourier-transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), Dynamic Light Scattering (DLS), Scanning Electron Microscopy with Energy Dispersive Spectroscopy (SEM/EDS). SVAgNP and FUAgNP possessed a crystalline structure with 48.42% and 60.41% silver weight, respectively. The highest percentage of nanoparticles in the solution had a diameter between 40 and 70 nm. In DPPH˙ and ABTS˙+ methods, FUAgNP (IC50 15.82 and 59.85 µg/mL, respectively) demonstrated a higher antioxidant capacity than SVAgNP (IC50 73.47 and 79.49 µg/mL, respectively). Obtained nanoparticles also showed pronounced antibacterial activity (MIC ˂ 39.1 µg/mL for most of the tested bacteria), as well as high biocompatibility with the human fibroblast cell line MRC-5 and significant cytotoxicity on some cancer cell lines, especially on the human colon cancer HCT-116 cells (IC50 31.50 and 66.51 µg/mL for SVAgNP and FUAgNP, respectively). The nanoparticles demonstrated high catalytic effectiveness in degrading Congo red dye with NaBH4. The results showed a rapid and low-cost methodology for the synthesis of AgNPs using S. verticillata and F. ulmaria with promising biological potential.

Investigation of Antimicrobial and Cytotoxic Properties and Specification of Silver Nanoparticles (AgNPs) Derived From Cicer arietinum L. Green Leaf Extract.

Using biological materials to synthesize metallic nanoparticles has become a frequently preferred method by researchers. This synthesis method is both fast and inexpensive. In this study, an aqueous extract obtained from chickpea (Cicer arietinum L.) (CA) leaves was used in order to synthesize silver nanoparticles (AgNPs). For specification of the synthesized AgNPs, UV-vis spectrophotometer, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction analysis (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), electron dispersive X-ray (EDX), and zeta potential (ZP) analyses data were used. Biologically synthesized AgNPs demonstrated a maximum surface plasmon resonance of 417.47 nm after 3 h. With the powder XRD model, the mean crystallite dimension of nanoparticles was determined as 12.17 mm with a cubic structure. According to the TEM results, the dimensions of the obtained silver nanoparticles were found to be 6.11-9.66 nm. The ZP of the electric charge on the surface of AgNPs was measured as -19.6 mV. The inhibition effect of AgNPs on food pathogen strains and yeast was determined with the minimum inhibition concentration (MIC) method. AgNPs demonstrated highly effective inhibition at low concentrations especially against the growth of B. subtilis (0.0625) and S. aureus (0.125) strains. The cytotoxic effects of silver nanoparticles on cancerous cell lines (CaCo-2, U118, Sk-ov-3) and healthy cell lines (HDF) were revealed. Despite the increase of AgNPs used against cancerous and healthy cell lines, no significant decrease in the percentage of viability was detected.

An Overview of the Beneficial Role of Antioxidants in the Treatment of Nanoparticle-Induced Toxicities.

Nanoparticles (NPs) are used in many products and materials for humans such as electronics, in medicine for drug delivery, as biosensors, in biotechnology, and in agriculture, as ingredients in cosmetics and food supplements. Besides that, NPs may display potentially hazardous properties on human health and the environment as a consequence of their abundant use in life nowadays. Hence, there is increased interest of researchers to provide possible therapeutic agents or dietary supplements for the amelioration of NP-induced toxicity. This review summarizes the new findings in the research of the use of antioxidants as supplements for the prevention and alleviation of harmful effects caused by exposure of organisms to NPs. Also, mechanisms involved in the formation of NP-induced oxidative stress and protective mechanisms using different antioxidant substances have also been elaborated. This review also highlights the potential of naturally occurring antioxidants for the enhancement of the antioxidant defense systems in the prevention and mitigation of organism damage caused by NP-induced oxidative stress. Based on the presented results of the most recent studies, it may be concluded that the role of antioxidants in the prevention and treatment of nanoparticle-induced toxicity is unimpeachable. This is particularly important in terms of oxidative stress suppression.

Alteration of Oxidative stress and apoptotic markers alterations in the rat prefrontal cortex influence behavioral response induced by cisplatin and N-acetylcysteine in the tail suspension test.

