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BACKGROUND. Endotoxemia provokes excessive host response to bacteria or microbial compounds, resulting in systemic inflammation, organ injury and mortality. Aim: This study examined the effects of simvastatin on survival and liver injury in endotoxic shock in a rat model of endotoxemia. METHODS. Male Wistar rats were injected intraperitoneally with E.coli-lipopolysaccharide (LPS) and the medial lethal dose (LD50) was determined. Simvastatin was given orally (5-40 mg/kg body weight) for five days prior to either a single LD50 dose of LPS or 2, 2.5 or 3x LD50. Liver damage was assessed by histological examination and expressed as a tissue damaged score (TDS). Another group of rats was treated with simvastatin and then challenged with LPS to determine the degree of apoptosis in hepatocytes, liver immune cells, and cleaved caspase-3 activity after 24h of endotoxemia. RESULTS. Endotoxemia caused substantial mortality with associated leukocyte infiltration, liver injury (TDS = 3.67, SD = 0.55), as well as notable apoptosis of hepatocytes and resident liver macrophages. Simvastatin, in a dose-dependent manner significantly reduced LPS-induced mortality, hepatocellular damage (TDS = 1.5, SD = 0.55), inflammatory infiltration, and dte drug markedly decreased apoptosis and expression of cleaved caspase-3. CONCLUSIONS. Simvastatin improves survival in endotoxic shock and prevents endotoxemic liver injury by inhibiting leukocyte infiltration and hepatocellular apoptosis. These results suggest that simvastatin could be used to prevent endotoxemia-associated liver dysfunction by simvastatin.

Background/Aim. Acute intoxication by ethanol constitutes a significant part of the acute pathology caused by toxic chemicals, which require medical care in specialized health care institutions. The aim of the study was to determine some principal characteristics of the patients treated after acute ethanol poisoning, such as: participation in the total number of patients treated after acute poisoning by all chemical agents, age, sex, severity of poisoning and capacities for ambulatory or hospital treatment. Methods. A five-year retrospective case study was conducted on 20,891 acute poisoned patients, of which 10,731 were treated after acute ethanol poisoning during the period 2011–2015. All the subjects satisfied the diagnostic criteria of poisoning according to the World Health Organization International Classification of Diseases-10 and standardized Poison Severity Score scale. Results. Monitored parameters were analyzed in 10,731 patients acutely poisoned by ethanol, and their average number during one study year was 2146.2 ± 437.95. The average number of treated patients due to poisoning by ethanol (51.47 ± 2.86%) was statistically significantly higher than that of other causes of acute poisoning (p < 0.001). The majority of poisoned patients were men, aged 19 to 65 years, with mild to moderate symptoms of acute ethanol intoxication. The highest number of patients poisoned by ethanol had Poison Severity Score 1 (70.25 ± 5.04%, p < 0.001). Very few acute poisoned with ethanol required hospital treatment (1.05%). Anticipated number of patients acutely poisoned by ethanol had high percentage of increase for the period 2016–2020 (slightly more than 20%), which is worrying, primarily due to their high absolute number. Conclusion. Acute alcohol poisoning represents a significant part of the pathology in the total number of patients treated due to acute poisoning with various chemical substances. The results of this analysis showed that certain populations are particularly vulnerable to abuse of alcohol to the level requiring health care (male population, age 19˗65 years). Only a small number of patients (1% of all patients treated for acute alcohol poisoning) required clinical treatment. The obtained data provided the basis for a more targeted preventive action in certain population groups, as well as the adequate planning of professional medical staff engagement, material, spatial and other capacities. These data, also, provided the basis for additional detailed social, economic, health and other researches in this area as well as a more detailed registration of this type of poisoning and establishing a monitoring system and database.

L-phenylalanine methyl ester derivative of dexamethasone - derived cortienic acid (DF) was synthesized and its crystal structure was characterized by X-ray diffraction method. The crystal system is orthorhombic with space group P212121 and cell constants a = 8.2969 (3) Å, b = 18.9358 (8) Å, c = 20.0904 (6) Å, V = 3156.4 (2) Å3 and Z = 4. Ring A of the steroid nucleus and phenyl ring in the 17β-side chain are almost planar. Rings B and C have a slightly distorted chair conformation, whereas ring D has an envelope conformation. The packing of DF is characterized by a network of intermolecular hydrogen bonds involving the O4 atom from one side of the steroid nucleus and O1 and F1 atoms from the other side as hydrogen bond acceptors. Apart from the intermolecular hydrogen bonds in the crystal packing, there are also numerous intramolecular hydrogen bonds of the N-H...O, C-H...O and C-H...F type. Local anti-inflammatory activity of DF was evaluated by use of croton oil-induced ear edema test. This derivative achieved maximal inhibition of ear edema at significantly lower concentration in comparison with dexamethasone. [Projekat Ministarstva nauke Republike Srbije, br. 172041, 172014 i 172035]

We examined the acceptance and palatability of baits containing different contents of sodium selenite as a rodenticide, in Swiss mice under laboratory conditions. In a no-choice and choice feeding test, the animals were exposed to baits containing 0.1, 0.05, 0.025 and 0.0125% of sodium selenite. The total bait consumption by Swiss mice in the no-choice feeding test was highly negatively correlated, while total sodium selenite intake was medium-positively correlated to the sodium selenite content in the bait. In the same test, daily intakes significantly depended on the content of sodium selenite in the bait, while the exposure and associated interactions of contents of sodium selenite and exposure had no statistically significant impact. Baits with sodium selenite contents of 0.05 and 0.1% had the most lethal effects. The negative impact of the sodium selenite content on bait acceptance and palatability was confirmed in choice feeding tests. Baits containing 0.05 and 0.1% of sodium selenite displayed the biological potential to be used as a rodenticide. It is necessary to improve its insufficient acceptability and palatability by adding adequate additives to the bait. The results of this study should be verified in experiments with wild rodents. [Projekat Ministarstva nauke Republike Srbije, br. III 46008 i br. OI 173039]

Health risks associated with the consumption of products contaminated with mycotoxins are worldwide recognized and depend on the extent to which they are consumed in diversified diet. To some extent, the presence of small amount of mycotoxins in cereals and related food products is unavoidable; this requires risk assessments which are to be carried out by regulatory bodies in several countries to help establish regulatory guidelines for the protection of public health. By assessing the levels at which these substances in food may pose a potential risk to human health, it is possible to devise appropriate risk management strategies. However, several important factors have to be taken into account in making a rational risk management decision, such as adequate toxicological data and information concerning the extent of exposure, availability of technically sound analytical procedures (including sampling), socioeconomic factors, food intake patterns and levels of mycotoxins in food commodities which may vary considerably between countries.

