Animal models demonstrating skeletal muscle (SM) disorders are rarely investigated, although these disorders accompany liver disorders and can occur during prolonged exercise/training. In cases of SM ...disorders exogenous antioxidants, such as melatonin, could help by generally improving tissues antioxidant capacities. We aimed to analyze the potential of melatonin in preventing biochemical and structural changes in rat biceps muscle (BM) occurring after an acute exposure to carbon tetrachloride (CCl4). Biceps muscles obtained from male Wistar rats belonging to different experimental groups were biochemically (determination of tissue MDA, total antioxidant capacity, GSH, CAT, SOD and GPx activities) and pathologically analyzed. Also, serum levels of potassium, LHD and CK were analyzed in all experimental animals. The obtained results were statically compared with those from vehicle-treated control group. The applied melatonin prevented potassium and intracellular enzyme leakage (CK and LDH) that was induced by CCl4, as well as an increase in tissue MDA. From a panel of determined oxidative stress parameters melatonin was able to statistically significantly prevent changes in total antioxidative capacity and in CAT, SOD and GPx activities induced by CCl4. Microscopic analysis of BM from the animals exposed to CCl4 revealed significant muscle fiber disorganization and massive inflammatory cell infiltration. All these changes were significantly ameliorated in the group that received melatonin prior to CCl4. Changes in serum and tissue biochemical parameters accompanied the observed pathological changes, which demonstrated a significant influence of melatonin in preventing skeletal muscle damage induced by CCl4.
Non-ionizing radiation has a significant and positive impact on modern society through a number of uses. There is increasing public concern regarding the health risks of radio-frequency (RF) ...radiation, particularly that produced by mobile phones. Concern regarding the potential risks of exposure to EMFs has led to many epidemiological investigations, but the effects of EMF exposure on human and other mammalian cells are still unclear. One of the most frequently asked questions about the effects of microwave radiation on biological systems is whether they produce genotoxic effects and could be there a possible link with oncogenic processes. It is most difficult to get accurate and reproducible results for the studies that tell us most about the effects of EMF on humans. Based on some “weak” evidence suggesting an association between exposure to radiofrequency fields (RF) emitted from mobile phones and two types of brain cancer, glioma and acoustic neuroma, the International Agency for Research on Cancer has classified RF as ‘possibly carcinogenic to humans’ in group 2B. Literature results suggest that pulsed microwaves from working environment can be the cause of genetic and cell alterations. Taken together, the increased frequency of DNA damages, increased intensity of oxydative stress and production of reactive oxygen species as well as prolonged disruption in DNA repair mechanisms could be possible mechanisms for microwave induced cytogenetic damages even at low-level electromagnetic fields. Although there were contradictory results about harmful effects of electromagnetic fields we recommend that the mobile phone should be kept as far as possible from the body during conversations and also during usual daily activities to reduce the absorption of radiation by cells. In addition, the appropriate intake of antioxidant-rich food or drugs may be helpful for preventing the genotoxic effects that could be caused by mobile phone use.
•QSAR models for inhibitors of both JNK3 and p38α MAPK were developed.•Different methods were used for QSAR modeling, with high inter-correlation.•Different methods were applied for QSAR models ...predictability determination.•Molecular fragments with influence on inhibitory action were determined.•Drug design is presented and the validation of their therapeutic potential.
This research paper employs different types of QSAR modeling for the molecules that act as dual inhibitors of JNK3 and p38α MAPK. The SMILES notation and the local molecular graph invariants served as descriptors for QSAR model building, while the Monte Carlo optimization method was assigned the purpose of a model developer. GA-MLR was utilized to obtain a QSAR model from the pool of vast 2D molecule descriptors. To assess the developed models’ quality, robustness, and predictability, several statistical methods were employed, and these yielded favorable results. The molecular fragments which were responsible for the increase/decrease of the examined activity were identified and used for the computer-aided design of new compounds. Molecular docking studies were utilized for the final assessment of the designed inhibitors, highlighting an exceptional correlation with the QSAR modeling results. ADME parameters, pharmacokinetic properties, the drug-like nature, and medicinal chemistry friendliness were predicted by computing physicochemical descriptors to support drug discovery. Based on the obtained results, all the designed molecules possess high drug-likeness.
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Due to high relative blood flow the kidney is prone to drug-induced damage. Aminoglycoside type antibiotic gentamicin is one of the leading cause of drug-induced nephrotoxicity. In recent years ...gentamicin nephrotoxicity is significantly reduced by shifting to once daily dosage as well as by eliminating known risk factors. Application of gentamicin is still related to serious side effects which are reported more often compared to other antibiotics. Because gentamicin is still heavily used and is highly efficient in treating infections, it is important to find mechanisms to reduce its nephrotoxicity. This aim can only be achieved through better understanding of kidney metabolism of gentamicin. This problem has been extensively researched in the last 20 years. The experimental results have provided evidence for almost complete understanding of mechanisms responsible for gentamicin nephrotoxicity. We now have well described morphological, biochemical and functional changes in kidney due to gentamicin application. During the years, this model has become so popular that now it is used as an experimental model for nephrotoxicity per se. This situation can mislead an ordinary reader of scientific literature that we know everything about it and there is nothing new to discover here. But quite opposite is true. The precise and complete mechanism of gentamicin nephrotoxicity is still point of speculation and an unfinished story. With emerge of new and versatile technics in biomedicine we have an opportunity to reexamine old beliefs and discover new facts. This review focuses on current knowledge in this area and gives some future perspectives.