Cisplatin therapy is often accompanied by neurotoxicity manifestation, and since the prefrontal cortex is strongly involved in emotion regulation, the aim of this study was to analyze the alterations in the oxidative and apoptotic status of this brain region, with its behavioral impact in rats, following cisplatin administration, with or without N-acetylcysteine supplementation. Thirty-two male Wistar albino rats were randomly divided into four equal experimental groups: control, cisplatin group (single dose of 7.5 mg/kg, intraperitoneally (i.p.), on the fifth day), N-acetylcysteine group (500 mg/kg i.p., on the first and the fifth day), cisplatin + N-acetylcysteine group. Behavioral testing was performed in the tail suspension test. Oxidative stress and apoptotic markers were determined in the prefrontal cortex tissue samples. Cisplatin administration increased lipid peroxidation and decreased the activity of antioxidant enzymes in the prefrontal cortex. Also, cisplatin induced increase in Bax and decrease in Bcl-2 relative gene expression. Simultaneous application of N-acetylcysteine diminished cisplatin-induced alterations in oxidative stress and apoptotic markers. The results obtained in the tail suspension test that nominally resembles antidepressant action of cisplatin (attenuated by N-acetylcysteine), should be attributed to strong motor expression of anxiogenic response to cisplatin (also reversed by N-acetylcysteine). The antioxidant supplementation with NAC diminished cisplatin-induced oxidative damage and pro-apoptotic action in the prefrontal cortex, and significantly influenced specific behavioral alterations.

The Antioxidant Supplementation with Filipendula ulmaria Extract Attenuates the Systemic Adverse Effects of Nanosized Calcium Phosphates in Rats.

The aim of this study was to investigate and compare the systemic toxicity of three nanosized calcium phosphates (CaPs): hydroxyapatite (HA), tricalcium phosphate (TCP), and amorphous calcium phosphate (ACP) in rats. Since those metallic compounds are widely used as bone replacement materials, including their use in oral surgery, CaPs were applied (per os) equimollary (17.8 mg/kg, 11 mg/kg, and 9.65 mg/kg b.w., respectively) for 30 days in order to mimic the previously described release rate from dental composites. Also, we employed antioxidant supplementation with Filipendula ulmaria (FU) extract. All the applied CaPs significantly increased serum calcium, triglycerides, LDL, and LDH, while serum levels of testosterone and LH declined, with no alterations in the liver enzymes. The evaluation of oxidative stress markers (in the liver, kidney, and testicle) showed an increase in TBARS values, while SOD and CAT activities and GSH levels were significantly reduced. The relative gene expression of Bax and Bcl-2 was shifted to proapoptotic action, accompanied by intense characteristic histological changes in architecture in all investigated organs. The toxic effects were most prominent in groups treated by ACP. FU administration attenuated the majority of nanosized CaP-induced adverse effects, thus recommending this therapeutic approach to minimize nano-CaP systemic toxicities.

Morphological and Morphometric Characteristics of Anterior Maxilla Accessory Canals and Relationship with Nasopalatine Canal Type-A CBCT Study.

This study aimed to evaluate principal morphological and morphometric characteristics of accessory canals (ACs) of the anterior maxilla, as well as to analyze the relationship with nasopalatine canal (NPC) type. The results of our study showed that ACs were observed in almost 50% of participants. They were mostly presented bilaterally and in a curved shape, with a palatal foramen position. The morphometric characteristics of ACs were significantly influenced by NPC type. NPC type had the strongest impact on the distance between the NPC and AC, as well as on the distance between the AC and the facial aspect of buccal bone wall, in inferior parts of the alveolar ridge. On the other hand, the distance between the AC and central incisors was not significantly influenced by NPC shape in the lower region of the anterior maxilla. However, the participants with the banana-type of the NPC expressed the reduction in distance from the AC to the central incisor at the upper part in comparison with the subjects with the cylindrical-type of the NPC. On the basis of the results of this study, the simultaneous estimation of ACs and the NPC seems reasonable, as this approach may be useful in the prevention of complications which could occur during implant surgery interventions.

Antioxidant Supplementation in the Treatment of Neurotoxicity Induced by Platinum-Based Chemotherapeutics-A Review.