Background/Aim. Amifostine (AMI) is a broad-spectrum cytoprotector which protects against variety of radio- and chemotherapy-related toxicities without decreasing their antitumor action. The aim of the study was to investigate the potential protective effects of AMI against acute cardiotoxic effects of doxorubicin (DOX) in male Wistar rats. Methods. AMI (300 mg/kg ip) was given 30 min before DOX (6 mg/kg and 10mg/kg b.w., iv). The evaluation of DOXinduced cardiotoxic effects, as well as cardioprotective efficacy of AMI was performed 48 h after their administration by determining serum activities of enzymes known to be markers of cardiac damage (creatine kinase - CK, aspartate aminotransferase - AST, lactate dehydrogenase - LDH, and its isoenzyme α-hydroxybutirate dehydrogenase - α- HBDH), as well as the histopathological and ultrastructural analysis of the heart tissue. Results. AMI successfully prevented a significant increase in serum activity of CK, AST, LDH and α-HBDH in animals treated with DOX in the dose of 6 mg/kg (121.14 ± 18.37 vs 167.70 ± 44.24; 771.42 ± 161.99 vs 1057.00 ± 300.00; 3230.00 ± 1031.73 vs 4243.10 ± 904.06; 202.57 ± 42.46 vs 294.90 ± 80.20 UI/l, respectively), and ameliorated DOX-induced structural damage of the rat myocardium. Pretreatment with AMI in rats given 10 mg/kg DOX reduced the cardiac damage score (CDS) from 2.62 ± 0.51 to 1.62 ± 0.51, i.e. to the CDS value obtained with the lower dose of DOX (6 mg/kg). The ultrastructural analysis of the rat myocardium showed that AMI successfully protected the sarcolemma of cardiomyocytes and reduced mitochondria damage induced by DOX given in the dose of 6 mg/kg. Besides, capillaries were less morphologically changed and apoptosis of endothelial cells was extremely rare in AMI-protected animals. AMI itself did not cause any prominent changes in the examined parameters in comparison with the control rats. Conclusion. AMI provided a significant protection against DOX-induced acute cardiotoxic effects in rats. This finding implies its potential to be a successful cardioprotector in patients treated with DOX due to malignant diseases.

Polychlorinated biphenyls (PCBs) and brominated flame retardants, polybrominated diphenylethers (PBDEs), are widespread environmental contaminants as a result of anthropogenic activities and due to their persistency and resistance to degradation. Both groups of chemicals are placed on the list of persistent organic pollutants (POPs), covered by the Stockholm convention which is aimed to limit or ban the production, use, emission, import and export of POPs in order to protect human health and the environment. Taking into account the structural similarity between PCBs and PBDEs, and the known effects of PCBs, these two groups of chemicals could have similar mechanisms of action. Also, because of real simultaneous exposure to these compounds, an examination of possible interactions is of great importance. Interactions of the compounds from these groups are likely at the system level of hormones, particularly thyroid and reproductive ones. As there are mechanisms of adverse effects of both groups of chemicals on the nervous system, including functional, neurological and behavioral changes, there are influences on neurotransmiters, changes in signal transduction and apoptosis. There are interactions affecting the occurrence of metabolic disorders as well. Data on the toxicity of mixtures of PCBs and PBDEs, as well as interactions of these chemicals would contribute to the processes of risk evaluation and risk characterisation. [Projekat Ministarstva nauke Republike Srbije, br. III 46009]

This paper deals with the biosynthetic capacity for ochratoxin A (OTA) production by Aspergillus ochraceus E'G isolate derived from A. ochraceus CBS 108.08 strain, during 2007. Preliminary analysis of fungal potential for the production of OTA were performed according to the modified method of Filtenborg et al. (1983). Toxin production was tested in the following liquid media: (i) glucose-peptone-yeast extract broth (GPY - pH 5.6), (ii) potato-dextrose broth (PDB - pH 6.9), (iii) yeast extract-sucrose broth (YES - pH 6.5), and (iv) YES broth supplemented with 0.23 mg/l ZnSO4 x 5 H2O (YESZn - pH 6.5) after stationary and submerged cultivation. Dynamics of OTA biosynthesis was tested after the cultivation of A. ochraceus E'G on natural solid substrates, such as wet sterilized rice, corn and wheat grain. Cultivations were performed during different time periods (ranging from four days to few weeks) at different temperatures (ranging from 21°C to 30°C). The presence of OTA was determined as follows: (i) in liquid media according to the method of Balzer et al. (1978) modified by Bočarov-Stančić et al. (2003), and (ii) in the solid substrates according to the Serbian official methods for sampling and analyzing of fodder (Official Gazette of SFRY, No. 15/87). After the cultivation of A. ochraceus E'G isolate in liquid media, the highest yield of OTA (6.4 mg/l) was obtained after submerged cultivation in PDB (4 days, 128 rpm, 21-23°C). In the case of cultivation on solid substrates, the highest amount of OTA (800.0 mg/kg of dry matter) was recorded after several week long cultivation on wheat grain at 30±1°C.