The aim of this research was to examine the relationship between inflammatory parameters and markers of cholestasis in patients with choledocholithiasis. All subjects underwent clinical, laboratory ...and ultrasound examination at the Department of Internal Medicine, Military Hospital Niš, Serbia. Inflammatory parameters and biochemical markers of cholestasis were measured by standard biochemical methods. Most of cholestasis markers showed no significant correlation with inflammatory parameters in blood, except for a weak significant correlation between the number of monocytes with the activity of aspartate aminotransferase (AST) (r=0.37, p<0.05). Hyperbilirubinemia was significantly correlated with the fibrinogen values (r=0.42, p<0.05), while albumin positive values were positively associated with alanine aminotransferase (ALT) activity (r=0.5, p<0.05), and negatively with the alkaline phosphatase (AP) (r=-0.43, p<0.05). In patients with choledocholithiasis, there was a positive correlation between the number of monocytes and the activities of AST, hyperbilirubinemia, and fibrinogen, albumin and ALT, while a negative correlation between albumin and AP was present.
The Monte Carlo method was used for QSAR modelling 2,4-dihydro-3
H
-1,2,4-triazol-3-ones derivatives as angiotensin II AT
1
receptor antagonists. QSAR models were calculated with the representation ...of the molecular structure by the simplified molecular input-line entry system (SMILES) and with optimal molecular descriptors based on the SMILES notation and local graph invariants. One random split into the training and the test set was used. The statistical quality of the developed model was good. The best calculated QSAR model had the following statistical parameters:
r
2
= 0.8701 for the training set and
r
2
= 0.8430 for the test set. Novel statistical metric entitled as the index of ideality of correlation was used for final model assessment, and the obtained results were good. Structural indicators defined as molecular fragments responsible for increases and decreases of the studied activity were calculated. The computer-aided design of new compounds as potential angiotensin II AT
1
receptor antagonists with the application of defined structural alerts was presented.
Sepsis is a life-threatening organ dysfunction. An animal model mimicking sepsis utilizes lipopolysaccharide (LPS), an endotoxin recognized as the most potent bacterial mediator of sepsis. Melatonin ...(MLT), an effective anti-inflammatory and antioxidant agent, is a promising adjunctive drug for sepsis. This study aimed to estimate the potential of MLT in preventing LPS-induced liver damage in Wistar rats by determining the levels of serum and tissue biochemical markers that reflect liver state and function, i.e., serum levels of transaminases and albumin, as well as a panel of oxidative stress-related biomarkers. Additionally, a pathohistological analysis of liver tissue was conducted. Pre-treatment with MLT prevented an LPS-induced increase in serum and tissue liver damage markers and a decrease in the tissue antioxidant capacity, in both enzymatic and non-enzymatic systems. Micromorphological liver tissue changes mirrored the alterations observed in the biochemical status. In rats with LPS-induced sepsis, melatonin was shown to be a crucial antioxidant and anti-inflammatory agent, with vital roles in the alleviation of oxidative stress, causing an increase of the antioxidant capacities and the improvement of the liver's microscopic appearance.
•Lipopolysaccharide induced liver oxidative and glutathione disbalance.•Lipopolysaccharide increased apoptosis and Nrf-2 concentration.•Melatonin ameliorated lipopolysaccharide caused oxidative damage.•Melatonin prevented lipopolysaccharide induced increase in liver DNAase activity.
Long-term exposure to amiodarone, an antiarrhythmic drug, can induce different organ damage, including liver. Cell damage included by amiodarone is a consequence of mitochondrial damage, reactive ...oxygen species production, and cell energy depletion leading to programmed cell death. In the present study, hepatoprotective potential of neurohormone melatonin (50 mg/kg/day) was evaluated in a chronic experimental model of liver damage induced by a 4-week application of amiodarone (70 mg/kg/day). The obtained results indicate that amiodarone induces an increase in xanthine oxidase activity, as well as the content of the lipid and protein oxidatively modified products and p53 levels. Microscopic analysis further corroborated the biochemical findings revealing hepatocyte degeneration, apoptosis, and occasional necrosis, with the activation of Kupffer cells. Coadministration of melatonin and amiodaron prevented an increase in certain damage associated parameters, due to its multiple targets. In conclusion, the application of melatonin together with amiodarone prevented an increase in tissue oxidative damage parameters and moderately prevented liver cell apoptosis, indicating that the damage of hepatocytes provoked by amiodarone supersedes the protective properties of melatonin in a given dose.
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•QSAR models for GABA A inhibitory action were developed.•Monte Carlo method with SMILES notation and molecular graph descriptors was used.•Different methods were applied for the ...determination of the robustness of the model.•Molecular fragments with influence on inhibitory action were determined.•Presented study can be useful in the search for novel anesthetics.
The inhibition of GABAA can be used in general anesthesia. Although, barbiturates and thiobarbiturates are used in anesthesia, the mechanism of their action hasn’t been established. QSAR modeling is a wieldy used technique in these cases and this study presents the QSAR modeling for a group of barbiturates and thiobarbiturates with determined anesthetic activity. Developed QSAR models were based on conformation independent and 2D descriptors as well as field contribution. As descriptors used for developing conformation independent QSAR models, (SMILES) notation and local invariants of the molecular graph were used. Monte Carlo optimization method was applied for building QSAR models for two defined activities. Methodology for developing QSAR models capable of dealing with the small dataset that integrates dataset curation, “exhaustive” double cross-validation and a set of optimal model selection techniques including consensus predictions was used. Two-dimensional descriptors with definite physicochemical meaning were used and modeling was done with the application of both partial least squares and multiple linear regression models with three latent variables related to simple and interpretable 2D descriptors. Different statistical methods, including novel method - the index of ideality of correlation, were used to test the quality of the developed models, especially robustness and predictability and all obtained results were good. In this study, obtained results indicate that there is a very good correlation between all developed models. Molecular fragments that account for the increase/decrease of a studied activity were defined and further used for the computer-aided design of new compounds as potential anesthetics.
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