Cancer represents one of the most pernicious public health problems with a high mortality rate among patients worldwide. Chemotherapy is one of the major therapeutic approaches for the treatment of various malignancies. Platinum-based drugs (cisplatin, oxaliplatin, carboplatin, etc.) are highly effective chemotherapeutic drugs used for the treatment of several types of malignancies, but their application and dosage are limited by their toxic effects on various systems, including neurotoxicity. Simultaneously, researchers have tried to improve the survival rate and quality of life of cancer patients and decrease the toxicity of platinum-containing drugs by combining them with non-chemotherapy-based drugs, dietary supplements and/or antioxidants. Additionally, recent studies have shown that the root cause for the many side effects of platinum chemotherapeutics involves the production of reactive oxygen species (ROS) in naive cells. Therefore, suppression of ROS generation and their inactivation with antioxidants represents an appropriate approach for platinum drug-induced toxicities. The aim of this paper is to present an updated review of the protective effects of different antioxidant agents (vitamins, dietary antioxidants and supplements, medicaments, medicinal plants and their bioactive compounds) against the neurotoxicity induced by platinum-based chemotherapeutics. This review highlights the high potential of plant antioxidants as adjuvant strategies in chemotherapy with platinum drugs.

N-Acetylcysteine Protects against the Anxiogenic Response to Cisplatin in Rats.

Since cisplatin therapy is usually accompanied with numerous toxicities, including neurotoxicity, that involve tissue oxidative damage, the aim of this study was to evaluate the possible protective effect of N-acetylcysteine (NAC) on the anxiogenic response to cisplatin (CIS). Thirty-two male Wistar albino rats divided into four groups (control, cisplatin, NAC, and CIS + NAC). All treatments were delivered intraperitoneally. On day one, the control and cisplatin groups received saline while the NAC and CIS + NAC groups were administered with NAC (500 mg/kg). On the fifth day, the control group received saline while the CIS group was treated with cisplatin (7.5 mg/kg), the NAC group again received NAC (500 mg/kg), and the CIS + NAC group was simultaneously treated with cisplatin and NAC (7.5 and 500 mg/kg, respectively). Behavioral testing, performed on the tenth day in the open field (OF) and elevated plus maze (EPM) tests, revealed the anxiogenic effect of cisplatin that was significantly attenuated by NAC. The hippocampal sections evaluation showed increased oxidative stress (increased lipid peroxidation and decline in antioxidant enzymes activity) and proapoptotic action (predominantly by diminished antiapoptotic gene expression) following a single dose of cisplatin. NAC supplementation along with cisplatin administration reversed the prooxidative and proapoptotic effects of cisplatin. In conclusion, the results obtained in this study confirmed that antioxidant supplementation with NAC may attenuate the cisplatin-induced anxiety. The mechanism of anxiolytic effect achieved by NAC may include the decline in oxidative damage that down regulates increased apoptosis and reverses the anxiogenic action of cisplatin.

The Impact of Hippocampal Sex Hormones Receptors in Modulation of Depressive-Like Behavior Following Chronic Anabolic Androgenic Steroids and Exercise Protocols in Rats.

The aim of this study was to evaluate alterations in depressive-like behaviors in rats following chronic administration of a supraphysiological dose of anabolic androgenic steroids (AASs) as well as exposure to a prolonged exercise protocol. The role of hippocampal sex hormones receptors in the modulation of depressive-like behavior was also assessed. A total of 48 male Wistar albino rats were divided into six groups: control, exercise (1 h/day, five consecutive days), nandrolone-decanoate (ND, 20 mg/kg/week, in a single dose), exercise plus ND, testosterone-enanthate (TE, 20 mg/kg/week, in a single dose), and exercise plus TE. After the 6-week protocols were complete, the rats underwent behavioral testing in the tail suspension test (TST). Rats were sacrificed for the collection of blood samples, to determine sex hormones levels, and isolation of the hippocampus, to determine [androgen receptors (AR) and estrogen receptors α (ERα)] expression. ND and TE treatment induced significant depressive-like behavior, opposing the antidepressant effect of exercise. Chronic TE administration elevated testosterone (T) and dihydrotestosterone (DHT) serum levels, and this was augmented by exercise. In contrast, ND and exercise alone did not alter T or DHT levels. There were no changes in serum estradiol levels in any of the groups. Immunohistochemical analysis showed that exercise reduced AR immunoreactivity in all hippocampal regions and increased the ERα expression in the CA1, dentate gyrus (DG), and total hippocampal sections, but not in the CA2/3 region. AASs administration increased AR expression in all hippocampal regions, although not the total hippocampal section in the TE group and did not significantly decrease ERα. The hippocampal AR/ERα expression index was lowered while parvalbumin (PV)-immunoreactivity was enhanced by exercise. AASs administration increased the AR/ERα index and reduced PV-immunoreactivity in the hippocampus. The number of PV-immunoreactive neurons negatively correlated with the antidepressant effects and the AR/ERα ratio. Our results suggest a potential role of the numerical relationship between two sex hormones receptors (stronger correlation than for each individual receptor) in the regulation of depressive-like behavior via the hippocampal GABAergic system in rats, which allow better understanding of the hippocampal sex hormones receptors role in modulation of depressive-like behavior.