All poultry is sensitive to mycotoxins. This partly depends on the type, age and production categories of poultry, their living conditions and nutritive status and partly on the type, quantity and duration of mycotoxin ingestion. The presence of mycotoxins results in significant health disorders and a decrease in production performances. This leads to considerable economic loss for the poultry industry - either direct losses, i.e. death of the poultry or the indirect ones, i.e. the decrease in body mass, number and quality of eggs, greater food conversion, and immunosuppression. Immunosuppression results in increased sensitivity to infective agents and a bad vaccinal response. Morevover, mycotoxin residues in poultry meat, eggs and products derived from them pose a threat to human health. In order to prevent and reduce the negative implications of mycotoxins in the poultry production, it is necessary to create both global and national strategies for combatting mycotoxins, advance diagnostic techniques and procedures, intensify the control of food quality, introduce new limits on the maximum amount of mycotoxins allowed in food and poultry feed used for certain species and categories of animals, and synchronise it with the European standards.

In this study female Wistar rats were treated with T-2 toxin (1 LD50 0.23 mg/kg sc) and sacrificed on days 1, 3, 5, 7, 14, 21, 28 and 60 after the treatment. Control groups of rats were treated by saline (1 ml/kg 0.9% NaCl). At each time-schedule, control groups of animals were sacrificed, too. Pathohistological alterations of the heart were evaluated in whole visual fields stained by haematoxylin and eosin (HE), periodic acid- -Schiff's (PAS), Masson-Trichrom's (MT) and Giemsa (GIM) methods. The changes observed were scored by using semiquantitative grading scale. The heart alterations detected in T-2 toxin-treated animals ranged from focal parenchymal or hyaline degeneration (HE = 2.5 - 4.0; p < 0.05 vs. control) to diffuse necrosis of muscle cells (HE = 5.0; p < 0.05 vs. control and 1st day after T-2 treatment). The myofibrils were slightly PAS-positive during the first week of the study (PAS = 2.0 - 3.2; p < 0.05 vs. control and 1st day after T-2 treatment), while a diffuse distribution of glycogen granules in endo- and perimisium were observed from day 21 to 60 in the whole heart' tissue (PAS = 4.0; p < 0.05 vs. control and 1st day after T-2 treatment). Massive hemorrhagic foci associated with diffuse accumulation and degranulation of MCs were the most intensive from day 28 to 60 of the study (MT = 5.0; p < 0.05 vs. control and 1st day after T-2 treatment). During the whole study period, irregular distribution of glycogen granules, intensity and total number of haemorrhages were in correlation with the degree of heart structural lesions, which showed the highest coefficient of correlation (r = 0.8750; p < 0.001). Our results indicate that basic histohemical methods can be a useful tool for evaluation of T-2 toxin-induced cardiac damage, which is probably a result of complex inflammatory mechanisms, eventually leading to vascular lesions and myocardial necrosis, as well as for some potential cardioprotectors in the future.

Background/Aim. The majority of symptoms and signs of acute diazepam poisoning are the consequence of its sedative effect on the CNS affecting selectively polisynaptic routes by stimulating inhibitory action of GABA. The aim of the present study was to examine the effects of combined application of theophylline and flumazenil on sedation and impaired motor function activity in acute diazepam poisoning in rats. Methods. Male Wistar rats were divided in four main groups and treated as follows: group I - with increasing doses of diazepam in order to produce the highest level of sedation and motor activity impairment; group II - diazepam + different doses of flumazenil; group III - diazepam + different doses of theophylline; group IV - diazepam + combined application of theophylline and flumazenil. Concentrations of diazepam and its metabolites were measured with LC-MS. The experiment was performed on a commercial apparatus for spontaneous motor-activity registration (LKBFarad, Sweden). Assessment of diazepam- induced neurotoxic effects and effects after theophylline and flumazenil application was performed with rotarod test on a commercial apparatus (Automatic treadmill for rats, Ugo Basile, Italy). Results. Diazepam in doses of 10 mg/kg and 15 mg/kg produced long-time and reproducible pharmacodynamic effects. Single application of flumazenil or theophylline antagonized effects of diazepam, but not completely. Combined application of flumazenile and theophylline resulted in best effects on diazepaminduced impairment of motoric activity and sedation. As a result of theopylline application there was better elimination of diazepam and its metabolites. Conclusion. Combined application of flumazenil and theophylline resulted in the best antidotal effects in the treatment of diazepam poisoned rats. These effects are a result of different mechanisms of their action, longer half-life of theophylline in relation to that of flumezenil and presumably the diuretic effect of theophylline.

T-2 mycotoxin, secondary metabolite of Fusarium fungi, is one of the most potent cytotoxic representatives of trichothecene mycotoxin type A. After ingestion, T-2 toxin affects actively dividing cells and irreversible post-mitotic cells. In our experiments, the best protective effects were produced by dexametasone (PI = 3.37) and different methylprednisolone formulations (PI = 2.43-2.64). Significant protective efficacy was shown by nimesulide (PI = 1.44) and N-acethyilcistein (PI = 1.29), but their values were higher in a combination with methylprednisolone (PI = 2.16-2.34). Radioprotector amifostine (WR-2721) expressed good protective effects (PI = 1.26) or/and different absorbent formulations, such as: activated charcoal (PI = 1.13) and various Min-a-zel® powder compounds, which are a well known zeolite clinoptilolite absorbents. Among the five zeolite regimens investigated, only Min-a-zel Plus® showed a significant protective effect (PI = 1.77). In summary, the steroidal anti-inflammatory drugs could be recommended as a regimen of choice for treatment of acute T-2 toxicosis while nonsteroidal anti-inflammatory compounds, different absorbent formulations and their combinations with antioxidants or radioprotectors could be important for the treatment of subacute and chronic T-2 toxin poisonings.

