Preliminary Report on the Influence of Acute Inflammation on Adiponectin Levels in Older Inpatients with Different Nutritional Status.

Inflammation can be triggered by a variety of factors, including pathogens, damaged cells, and toxic compounds. It is a biological response of the immune system, which can be successfully assessed in clinical practice using some molecular substances. Because adiponectin, a hormone released by adipose tissue, influences the development of inflammation, its evaluation as a potential measure of inflammation in clinical practice is justified. In the present contribution, statistical comparison of adiponectin concentration and selected molecular substances recognized in clinical practice as measures of inflammation were utilized to demonstrate whether adipose tissue hormones, as exemplified by adiponectin, have the potential to act as a measure of rapidly changing inflammation when monitoring older hospitalized patients in the course of bacterial infection. The study showed no statistically significant differences in adiponectin levels depending on the rapidly changing inflammatory response in its early stage. Interestingly, the concentration of adiponectin is statistically significantly higher in malnourished patients than in people with normal nutritional levels, assessed based on the MNA. According to the results obtained, adiponectin is not an effective measure of acute inflammation in clinical practice. However, it may serve as a biomarker of malnutrition in senile individuals.

Novel Thiourea and Oxime Ether Isosteviol-Based Anticoagulants: MD Simulation and ADMET Prediction.

Activated blood coagulation factor X (FXa) plays a critical initiation step of the blood-coagulation pathway and is considered a desirable target for anticoagulant drug development. It is reversibly inhibited by nonvitamin K antagonist oral anticoagulants (NOACs) such as apixaban, betrixaban, edoxaban, and rivaroxaban. Thrombosis is extremely common and is one of the leading causes of death in developed countries. In previous studies, novel thiourea and oxime ether isosteviol derivatives as FXa inhibitors were designed through a combination of QSAR studies and molecular docking. In the present contribution, molecular dynamics (MD) simulations were performed for 100 ns to assess binding structures previously predicted by docking and furnish additional information. Moreover, three thiourea- and six oxime ether-designed isosteviol analogs were then examined for their drug-like and ADMET properties. MD simulations demonstrated that four out of the nine investigated isosteviol derivatives, i.e., one thiourea and three oxime ether ISV analogs, form stable complexes with FXa. These derivatives interact with FXa in a manner similar to Food and Drug Administration (FDA)-approved drugs like edoxaban and betrixaban, indicating their potential to inhibit factor Xa activity. One of these derivatives, E24, displays favorable pharmacokinetic properties, positioning it as the most promising drug candidate. This, along with the other three derivatives, can undergo further chemical synthesis and bioassessment.

Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation.

Direct oral anticoagulants are an important and relatively new class of synthetic anticoagulant drugs commonly used for the pharmacotherapy of thromboembolic disorders. However, they still have some limitations and serious side effects, which continuously encourage medicinal chemists to search for new active compounds acting as human-activated coagulation factor X (FXa) inhibitors. Isosteviol is a nontoxic hydrolysis product of naturally occurring stevioside and possesses a wide range of therapeutic properties, including anticoagulant activity. The present contribution describes the in silico design of novel oxime ether isosteviol derivatives as well as a molecular modeling approach based on QSAR analysis and a docking simulation for searching for novel isosteviol-based compounds as potential FXa inhibitors. The elaborated ANN model, encompassing topological and geometrical information, exhibited a significant correlation with FXa-inhibitory activity. Moreover, the docking simulation indicated six of the most promising isosteviol-like compounds for further investigation. Analysis showed that the most promising derivatives contain heterocyclic, aromatic, five-membered moieties, with substituents containing chlorine or fluorine atoms. It is anticipated that the findings reported in the present work may provide useful information for designing effective FXa inhibitors as anticoagulant agents.

Predicting Antitumor Activity of Anthrapyrazole Derivatives using Advanced Machine Learning Techniques.

BACKGROUND: Anthrapyrazoles are a new class of antitumor agents and successors to anthracyclines possessing a broad range of antitumor activity in various model tumors. OBJECTIVE: The present study introduces novel QSAR models for the prediction of antitumor activity of anthrapyrazole analogues. METHODS: The predictive performance of four machine learning algorithms, namely artificial neural networks, boosted trees, multivariate adaptive regression splines, and random forest, was studied in terms of variation of the observed and predicted data, internal validation, predictability, precision, and accuracy. RESULTS: ANN and boosted trees algorithms met the validation criteria. It means that these procedures may be able to forecast the anticancer effects of the anthrapyrazoles studied. Evaluation of validation metrics, calculated for each approach, indicated the artificial neural network (ANN) procedure as the algorithm of choice, especially with regard to the obtained predictability as well as the lowest value of mean absolute error. The designed multilayer perceptron (MLP)-15-7-1 network displayed a high correlation between the predicted and the experimental pIC50 value for the training, test, and validation set. A conducted sensitivity analysis enabled an indication of the most important structural features of the studied activity. CONCLUSION: The ANN strategy combines topographical and topological information and can be used for the design and development of novel anthrapyrazole analogues as anticancer molecules.