The role of galectin-3 in modulation of anxiety state level in mice.

Galectin-3 (Gal-3), a member of lectin family that binds to oligosaccharides, is involved in several biological processes, including maturation and function of nervous system. It had been reported that Gal-3 regulates oligodendrocytes differentiation and that Gal-3/Toll-like receptor-4 (TLR4) axis is involved in neuroinflammation. As both, central nervous system (CNS) maturation and neuroinflammation may affect behavior, the principle aim of this study was to examine the effects of Gal-3 gene deletion on behavior. Here we provide the evidence that Gal-3 deficiency shows clear anxiogenic effect in mature untreated animals (basal conditions). This was accompanied with lower interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) relative gene expression and hippocampal content, with no effect on TLR4 expression. Gal-3 deficiency was also accompanied with lower brain-derived neurotrophic factor (BDNF) relative gene expression and immunoreactivity in hippocampus (predominantly in CA1 region). Besides, the Gal-3 gene deletion resulted in attenuation of the hippocampal relative gene expression of GABA-A receptor subunits 2 and 5 (GABA-AR2S and GABA-AR5S), On the other hand, Gal-3 deficiency attenuates LPS-induced neuroinflammation. The anxiogenic effect of acute neuroinflammation was accompanied with increased hippocampal IL-6, TNF-α and TLR4 gene expression, as well as decreased gene and immunohistochemical BDNF expression in hippocampus, with significant decline in GABA-AR2S in wild type (WT) mice in comparison to basal conditions. Gal-3 gene deletion prevented the increase in IL-6, the decline in BDNF gene expression and immunoreactivity, and reduction in hippocampal GABA-AR2S, and therefore attenuated the anxiogenic effect of neuroinflammation. In summary, our data demonstrate that apparently opposite effects of Gal-3 deficiency on anxiety levels (anxiogenic effect under basal conditions and anxiolytic action during neuroinflammation) seem to be related to the shift in IL-6, TNF-α and hippocampal BDNF.

Phytochemical analysis and anti-inflammatory effects of Filipendula vulgaris Moench extracts.

Filipendula vulgaris Moench (dropwort) is used in traditional medicine for relieving various inflammation-related diseases. In the present study, the phytochemical profile of F. vulgaris aerial part (FVA) and root (FVR) methanolic extracts was evaluated by LC-DAD-HRMS analysis. Furthermore, their in vitro and in vivo anti-inflammatory effects, as well as their potential cytotoxicity, were assessed. Results showed that the extracts mainly contain phenolics like flavonoids, hydrolyzable tannins, procyanidins, and phenolic acid derivatives, including gaultherin. No in vitro cytotoxicity was found at the highest concentration (50 µg/mL). FVA extract (50 µg/mL) significantly inhibited cyclooxygenase-1 and -2 (COX-1 and COX-2) activities in vitro (>50% inhibition), and FVR extract considerably inhibited COX-2 activity (52.5 ±â€¯2.7%) without affecting COX-2 gene expression in LPS-stimulated THP-1 cells. The extracts demonstrated prominent in vivo anti-inflammatory potential upon oral administration in rats. Especially FVA extract at 100 and 200 mg/kg significantly inhibited carrageenan-induced edema formation. From these results, it can be concluded that F. vulgaris extracts possess interesting anti-inflammatory properties.

Summer savory (Satureja hortensis L.) extract: Phytochemical profile and modulation of cisplatin-induced liver, renal and testicular toxicity.