Type A trichothecenes, T-2 toxin and diacetoxyscirpenol - DAS, belong to one of the most toxic groups of fusariotoxins. Although larger quantities of them can be found more often in cooler parts of Europe, regarding their metabolic characteristics and the types of illnesses they provoke, it is obvious that even smaller quantities of these toxins can cause serious health disturbances of humans and animals in climatic conditions of Serbia. Having in mind the importance of these substances, the aim of this study was to carry out the optimization of laboratory conditions under which screening of Fusarium spp. isolates from Serbia, regarding T-2 toxin and DAS production, should be done. Four cultures of Fusarium sporotrichioides originating from different regions throughout the world, were under present investigation: ITM-391 (Italy), KF-38/1 (Poland), M-1-1 (Japan) and R-2301 (Germany). According to the previous literature data, all of these isolates were T-2 toxin producers, and some of them were also DAS producers. The influence of medium composition (different C and N atoms sources microelements etc), as well as aeration (in liquid media), on biosynthesis process of these mycotoxins, in vitro conditions was investigated. In the case of most Fusarium sporotrichioides isolates, highest yields of T-2 toxin and DAS were achieved under the conditions of more intense aeration, and with the use of glucose (5 or 20%) as a C atom source. Fermentation in semi-synthetic liquid medium, using a rotary shaker, was more suitable for screening the toxicity of the fungal isolates in pure culture because of shorter period of incubation, more simpler sample preparation, obtaining less interfering materials in crude toxin extracts, and possibility for more precise definition of factors influencing the yield of trichothecenes.

Oxidative stress status, as a disruption of redox homeostasis, in the blood sera of Wistar rats caused by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Throughout this study, each oxime in a dose of 0.1 of LD 50 /kg im was given 2x/week for 4 weeks. Then, seven days after the last oximes' application, markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, reduced glutathione, GSH, and oxidized glutathione, GSSG), were determined. Oxidative stress parameters, MDA and AOPP were significantly highest in the K048-, K074- and K075-treated groups (p < 0.001). The activity of CAT was significantly elevated in the obidoxime-treated group (p < 0.05), while treatment with K027, K048, and K074 induced high elevation in SOD levels (p < 0.01, p < 0.001). Interestingly, the activity of GSH in each oxime-treated group was significantly elevated. Unlike, treatment with obidoxime caused elevation in GSSG levels (p < 0.01). As a continuation of our previously published data, these results assure that applied oximes following subacute treatment ameliorated the oxidative status and further adverse systemic toxic effects in rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper. None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cardiovascular diseases (CVDs) are a group of diseases with a very high rate of morbidity and mortality. The clinical presentation of CVDs can vary from asymptomatic to classic symptoms such as chest pain in patients with myocardial infarction. Current therapeutics for CVDs mainly target disease symptoms. The most common CVDs are coronary artery disease, acute myocardial infarction, atrial fibrillation, chronic heart failure, arterial hypertension, and valvular heart disease. In their treatment, conventional therapies and pharmacological therapies are used. However, the use of herbal medicines in the therapy of these diseases has also been reported in the literature, resulting in a need for critical evaluation of advances related to their use. Therefore, we carried out a narrative review of pharmacological and herbal therapeutic effects reported for these diseases. Data for this comprehensive review were obtained from electronic databases such as MedLine, PubMed, Web of Science, Scopus, and Google Scholar. Conventional therapy requires an individual approach to the patients, as when patients do not respond well, this often causes allergic effects or various other unwanted effects. Nowadays, medicinal plants as therapeutics are frequently used in different parts of the world. Preclinical/clinical pharmacology studies have confirmed that some bioactive compounds may have beneficial therapeutic effects in some common CVDs. The natural products analyzed in this review are promising phytochemicals for adjuvant and complementary drug candidates in CVDs pharmacotherapy, and some of them have already been approved by the FDA. There are insufficient clinical studies to compare the effectiveness of natural products compared to approved therapeutics for the treatment of CVDs. Further long-term studies are needed to accelerate the potential of using natural products for these diseases. Despite this undoubted beneficence on CVDs, there are no strong breakthroughs supporting the implementation of natural products in clinical practice. Nevertheless, they are promising agents in the supplementation and co-therapy of CVDs.

Oxidative stress status and morphological injuries in the brain of Wistar rats induced by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Each oxime in a dose of 0.1 of LD 50 /kg im was given 2x/week for 4 weeks. Markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, glutathione reductase, GR, and glutathione peroxidase, GPx), were estimated in the brain tissue homogenates on day 35 of the study. Brain alterations were carefully quantified by semiquantitative grading scales - brain damage score (BDS). Oxidative stress parameters, MDA and AOPP were significantly highest in the asoxime-, obidoxime- and K075-treated groups (p < 0.001). The activity of SOD and CAT was significantly elevated in the obidoxime-, K048-, and K075-treated groups (p < 0.001). Besides, GR was markedly decreased in the obidoxime- and K074-treated groups (p < 0.01), while treatment with K048, K074 and K075 induced extremely high elevation in GPx levels (p < 0.001). In the same groups of rats, brain alterations associated with polymorphonuclear cell infiltrate were significantly more severe than those observed in animals receiving only asoxime or K027 (p < 0.001). The presented results confirmed that treatment with different oximes significantly improved the oxidative status and attenuated signs of inflammation in rats' brains. Presented results, together with our previously published data can help to predict likely adverse systemic toxic effects, and target organ systems, which are crucial for establishing risk categories, as well as in dose selection of K-oximes as drug candidates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience treatment resistance to the first-line R-CHOP regimen. ATP binding cassette (ABC) transporters and survivin might play a role in multidrug resistance (MDR) in various tumors. The aim was to investigate if the coexpression of ABC transporters and survivin was associated with R-CHOP treatment response., Methods: The expression of Bcl-2, survivin, P-glycoprotein/ABCB1, MRP1/ABCC1, and BCRP/ABCC2 was analyzed using immunohistochemistry in tumor specimens obtained from patients with DLBCL, and classified according to the treatment response as Remission, Relapsed, and (primary) Refractory groups. All patients received R-CHOP or equivalent treatment., Results: Bcl-2 was in strong positive correlation with clinical parameters and all biomarkers except P-gp/ABCB1. The overexpression of MRP1/ABCC1, survivin, and BCRP/ABCC2 presented as high immunoreactive scores (IRSs) was detected in the Refractory and Relapsed groups ( p < 0.05 vs. Remission), respectively, whereas the IRS of P-gp/ABCB1 was low. Significant correlations were found among either MRP1/ABCC1 and survivin or BCRP/ABCC2 in the Refractory and Relapsed groups, respectively. In multiple linear regression analysis, ECOG status along with MRP1/ABCC1 or survivin and BRCP/ABCG2 was significantly associated with the prediction of the R-CHOP treatment response., Conclusions: DLBCL might harbor certain molecular signatures such as MRP1/ABCC1, survivin, and BCRP/ABCC2 overexpression that can predict resistance to R-CHOP.