Evaluation of Selected Parameters of Oxidative Stress and Adipokine Levels in Hospitalized Older Patients with Diverse Nutritional Status.

Malnutrition is classified as one of the Giant Geriatric Syndromes. It carries serious consequences, such as sarcopenia or depression, which lead to functional disability. The main objective of this study was to identify parameters of oxidative stress and adipokines, which may be potential biomarkers of malnutrition in hospitalized older patients. During the study, selected parameters were determined in 137 senile patients, taking into account their nutritional status determined according to the Mini Nutritional Assessment (MNA), as well as an additional tool, namely the Geriatric Nutritional Risk Index (GNRI). Leptin and resistin were determined as the parameters with statistically significant differences between the patients classified according to the MNA. This phenomenon was confirmed using the GNRI classification. However, additional parameters for which differences were observed include the oxidized low-density lipoprotein level and activity of glutathione peroxidase. In conclusion, the determination of the mentioned markers in hospitalized senile patients as an adjunct to the routine assessment of nutritional status might be suggested to identify the early risk of malnutrition so that a personalized nutritional therapy can be implemented as early as possible.

Amino Acid Levels as Potential Biomarkers of Multiple Sclerosis in Elderly Patients: Preliminary Report.

BACKGROUND AND PURPOSE: Aging in multiple sclerosis is associated with both disease- and age-dependent neurodegeneration. Serum metabolomic profiling of amino acids seems to be a promising method for searching for biomarkers of neurodegenerative disorders. The aim of this study was to determine the profile of nonessential amino acids in the serum of elderly patients with secondary progressive multiple sclerosis (SPMS). METHODS: We used high-performance liquid chromatography to evaluate the serum concentrations of nonessential amino acids in subjects aged >65 years: six patients with SPMS and 20 control subjects (CS). RESULTS: The serine and alanine levels were significantly higher in SPMS patients than in CS, whereas the concentrations of aspartic acid, arginine, and cysteine were significantly lower in SPMS patients. These observations indicate that amino acids may be involved in SPMS neurodegeneration mechanisms. There were no significant differences in the serum concentrations of the other four amino acids investigated (glutamic acid, glycine, proline, and tyrosine) between patients with SPMS and CS. CONCLUSIONS: The preliminary results obtained in the study suggest that the metabolism of some amino acids is altered in patient with SPMS. We also conclude that amino acid profiling might be helpful in searching for putative biomarkers of central nervous system diseases. However, considering the multifactorial, heterogeneous, and complex nature of SPMS, further validation research involving larger study samples is required before applying these biomarkers in diagnostic practice.

Quantitative Structure-Activity Relationship Analysis of Isosteviol-Related Compounds as Activated Coagulation Factor X (FXa) Inhibitors.

Stevioside, one of the natural sweeteners extracted from stevia leaves, and its derivatives are considered to have numerous beneficial pharmacological properties, including the inhibition of activated coagulation factor X (FXa). FXa-PAR signaling is a possible therapeutic target to enhance impaired metabolism and insulin resistance in obesity. Thus, the goal of the investigation was a QSAR analysis using multivariate adaptive regression splines (MARSplines) applied to a data set of 20 isosteviol derivatives bearing thiourea fragments with possible FXa inhibitory action. The best MARS submodel described a strong correlation between FXa inhibitory activity and molecular descriptors, such as: B01[C-Cl], E2m, L3v, Mor06i, RDF070i and HATS7s. Five out of six descriptors included in the model are geometrical descriptors quantifying three-dimensional aspects of molecular structure, which indicates that the molecular three-dimensional conformation is of high significance for the MARSplines modeling procedure and obviously for FXa inhibitory activity. High model performance was confirmed through an extensive validation protocol. The results of the study not only confirmed the enhancement in pharmacological activity by the presence of chlorine in a phenyl ring, but also, and primarily, may provide the basis for searching for new active isosteviol analogues, which may serve as drugs or health-beneficial food additives in patients suffering from obesity and comorbidities.