The aim of our study was to examine the potential ameliorating effect of the methanolic extract of Satureja hortensis L. (summer savory) aerial parts against cisplatin-induced oxidative damage in renal, hepatic, and testicular tissues. S. hortensis methanol extract at the doses of 50, 100 and 200 mg/kg of body weight were orally administered to Wistar rats once daily for 10 days. Toxicity was induced by intraperitoneal injection of a single dose of cisplatin (7.5 mg/kg of body weight) on the 5th day of the experiment. Applied treatment with S. hortensis extract restored tissue morphology, ameliorated levels of serum parameters for liver, renal and testes function, tissue oxidative stress parameters, and increased Bcl-2/Bax ratio as an indicator of apoptosis in experimental animals caused by application of cisplatin. UHPLC/DAD/HESI-MS/MS analysis revealed that S. hortensis extract was rich in phenolic compounds with rosmarinic acid (24.9 mg/g) as the main compound, followed by caffeic acid (1.28 mg/g) and naringenin (1.06 mg/g). Our findings suggest that S. hortensis may be a valuable source of dietary and pharmacologically important phenolic compounds, especially rosmarinic acid, in pharmaceutical and functional food formulations in order to maintain normal health conditions or as a remedy in various diseases caused by oxidative damage.

The Beneficial Effects of Sulfur-containing Amino Acids on Cisplatininduced Cardiotoxicity and Neurotoxicity in Rodents.

BACKGROUND: Cisplatin is one the most frequently used chemotherapeutic drugs for several decades. Although its antineoplastic effect has been reported in treatment of numerous malignances, various adverse effects seem to be the crucial limiting factor for its administration. OBJECTIVE: Beside the most commonly described nephro- and hepatotoxicity, cisplatin therapy is also accompanied with gastrointestinal, reproductive, hematological, cardiovascular and neurological side effects. Since it has been reported that cisplatin induce oxidative damage in various tissues, it seems reasonable to investigate an antioxidant supplementation as potential therapeutical approach for attenuation of cisplatin toxicities. METHODS: We performed a structured search of bibliographic databases for research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers (101 in total) was appraised using standard tools. RESULTS: Numerous antioxidants (such as thiol compounds, polyphenols, vitamins, etc.) had been reported for their beneficial effects on cisplatin-induced cardiotoxicity. The effects of various antioxidants, including sulfur-containing amino acids, have also been explored for mitigation of cisplatin neurotoxicity. However, the results for antioxidant supplementation in reduction of cisplatin-induced toxicities are still to be applied in clinical trials. CONCLUSION: Considering the facts that sulfur-containing amino acids: (a) do not interfere with chemotherapeutics antitumor action; (b) do not exhibit any toxic effect (unless applied in dose several times above the recommended); and (c) produce significant protective effects on some cisplatin-induced toxicities connected to augmentation of oxidative damage - it seems that their administration can be harmless and protective supplementation against numerous adverse effects of certain antineoplastic agents.

In vitro and in vivo assessment of meadowsweet (Filipendula ulmaria) as anti-inflammatory agent.

ETHNOPHARMACOLOGICAL RELEVANCE: Meadowsweet (Filipendula ulmaria (L.) Maxim, Rosaceae) has been traditionally used in most European countries for the treatment of inflammatory diseases due to its antipyretic, analgesic, astringent, and anti-rheumatic properties. However, there is little scientific evidence on F. ulmaria anti-inflammatory effects regarding its impact on cyclooxygenases enzymatic activity and in vivo assessment of anti-inflammatory potential. This study aims to reveal the anti-inflammatory activity of methanolic extracts from the aerial parts (FUA) and roots (FUR) of F. ulmaria, both in in vitro and in vivo conditions. MATERIALS AND METHODS: The characteristic phenolic compounds in F. ulmaria extracts were monitored via high performance thin layer chromatography (HPTLC). The in vitro anti-inflammatory activity of F. ulmaria extracts was evaluated using cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme assays, and an assay for determining COX-2 gene expression. The in vivo anti-inflammatory effect of F. ulmaria extracts was determined in two doses (100 and 200 mg/kg b.w.) with hot plate test and carrageenan-induced paw edema test in rats. Inflammation was also evaluated by histopathological and immunohistochemical analysis. RESULTS: FUA extract showed the presence of rutoside, spiraeoside, and isoquercitrin. Both F. ulmaria extracts at a concentration of 50µg/mL were able to inhibit COX-1 and -2 enzyme activities, whereby FUA extract (62.84% and 46.43% inhibition, respectively) was double as effective as the root extract (32.11% and 20.20%, respectively). Extracts hardly inhibited the level of COX-2 gene expression in THP-1 cells at a concentration of 25µg/mL (10.19% inhibition by FUA and 8.54% by FUR). In the hot plate test, both extracts in two doses (100 and 200mg/kg b.w.), exhibited an increase in latency time when compared with the control group (p<0.05). In the carrageenan-induced acute inflammation test, FUA at doses of 100 and 200mg/kg b.w., and FUR at 200mg/kg, were able to significantly reduce the mean maximal swelling of rat paw until 6h of treatment. Indomethacin, FUA, and FUR extracts significantly decreased inflammation score and this effect was more pronounced after 24h, compared to the control group (p<0.05). CONCLUSIONS: The observed results of in vitro and, for the first time, in vivo anti-inflammatory activity of meadowsweet extracts, provide support of the traditional use of this plant in the treatment of different inflammatory conditions. Further investigation of the anti-inflammatory compounds could reveal the mechanism of anti-inflammatory action of these extracts.