Serious health risks associated with the consumption of food products contaminated with aflatoxins (AFs) are worldwide recognized and depend predominantly on consumed AF concentration by diet. A low concentration of aflatoxins in cereals and related food commodities is unavoidable, especially in subtropic and tropic regions. Accordingly, risk assessment guidelines established by regulatory bodies in different countries help in the prevention of aflatoxin intoxication and the protection of public health. By assessing the maximal levels of aflatoxins in food products which are a potential risk to human health, it's possible to establish appropriate risk management strategies. Regarding, a few factors are crucial for making a rational risk management decision, such as toxicological profile, adequate information concerning the exposure duration, availability of routine and some novel analytical techniques, socioeconomic factors, food intake patterns, and maximal allowed levels of each aflatoxin in different food products which may be varied between countries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The main cause of death among patients with malignant hypertension is a kidney failure. The promising field in essential and malignant hypertension therapy could be centered on the amelioration of oxidative stress using antioxidant molecules like resveratrol. Resveratrol is a potent antioxidative agent naturally occurred in many plants that possess health-promoting properties., Methods: In the present study, we investigated the therapeutic potential of resveratrol, a polyphenol with anti-oxidative activity, in N G -L-Arginine Methyl Ester (L-NAME) treated spontaneously hypertensive rats (SHR) - malignantly hypertensive rats (MHR)., Results: Resveratrol significantly improves oxidative damages by modulation of antioxidant enzymes and suppression of prooxidant factors in the kidney tissue of MHR. Enhanced antioxidant defense in the kidney improves renal function and ameliorates the morphological changes in this target organ. Besides, protective properties of resveratrol are followed by the restoration of the nitrogen oxide (NO) pathway. 4) Conclusion: Antioxidant therapy with resveratrol could represent promising therapeutical approach in hypertension, especially malignant, against kidney damage., Competing Interests: Conflict of interest statement None., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5 ® . Genetic polymorphism in CYP3A4 , CYP3A5 , CYP1A1 , CYP2C9 , and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of C max and AUC and increment of V d in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miljković, Rančić, Kovačević, Cikota-Aleksić, Skadrić, Jaćević, Mikov and Dragojević-Simić.)

Disruption of the alveolar−endothelial barrier caused by inflammation leads to the progression of septic acute lung injury (ALI). In the present study, we investigated the beneficial effects of simvastatin on the endotoxin lipopolysaccharide (LPS)-induced ALI and its related mechanisms. A model of ALI was induced within experimental sepsis developed by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment (10−40 mg/kg orally). The severity of the lung tissue inflammatory injury was expressed as pulmonary damage scores (PDS). Alveolar epithelial cell apoptosis was confirmed by TUNEL assay (DNA fragmentation) and expressed as an apoptotic index (AI), and immunohistochemically for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL, an inhibitor of apoptosis, survivin, and transcriptional factor, NF-kB/p65. Severe inflammatory injury of pulmonary parenchyma (PDS 3.33 ± 0.48) was developed after the LPS challenge, whereas simvastatin significantly and dose-dependently protected lung histology after LPS (p < 0.01). Simvastatin in a dose of 40 mg/kg showed the most significant effects in amelioration alveolar epithelial cells apoptosis, demonstrating this as a marked decrease of AI (p < 0.01 vs. LPS), cytochrome C, and cleaved caspase-3 expression. Furthermore, simvastatin significantly enhanced the expression of Bcl-xL and survivin. Finally, the expression of survivin and its regulator NF-kB/p65 in the alveolar epithelium was in strong positive correlation across the groups. Simvastatin could play a protective role against LPS-induced ALI and apoptosis of the alveolar−endothelial barrier. Taken together, these effects were seemingly mediated by inhibition of caspase 3 and cytochrome C, a finding that might be associated with the up-regulation of cell-survival survivin/NF-kB/p65 pathway and Bcl-xL.

The molecular target of mycotoxins is not fully understood. Extensive data derived from cell and animal experimental studies demonstrate that long non-coding RNAs (lncRNAs) play crucial roles in mycotoxin-induced toxicities. Mycotoxins stimulate the upregulation/downregulation of lncRNA expression, which further promote apoptosis, is related to the mTOR/FoxO signaling pathway, and contributes to tumor cell growth, death, and liver and chondrocyte damage. Moreover, lncRNA can establish interactions with NF-κB and cause immune evasion. These preliminary data suggest that lncRNAs are involved in potential upstream regulatory events and further regulate downstream apoptosis, oxidative stress, and anti-apoptotic events that affect cell death and survival. Therefore, we hypothesize that lncRNAs are potential targets of mycotoxins. Investigation of the expression of the potential target lncRNAs by mycotoxin-mediated stimulation, and exploration of the upstream and downstream relationship between lncRNA and the key proteins involved in mycotoxin toxicity, should be performed. This Hypothesis provides clues for further understanding of the molecular mechanisms of mycotoxins., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