Application of Multivariate Adaptive Regression Splines (MARSplines) for Predicting Antitumor Activity of Anthrapyrazole Derivatives.

An approach using multivariate adaptive regression splines (MARSplines) was applied for quantitative structure-activity relationship studies of the antitumor activity of anthrapyrazoles. At the first stage, the structures of anthrapyrazole derivatives were subjected to geometrical optimization by the AM1 method using the Polak-Ribiere algorithm. In the next step, a data set of 73 compounds was coded over 2500 calculated molecular descriptors. It was shown that fourteen independent variables appearing in the statistically significant MARS model (i.e., descriptors belonging to 3D-MoRSE, 2D autocorrelations, GETAWAY, burden eigenvalues and RDF descriptors), significantly affect the antitumor activity of anthrapyrazole compounds. The study confirmed the benefit of using a modern machine learning algorithm, since the high predictive power of the obtained model had proven to be useful for the prediction of antitumor activity against murine leukemia L1210. It could certainly be considered as a tool for predicting activity against other cancer cell lines.

Amino acids levels as a potential biomarker in myasthenia gravis.

The search for new diagnostic and therapeutic approaches for myasthenia gravis (MG) is highly desirable. Therefore, the aim of the present study is to assess the profile of non-essential amino acids in the serum of MG patients. We evaluated the serum levels of non-essential amino acids in MG patients (n = 10) and control subjects (CS, n = 10) using high-performance liquid chromatography (HPLC) method and assuming a two-fold concentration difference between the groups as significant. Serum levels of aspartic acid and glutamic acid in MG patients were significantly higher than in CS. There were no significant differences in mean serum levels of glycine, proline, alanine, serine, cysteine, arginine and tyrosine between MG patients and CS. The results indicate the need for further research to assess the role of non-essential amino acids in MG. Moreover, our preliminary results suggest that the metabolism of some amino acids seems to be changed in patients with MG. Therefore, we conclude that amino acids profiling might be helpful in searching for putative biomarkers of the central nervous system diseases such as myasthenia gravis.

Cardiovascular Effects of Chocolate and Wine-Narrative Review.

The consumption of food for pleasure is mainly associated with adverse health effects. This review was carried out to verify recent reports on the impact of chocolate and wine consumption on cardiovascular health, with a particular focus on atherosclerosis. On one side, these products have proven adverse effects on the cardiovascular system, but on the other hand, if consumed in optimal amounts, they have cardiovascular benefits. The submitted data suggest that the beneficial doses are 30-50 g and 130/250 mL for chocolate and wine, respectively, for women and men. The accumulated evidence indicates that the active ingredients in the products under consideration in this review are phenolic compounds, characterized by anti-inflammatory, antioxidant, and antiplatelet properties. However, there are also some reports of cardioprotective properties of other compounds such as esters, amines, biogenic amines, amino acids, fatty acids, mineral ingredients, and vitamins. Our narrative review has shown that in meta-analyses of intervention studies, consumption of chocolate and wine was positively associated with the beneficial outcomes associated with the cardiovascular system. In contrast, the assessment with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) scale did not confirm this phenomenon. In addition, mechanisms of action of bioactive compounds present in chocolate and wine depend on some factors, such as age, sex, body weight, and the presence of additional medical conditions. Patients using cardiovascular drugs simultaneously with both products should be alert to the risk of pharmacologically relevant interactions during their use. Our narrative review leads to the conclusion that there is abundant evidence to prove the beneficial impact of consuming both products on cardiovascular health, however some evidence still remains controversial. Many authors of studies included in this review postulated that well-designed, longitudinal studies should be performed to determine the effects of these products and their components on atherosclerosis and other CVD (Cardiovascular Disease) disease.

Recent Applications of Capillary Electrophoresis in the Determination of Active Compounds in Medicinal Plants and Pharmaceutical Formulations.

The present review summarizes scientific reports from between 2010 and 2019 on the use of capillary electrophoresis to quantify active constituents (i.e., phenolic compounds, coumarins, protoberberines, curcuminoids, iridoid glycosides, alkaloids, triterpene acids) in medicinal plants and herbal formulations. The present literature review is founded on PRISMA guidelines and selection criteria were formulated on the basis of PICOS (Population, Intervention, Comparison, Outcome, Study type). The scrutiny reveals capillary electrophoresis with ultraviolet detection as the most frequently used capillary electromigration technique for the selective separation and quantification of bioactive compounds. For the purpose of improvement of resolution and sensitivity, other detection methods are used (including mass spectrometry), modifiers to the background electrolyte are introduced and different extraction as well as pre-concentration techniques are employed. In conclusion, capillary electrophoresis is a powerful tool and for given applications it is comparable to high performance liquid chromatography. Short time of execution, high efficiency, versatility in separation modes and low consumption of solvents and sample make capillary electrophoresis an attractive and eco-friendly alternative to more expensive methods for the quality control of drugs or raw plant material without any relevant decrease in sensitivity.