The effects of N-acetylcysteine on cisplatin-induced changes of cardiodynamic parameters within coronary autoregulation range in isolated rat hearts.

The aim of this study was to evaluate the effects of chronic NAC administration along with cisplatin on cisplatin-induced cardiotoxicity by means of coronary flow (CF), cardiodynamic parameters, oxidative stress markers and morphological changes in isolated rat heart. Isolated hearts of Wistar albino rats (divided into four groups: control, cisplatin, NAC and cisplatin+NAC group) were perfused according to Langendorff technique at constant coronary perfusion pressure starting at 50 and gradually increased to 65, 80, 95 and 110 cm H2O to evaluate cardiodynamic parameters within autoregulation range. Samples of coronary venous effluent (CVE) were collected for determination of CF and biochemical assays, and heart tissue samples for biochemical assays and histopathological examination. Cisplatin treatment decreased CF and heart rate, and increased left ventricular systolic pressure and maximum left ventricular pressure development rate. Cisplatin increased H2O2 and TBARS, but decreased NO2(-) levels in CVE. In tissue samples, cisplatin reduced pathological alterations in myocardium and coronary vessels, with no changes in the amount of total glutathione, as well as in activity of glutathione peroxidase and glutathione reductase. NAC coadministration, by reducing oxidative damage, attenuated cisplatin-induced changes of cardiodynamic and oxidative stress parameters, as well as morphological changes in myocardium and coronary vasculature.

The effects of N-acetylcysteine on cisplatin-induced cardiotoxicity on isolated rat hearts after short-term global ischemia.

The aim of this study was to estimate the protective effect of N-acetyl-l-cysteine (NAC) against cisplatin-induced cardiotoxicity under conditions of ischemic-reperfusion injury. Wistar albino rats were randomly divided into three groups (n = 8): control, cisplatin (5 mg/kg/w, i.p., 5 weeks) and cisplatin + NAC group (cisplatin - 5 mg/kg/w, i.p. and NAC - 500 mg/kg/w, i.p., 5 weeks). Isolated hearts were perfused according to the modified Langendorff technique at constant pressure (70 cmH2O). Following cardiodynamic parameters were measured: maximum rate of left ventricular pressure development, minimum rate of left ventricular pressure development, left ventricular systolic pressure (SLVP), left ventricular diastolic pressure and heart rate. The ischemic vasodilation episodes were induced by the complete interruption of coronary inflow for 30, 60 and 120 s. The samples of the coronary venous effluent (CVE) were continuously collected during the reperfusion period for determination of coronary flow (CF) rate and oxidative stress markers (H2O2, O2-, NO2- and thiobarbituric acid reactive substances - TBARS). Cisplatin reduced CF, heart rate and overflow (total, maximal and duration of overflow) during reperfusion, and increased SLVP (under basal conditions and after global ischemias). Cisplatin increased levels of H2O2 (under basal conditions), O2- and TBARS (under basal conditions and after ischemia), but decreased NO2- levels (during reperfusion) in CVE, and decreased superoxide dismutase and reduced glutathione in serum. NAC attenuated cisplatin-induced changes of cardiodynamic parameters (except CF under basal conditions) and oxidative stress parameters. Those results suggest that NAC, by decreasing oxidative stress, may be useful in cardioprotection during cisplatin therapy.