T-2 toxin and deoxynivalenol (DON) are type A and B trichothecenes, respectively. They widely occur as pollutants in food and crops and cause a series of toxicities, including immunotoxicity, hepatotoxicity, and neurotoxicity. Oxidative stress is the primary mechanistic basis of these toxic effects. Increasing amounts of evidence have shown that mitochondria are significant targets of apoptosis caused by T-2 toxin- and DON-induced oxidative stress via regulation of Bax/B-cell lymphoma-2 and caspase-3/caspase-9 signaling. DNA methylation and autophagy are involved in oxidative stress related to apoptosis, and hypoxia and immune evasion are related to oxidative stress in this context. Hypoxia induces oxidative stress by stimulating mitochondrial reactive oxygen species production and regulates the expression of cytokines, such as interleukin-1β and tumor necrosis factor-α. Programmed cell death-ligand 1 is upregulated by these cytokines and by hypoxia-inducible factor-1, which allows it to bind to programmed cell death-1 to enable escape of immune cell surveillance and achievement of immune evasion. This review concentrates on novel findings regarding the oxidative stress mechanisms of the trichothecenes T-2 toxin and DON. Importantly, we discuss the new evidence regarding the connection of hypoxia and immune evasion with oxidative stress in this context. Finally, the trinity of hypoxia, oxidative stress and immune evasion is highlighted. This work will be conducive to an improved understanding of the oxidative stress caused by trichothecene mycotoxins.

Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-β and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.

In plants, there is a complex and multilevel network of the antioxidative system (AOS) operating to counteract harmful reactive species (RS), the foremost important of which are reactive oxygen species (ROS), and maintain homeostasis within the cell. Specific AOSs for plant cells are, first and foremost, enzymes of the glutathione-ascorbate cycle (Asc-GSH), followed by phenolic compounds and lipophilic antioxidants like carotenoids and tocopherols. Evidence that plant cells have excellent antioxidative defense systems is their ability to survive at H 2 O 2 concentrations incompatible with animal cell life. For the survival of stressed plants, it is of particular importance that AOS cooperate and participate in redox reactions, therefore, providing better protection and regeneration of the active reduced forms. Considering that plants abound in antioxidant compounds, and humans are not predisposed to synthesize the majority of them, new fields of research have emerged. Antioxidant potential of plant compounds has been exploited for anti-aging formulations preparation, food fortification and preservation but also in designing new therapies for diseases with oxidative stress implicated in etiology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dumanović, Nepovimova, Natić, Kuča and Jaćević.)

In this paper, the potential antidote efficacy of commercially available formulations of various feed additives such as Minazel-Plus ® , Mycosorb ® , and Mycofix ® was considered by recording their incidence on general health, body weight, and food and water intake, as well as through histopathology and semiquantitative analysis of gastric alterations in Wistar rats treated with the T-2 toxin in a single-dose regimen of 1.67 mg/kg p.o. (1 LD 50 ) for 4 weeks. As an organic adsorbent, Mycosorb ® successfully antagonized acute lethal incidence of the T-2 toxin (protective index (PI) = 2.25; p < 0.05 vs. T-2 toxin), and had adverse effects on body weight gain as well as food and water intake during the research ( p < 0.001). However, the protective efficacy of the other two food additives was significantly lower ( p < 0.05). Treatment with Mycosorb ® significantly reduced the severity of gastric damage, which was not the case when the other two adsorbents were used. Our results suggest that Mycosorb ® is a much better adsorbent for preventing the adverse impact of the T-2 toxin as well as its toxic metabolites compared with Minazel-plus ® or Mycofix-plus ® , and it almost completely suppresses its acute toxic effects and cytotoxic potential on the gastric epithelial, glandular, and vascular endothelial cells.

Increasing evidence suggests that apoptosis of tubular cells and renal inflammation mainly determine the outcome of sepsis-associated acute kidney injury (AKI). The study aim was to investigate the molecular mechanism involved in the renoprotective effects of simvastatin in endotoxin (lipopolysaccharide, LSP)-induced AKI. A sepsis model was established by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment. The severity of the inflammatory injury was expressed as renal damage scores (RDS). Apoptosis of tubular cells was detected by Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL assay) (apoptotic DNA fragmentation, expressed as an apoptotic index, AI) and immunohistochemical staining for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL and survivin. We found that endotoxin induced severe renal inflammatory injury (RDS = 3.58 ± 0.50), whereas simvastatin dose-dependently prevented structural changes induced by LPS. Furthermore, simvastatin 40 mg/kg most profoundly attenuated tubular apoptosis, determined as a decrease of cytochrome C, caspase-3 expression, and AIs ( p   <  0.01 vs. LPS). Conversely, simvastatin induced a significant increase of Bcl-XL and survivin, both in the strong inverse correlations with cleaved caspase-3 and cytochrome C. Our study indicates that simvastatin has cytoprotective effects against LPS-induced tubular apoptosis, seemingly mediated by upregulation of cell-survival molecules, such as Bcl-XL and survivin, and inhibition of the mitochondrial cytochrome C and downstream caspase-3 activation.

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.