Application of Capillary Electrophoresis to the Analysis of Bioactive Compounds in Herbal Raw Materials.

The article is a summary of scientific reports from the last 16 years (2005-2021) on the use of capillary electrophoresis to analyze polyphenolic compounds, coumarins, amino acids, and alkaloids in teas or different parts of plants used to prepare aqueous infusions, commonly known as "tea" or decoctions. This literature review is based on PRISMA guidelines and articles selected in base of criteria carried out using PICOS (Population, Intervention, Comparison, Outcome, Study type). The analysis showed that over 60% of articles included in this manuscript comes from China. The literature review shows that for the selective electrophoretic separation of polyphenolic and flavonoid compounds, the most frequently used capillary electromigration technique is capillary electrophoresis with ultraviolet detection. Nevertheless, the use of capillary electrophoresis-mass spectrometry allows for the sensitive determination of analytes with a lower limit of detection and gives hope for routine use in the analysis of functional foods. Moreover, using the modifications in electrochemical techniques allows methods sensitivity reduction along with the reduction of analysis time.

Serum amino acid profiles in patients with mild cognitive impairment and in patients with mild dementia or moderate dementia.

Neurodegenerative disorders are one of the greatest global challenges for social and health care in the twenty-first century. Nowadays, determination of cerebrospinal fluid biomarkers for early diagnosis is served by a complex sample preparation procedure with limited diagnostic accuracy. Furthermore, neuroimaging methods are expensive, time-consuming and are not readily available for use as a complimentary and common screening method. Recently, researchers have shown an increased interest in the identification and characterization of new blood biomarkers of dementia to minimize the limitations associated with the current methods of biomarker determination. Amino acids play many important roles in the central nervous system, acting as neuromodulators, neurotransmitters and regulators of energy metabolism. The aim of this study was to evaluate if serum amino acid levels change along the continuum from no cognitive impairment to moderate dementia, and to identify putative biomarkers for early diagnosis of neurodegenerative diseases. Serum levels of 16 amino acids were determined in 3 groups of patients-22 with mild cognitive impairment, 45 with mild dementia and 28 with moderate dementia-by high-performance liquid chromatography (HPLC) with fluorescence detection using AccQ Tag column (Waters). The most exciting result is the significantly elevated concentration of arginine in patients with both stages of dementia as compared to mild cognitive impairment individuals. Recent accumulating evidence suggests the implication of changed arginine metabolism in the pathogenesis of neurodegenerative diseases. We conclude that amino acids profiling might be helpful in searching for biomarkers of neurogenerative diseases. In the present study, we discovered that arginine in plasma may have a putative diagnostic value for dementia.

Amino Acid Levels as Potential Biomarker of Elderly Patients with Dementia.

Dementia is a clinical syndrome characterized by cognitive impairment, in which there is disturbance of multiple higher cortical functions. The primary risk factor of dementia is old age, and due to significant changes in the worldwide demographic structure, the prevalence of cognitive impairment is increasing dramatically with aging populations in most countries. Alzheimer's disease is the predominant and leading cause of dementia. The aim of this study was to evaluate the modifications of amino acids that characterize the initial stages of dementia to help our understanding of the complex and multifactorial pathogenesis of neurodegenerative disorders. A total of 123 participants were divided into two groups: healthy elderly subjects and patients with mild or moderate dementia. The results of this study indicate that the serum levels of three amino acids were changed significantly in patients with dementia, in relation to the subjects without dementia. In particular, we observed differences in concentrations for serine, arginine and isoleucine (all of them were significantly increased in patients with dementia, compared with the control group). Our results suggest that the metabolisms of some amino acids seem be changed in patients with dementia. We conclude that amino acid profiling might be helpful for the better understanding of biochemical and metabolic changes related to the pathogenesis and progression of dementia. However, considering the multifactorial, heterogenous and complex nature of this disease, validation with a greater study sample in further research is required.

Comparison of Pteridine Normalization Methods in Urine for Detection of Bladder Cancer.