T-2 toxin, A trichothecenes mycotoxin, is immunotoxic to animals and humans. Although it is highly cardiotoxic, the pathogenesis of cardiomyopathy caused by T-2 toxin is not entirely clear. Hence, in our research, cardiomyopathy was induced by a single injection of T-2 mycotoxin (0.23 mg/kg s.c., 1 LD 50 ) to Wistar rats. The cardiac tissue was carefully examinated by using basic histopathology, semiquantitative (tissue grading score scales) and imaging (a total number of mast cells - MCs) analyses on days 1, 7, 14, 21, 28 and 60 of the study. The most intensive myocardial alterations (cardiac damage score, CDS = 4.20-4.40), irregular glycogen distribution (glycogen distribution score, GDS = 4.07-4.17), haemorrhagic foci (vascular damage score, VDS = 4.57-4.90), diffuse accumulation and degranulation of MCs were observed on day 28 and 60 after treatment (p < 0.001 vs. control and 1st T-2-toxin-treated group, respectively). Besides, statistically significant positive correlations were obtained regarding myocardial injury, glycogen distribution and intensity of haemorrhage, and a negative correlation was found in the case of MCs. Obtained results are essential and crucial for further in vivo experimental studies, including the development of medications able to reduce T-2 toxin-induced cardiotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Certain AChE reactivators, asoxime, obidoxime, K027, K048, and K075, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure the different organs. As a continuation of previously published data, in this study, Wistar rats have sacrificed 24 hrs and 7 days after single im application of 0.1LD 50 , 0.5LD 50 and 1.0LD 50 of each reactivator, and examinated tissue samples were obtained for pathohistological and semiquantitative analysis. A severity of tissue alteration, expressed as different tissue damage scores were evaluated. Morphological structure of examinated tissues treated with of 0.1LD 50 of all reactivators was comparable with the control group of rats. Moderate injuries were seen in visceral tissues treated with 0.5LD 50 of asoxime, obidoxime and K027. Acute damages were enlarged after treatment with 0.5LD 50 and 1.0LD 50 of all reactivators during the next 7 days. The most prominent changes were seen in rats treated with 1.0LD 50 of K048 and K075 (P < 0.001 vs. control and asoxime-treated group). All reactivators given by a single, high, unitary dose regimen, have an adverse effect not only on the main visceral tissue, but on the whole rat as well, but the exact mechanism of cellular injury remains to be confirmed in further investigation.

Our aim was to compare the protective efficacy of two different formulations of methylprednisolone in T-2 toxin-induced cardiomyopathy. Methylprednisolone (soluble form, Lemod-solu ® and/or depot form, Lemod-depo ® , a total single dose of 40 mg/kg im) was given immediately after T-2 toxin (1 LD 50 0.23 mg/kg sc). The myocardial tissue samples were examinated by using histopathology, semiquantitative and imaging analyses on day 1, 7, 14, 21, 28 and 60 of the study. Therapeutic application of Lemod-solu ® significantly decreased the intensity of myocardial degeneration and haemorrhages, distribution of glycogen granules in the endo- and perimysium, a total number of mast cells and the degree of their degranulation was in correlation with the reversible heart structural lesions (p <  0.01 vs. T-2 toxin). These changes were completely abolished by the therapeutic use of Lemod-solu ® plus Lemod-depo ® (p <  0.001 vs. T-2 toxin). Our results show that a significant cardioprotective efficacy of methylprednisolone is mediated by its anti-inflammatory activity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

K-oximes were developed as modern drug candidates acting as AChE reactivators. In this study, it has been investigated which interspecies and intergender differences changes could be observed in Wistar rats and Swiss mice, both genders, after the treatment with increasing doses of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, and K075. After the 24 h, a number of died animals was counted and the median lethal dose (LD 50 ) for each oxime was calculated. By using the intramuscular route of administration, asoxime and K027 had the least toxicity in female rats (640.21 mg/kg and 686.08 mg/kg), and in female mice (565.75 mg/kg and 565.74 mg/kg), respectively. Moreover, asoxime and K027 showed 3, 4 or 8 times less acute toxicity in comparison to K048, obidoxime and K075, respectively. Beyond, K075 had the greatest toxicity in male rats (81.53 mg/kg), and in male mice (57.34 mg/kg), respectively. Our results can help to predict likely adverse toxic effects, target organ systems and possible outcome in the event of massive human overexposure, and in establishing risk categories or in dose selection for the initial repeated dose toxicity tests to be conducted for each oxime., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Endotoxemia is associated by dysregulated apoptosis of immune and non-immune cells. We investigated whether simvastatin has anti-apoptotic effects, and induces hepatocytes and lymphocytes survival signaling in endotoxin-induced liver and spleen injuries. Wistar rats were divided into the groups pretreated with simvastatin (20 or 40 mg/kg, orally) prior to a non-lethal dose of lipopolysaccharide (LPS), the LPS group, and the control. The severity of tissue inflammatory injuries was expressed as hepatic damage scores (HDS) and spleen damage scores (SDS), respectively. The apoptotic cell was detected by TUNEL (Terminal deoxynucleotidyl transferase dUTP Nick End Labeling) and immunohistochemical staining (expression of cleaved caspase-3, and anti-apoptotic Bcl-xL, survivin and NF-κB/p65). Simvastatin dose-dependently abolished HDS and SDS induced by LPS ( p < 0.01), respectively. Simvastatin 40 mg/kg significantly decreased apoptotic index and caspase-3 cleavage in hepatocytes and lymphocytes ( p < 0.01 vs. LPS group, respectively), while Bcl-XL markedly increased accordingly with simvastatin doses. In the simvastatin, groups were determined markedly increased cytoplasmic expression of survivin associated with nuclear positivity of NF-κB, in both hepatocytes and lymphocytes ( p < 0.01 vs. LPS group). Cell-protective effects of simvastatin against LPS seemed to be mediated by up-regulation of survivin, which leads to reduced caspase-3 activation and inhibition of hepatocytes and lymphocytes apoptosis.