Pterin compounds belong to the group of biomarkers for which an increase in interest has been observed in recent years. Available literature data point to this group of compounds as potential biomarkers for cancer detection, although the biochemical justification for this claim is not yet fully understood. The aim of this study was to evaluate the usefulness of pterin compounds in the diagnosis of bladder cancer, with particular emphasis on the role of creatinine and the specific gravity of urine as factors for normalizing the concentration of pterin compounds in urine. The standardization of the concentration of pterin compounds to urine specific gravity allows the building of better classification models for screening patients with potential cancer of the bladder. Of the compounds that make up the pterin profile, isoxanthopterin appears to be a compound that can potentially be described as a biomarker of bladder cancer.

Comparison of high-performance thin layer chromatography/UV-densitometry and UV-derivative spectrophotometry for the determination of trimetazidine in pharmaceutical formulations.

New methods for assaying trimetazidine dihydrochloride on the basis of thin layer chromatography and spectrophotometry are proposed and compared in the paper. In HPTLC/UV-densitometry, separation is achieved by using a mobile phase composed of ammonia-methanol (30:70, V/V) on silica gel HPTLC plates F254. Quantification using a non-linear calibration curve is accomplished by densito-metric detection at 230 nm. Derivative spectrophotometric determination of trimetazidine dihydrochloride is carried out from the fourth derivative of the absorbance at 233 nm in peak-zero mode. Statistical comparison led to the conclusion that there is no significant difference between the two studied methods and, moreover, that they demonstrate satisfactory accuracy and precision for routine applications.

Chemometric Analysis for the Classification of some Groups of Drugs with Divergent Pharmacological Activity on the Basis of some Chromatographic and Molecular Modeling Parameters.

AIM AND OBJECTIVE: In this study, chemometric methods as correlation analysis, cluster analysis (CA), principal component analysis (PCA), and factor analysis (FA) have been used to reduce the number of chromatographic parameters (logk/logkw) and various (e.g., 0D, 1D, 2D, 3D) structural descriptors for three different groups of drugs, such as 12 analgesic drugs, 11 cardiovascular drugs and 36 "other" compounds and especially to choose the most important data of them. MATERIAL AND METHODS: All chemometric analyses have been carried out, graphically presented and also discussed for each group of drugs. At first, compounds' structural and chromatographic parameters were correlated. The best results of correlation analysis were as follows: correlation coefficients like R = 0.93, R = 0.88, R = 0.91 for cardiac medications, analgesic drugs, and 36 "other" compounds, respectively. Next, part of molecular and HPLC experimental data from each group of drugs were submitted to FA/PCA and CA techniques. RESULTS: Almost all results obtained by FA or PCA, and total data variance, from all analyzed parameters (experimental and calculated) were explained by first two/three factors: 84.28%, 76.38 %, 69.71% for cardiovascular drugs, for analgesic drugs and for 36 "other" compounds, respectively. Compounds clustering by CA method had similar characteristic as those obtained by FA/PCA. In our paper, statistical classification of mentioned drugs performed has been widely characterized and discussed in case of their molecular structure and pharmacological activity. CONCLUSION: Proposed QSAR strategy of reduced number of parameters could be useful starting point for further statistical analysis as well as support for designing new drugs and predicting their possible activity.

Melatonin Supplementation Lowers Oxidative Stress and Regulates Adipokines in Obese Patients on a Calorie-Restricted Diet.

Obesity is one of the major global health problems. Melatonin deficiency has been demonstrated to correlate with obesity. The aim of the study was to estimate the effect of melatonin on oxidative stress and adipokine levels in obese patients on a calorie-restricted diet. Thirty obese patients were supplemented with a daily dose of 10 mg of melatonin (n = 15) or placebo (n = 15) for 30 days with a calorie-restricted diet. Serum levels of melatonin, 4-hydroxynonenal (HNE), adiponectin, omentin-1, leptin, and resistin, as well as erythrocytic malondialdehyde (MDA) concentration and Zn/Cu-superoxide dismutase, catalase, and glutathione peroxidase (GPx) activities, were measured at baseline and after supplementation. Significant body weight reduction was observed only in the melatonin group. After melatonin supplementation, the adiponectin and omentin-1 levels and GPx activities statistically increased, whereas the MDA concentrations were reduced. In the placebo group, a significant rise in the HNE and a drop in the melatonin concentrations were found. The results show evidence of increased oxidative stress accompanying calorie restriction. Melatonin supplementation facilitated body weight reduction, improved the antioxidant defense, and regulated adipokine secretion. The findings strongly suggest that melatonin should be considered in obesity management. This trial is registered with CTRI/2017/07/009093.