Therapeutic application of newly developed oximes is limited due to their adverse effects on different tissues. Within this article, it has been investigated which morphological changes could be observed in Wistar rats after the treatment with increasing doses of selected acetyl cholinesterase reactivators - asoxime, obidoxime, K027, K048, and K075. Subsequently, heart, diaphragm and musculus popliteus were obtained for pathohistological and semiquantitative analysis 24 hrs and 7 days after im administration of a single dose of 0.1 LD 50 , 0.5 LD 50 , and 1.0 LD 50 of each oxime. Different muscle damage score was based on an estimation scale from 0 (no damage) to 5 (strong damage). In rats treated with 0.1 LD 50 of each oxime, muscle fibres did not show any change. The intensive degeneration was found in all muscles after treatment with 0.5 LD 50 of asoxime and obidoxime, respectively. Acute toxic muscle injury was developed within 7 days following treatment with 0.5 LD 50 and 1.0 LD 50 of each oxime, with the highest values in K048 and K075 group (P < 0.001 vs. control and asoxime), respectively. The early muscle alterations observed in our study seem to contribute to the pathogenesis of the oxime-induced toxic muscle injury, which probably manifests as necrosis and/or inflammation.

This study is aimed to investigate whether simvastatin induces cardiomyocytes survival signaling in endotoxin (lipopolysaccharide, LSP)-induced myocardial injury, and if so, further to determine a role of survivin in simvastatin-anti-apoptotic effect. Wistar rats were pretreated with simvastatin (10-40 mg/kg po) before a single non-lethal dose of LPS. In myocardial tissue, LPS induced structural disorganization of myofibrils with significant inflammatory infiltrate (cardiac damage score, CDS = 3.87 ± 0.51, p < 0.05), whereas simvastatin dose-dependently abolished structural changes induced by LPS (p < 0.01). Simvastatin in 20 mg/kg and 40 mg/kg pretreatment, dose dependently, attenuated myocardial apoptosis determined as apoptotic index (28.8 ± 4.5% and 18.9 ± 3.5, p < 0.05), decreased cleaved caspase-3 expression (32.1 ± 5.8%, p < 0.01), along with significant Bcl-xL expression in the simvastatin groups (p < 0.01). Interestingly, in the simvastatin groups were determined significantly increased expression of survivin (p < 0.01), but in negative correlation with cleaved caspase-3 and apoptotic indices (p < 0.01). Simvastatin has a cardioprotective effects against LPS induced apoptosis. The effect may be mediated by up-regulation of survivin via activation of NF-κB, which leads to reduced activation of caspase-3 and consequent apoptosis of cardiomyocytes in experimental sepsis.

Background: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations., Research Design and Methods: The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC 0-72h , AUC 0-∝ , C max , T max , T 1/2 and K el ., Results: The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC 0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for C max , the 90% CI for this parameter for itraconazole was 93.49-133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15-138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events., Conclusions: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.

Amifostine is well known cytoprotector which is efficient when administered before a wide range of antineoplastic agents. The aim of our study was to investigate amifostine effects on doxorubicin-induced toxic changes in rats. Amifostine (75 mg/kg ip) was given 30 min before each dose of doxorubicin (cumulatively 20 mg/kg ip, for 28 days). The animals' whole-body, liver, and kidney weight, serum biochemical examination, as well as microscopic examination of bone marrow, peripheral blood, liver, and kidney, were done on day 56 of the study. Hepatic and renal alterations were carefully quantified by semiquantitative grading scales-hepatic and renal damage score, respectively. In amifostine-pretreated rats, the number of peripheral blood leukocytes was significantly higher in comparison to doxorubicin-only treated group, preferentially protecting neutrophils. In the same group of rats, hepatic and renal alterations associated with polymorphonuclear cell infiltrates were significantly less severe than those observed in animals receiving only doxorubicin. Our results showed that amifostine successfully protected rats against multiple-dose doxorubicin-induced toxicity by complex, and still not fully elucidated mechanisms of action.

Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17β-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC 50 values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Molecular docking studies were performed on 18 17β-carboxamide steroids in order to select compounds with potential local anti-inflammatory activity. These derivatives are amides of cortienic acids (obtained from hydrocortisone, prednisolone, and methylprednisolone) with methyl or ethyl esters of six amino acids. Interactions with the glucocorticoid receptor (GR), binding energies and ligand efficiency values of these compounds were compared with dexamethasone and cortienic acid obtained from prednisolone (inactive metabolite). On the basis of molecular docking studies, seven compounds were selected and their binding affinities for the GR were predicted by use of the exponential model created in this study. Subsequently, selected compounds were synthesized in good yields by use of modified N,N'-dicyclohexylcarbodiimide (DCC)/1-hydroxybenzotriazole (HOBt) coupling procedure. Finally, the local anti-inflammatory activity of the synthesized compounds was examined by use of the croton oil-induced ear edema test. In vivo evaluation of systemic side effects as well as in silico prediction of metabolism were performed on the derivative with the best local anti-inflammatory activity. The combination of molecular docking studies and the exponential model for the GR binding affinity prediction could be used as an in silico tool for the rational design of novel 17β-carboxamide steroids with potentially better biological profile than dexamethasone., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Endocrine-disrupting chemicals currently represent one of the major concerns and this study was aimed to investigate the effects of different doses of cadmium, widespread toxic metal, on the levels of thyroid hormones and to calculate Benchmark doses for these effects. Furthermore, the effects of co-exposure to cadmium and polychlorinated biphenyls on thyroid function were investigated. Six orally-treated groups of rats were receiving 0.3, 0.6, 1.25, 2.5, 5 and 10mgCd/kgb.w./day, five groups were orally treated with 0.5, 1, 2, 4 and 8mgPCBs/kgb.w./day, while nine groups of rats were orally-treated with different dose combinations of Cd and PCBs (0.6, 1.25 and 2.5mgCd/kgb.w. and 2, 4 and 8mgPCBs/kgb.w./day), during 28 days. Thyroid hormones were adversely affected by cadmium, with most prominent effect observed on triiodothyroxine levels indicating Cd interference with thyroid function at extrathyroidal level. Calculated Benchmark doses for Cd effects on thyroid hormones indicate triiodothyroxine as the most sensitive one that can be used as a basis for risk assessment. This study also implicates possible synergistic effects of Cd and PCBs on thyroid function as a consequence of their interference at different levels of thyroid homeostasis., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)