Biological evaluation, molecular docking, and sar studies of novel 2-(2,4-dihydroxyphenyl)- 1H- benzimidazole analogues

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman’s spectrophotometric method was applied for the biological evaluation. The compounds showed strong $IC_{50}$ 5-0.2 $\mu$ M AChE and moderate ($IC_{50}$ 5-0.2 M) BuChE inhibition in vitro. Some compounds were e ective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure–activity relationships were discussed. The compounds inhibited also in vitro self-induced A$\beta$ (1-42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine

Selected matrix metalloproteinases activity and hypertension-mediated organ damage in relation to uric acid serum level

Background: Atherosclerosis is as a systemic inflammatory disease associated with the activation of many mediators, including matrix metalloproteinases (MMPs), and may be amplified by abnormal high serum uric acid (UA) concentration (hyperuricemia, HU). The aim of the study was to determine the relationship between serum UA concentration and activity of MMPs and their correlation with the hypertension-mediated organ damage (HMOD) intensity. Methods: 109 patients untreated with antihypertensive, hypolipemic or urate-lowering drugs with diagnosed stage 1–2 essential hypertension were included in this study. In all participants blood pressure (BP) was measured, carotid-femoral pulse wave velocity (PWV), intima–media thickness (IMT),  echocardiography and blood tests including UA, lipids and serum concentrations of MMPs (1, 2, 3, 9) were observed. The participants were divided into hyper- and normuricemic groups. Results: Uric acid concentration in the whole study group positively correlated with some HMOD parameters (IMT, PWV, left ventricular mass index, left atrial dimension). Among the studied metalloproteinases only MMP-3 activity positively correlated with serum UA concentration independently of age, body mass index and serum lipids (R2 = 0.11, p = 0.048). Multivariate regression analysis showed positive association between IMT and BP, UA concentration and MMP-3 activity, independently of waist circumference and serum lipids (R2 = 0.328, p < 0.002). Patients with HU were characterized by higher activity of MMP-3 than those without (19.41 [14.45; 21.74] vs. 13.98 [9.52; 18.97] ng/mL, p = 0.016). Conclusions: The present results may support the thesis that UA and the increased by UA activity of MMPs may take part in the development of HMOD, especially IMT

New hybrids of tacrine and indomethacin as multifunctional acetylcholinesterase inhibitors

A new series of hybrid compounds were designed, consisting of anti-AChE and BuChE activity components with an antiinfammatory component. A series of 9-amino-1,2,3,4-tetrahydroacridine and indomethacin derivatives were synthesized. All compounds were created using alkyldiamine with diferent chain lengths as a linker. Various biological activities were evaluated, including inhibitory activity against AChE and BuChE. The tested compounds showed high inhibitory activities against cholinesterases. The IC50 values for all compounds ranging from 10 nM to 7 µM. The potency of inhibition was much higher than well-known AChE and BuChE inhibitors (tacrine and donepezil). Compound 3h had the strongest inhibitory activity; kinetic studies showed it to have a mixed-type of acetylcholinesterase inhibition properties. The cytotoxicity of the newly-synthesized compounds against HepG2 (hepatocarcinoma cells) and EA.hy96 (human vein endothelial cells) cell lines was determined using the MTT and MTS tests. All investigated compounds presented similar cytotoxic activity against HepG2 and EA.hy926 cell line, ranged in micromolar values. Compounds with longer linkers showed higher antioxidant activity. The most active compound was 3h. Docking studies confrmed interactions with important regions of AChE and BuChE. Its multifunctional properties, i.e. high activity against AChE and BuChE, antioxidant activity and low cytotoxicity, highlight 3h as a promising agent for the treatment of AD

New tetrahydroacridine hybrids with dichlorobenzoic acid moiety demonstrating multifunctional potential for the treatment of Alzheimers disease

A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, and 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition with IC50 values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC50 = 24 nM). Additionally, 3c (IC50 for EeAChE = 25 nM and IC50 for EqBuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver-Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H)

Novel inflammatory biomarkers may reflect subclinical inflammation in young healthy adults with obesity

Introduction: Obesity is often accompanied by low-grade inflammation. In recent years a few blood-based inflammatory markers — neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), lymphocyteto-monocyte ratio (LMR), and monocyte-to-high-density lipoprotein ratio (MHR) — have been identified. They have been proven to correlate well with established inflammatory markers such as hsCRP and have a prognostic value among others in patients with coronary artery disease, heart failure, and malignancies. The aim of the study was to find markers associated with obesity in young heathy adults. Material and methods: The study group included 321 young healthy adults aged 18-35 years (210 males and 111 females). Partial least squares regression analysis was used to find variables associated with body mass index (BMI). Analysed variables included complete blood count, lipid profile, sex hormone levels, acute-phase protein levels, and blood-based inflammatory markers. Results: Variables with the strongest association with BMI in the group of men were HDL% and apolipoprotein B, and in the group of women, HDL, HDL%, triglycerides, and MHR. Novel inflammatory markers were not associated with BMI, except MHR. We found significant (p < 0.001) correlations between novel biomarkers (NLR, dNLR) and hsCRP and fibrinogen levels in the group of subjects with obesity. Conclusions: Blood-based inflammatory markers significantly correlate with hsCRP and fibrinogen in young healthy adults with obesity, which may reflect the subclinical inflammation in this group of individuals

Attitiude towards body, tie strenght and adult attachment style in close relationship among young women (age 19-30).

Celem poniższej pracy było zbadanie, czy istnieje związek między postawą wobec ciała, a siłą relacji oraz stylem przywiązania w bliskim związku wśród młodych kobiet w przedziale wiekowym 19-30 lat. Dotychczasowe badania pokazywały różnice m.in. w obrazie ciała u osób charakteryzujących się różnymi stylami przywiązania oraz związek miedzy oceną ciała i zaufaniem oraz zazdrością w związku. W ostatecznej analizie wzięto pod uwagę 124 osoby, które przydzielono do czterech grup pod kątem stylu przywiązania. W celu weryfikacji hipotez wykorzystano szereg kwestionariuszy: Kwestionariusz siły relacji interpersonalnej (KRSI), Doświadczenia w bliskich związkach (ECR), Kwestionariusz zaburzeń odżywiania (EDI), podskala niezadowolenie z ciała, Test Sylwetek, Kwestionariusz zachowań wobec ciała (KZWC), Kwestionariusz zachowań wobec wyglądu zewnętrznego i wizerunku ciała (SATAQ-3), Skala oceny ciała, Skala włączania innego w Ja. Analiza statystyczna nie potwierdziła w pełni żadnej z postawionych hipotez. W badaniu wykazano słaby związek między oceną ciała w kontekście atrakcyjności seksualnej i niezadowolenia z ciała, a intymnością w relacji oraz między oceną ciała w kontekście atrakcyjności seksualnej a spostrzeganym podobieństwem w relacji. Jeżeli chodzi o styl przywiązania to styl bezpieczny różnił się od lękowego pod kątem internalizacji norm socjokulturowych oraz oceny ciała w kontekście atrakcyjności seksualnej. W przypadku drugiego wskaźnika styl bezpieczny różnił się również od odrzucającego. Wykazano również, że kontrolowany w badaniu poziom spostrzeganego wsparcia otrzymywanego od partnera może pośredniczyć pomiędzy tymi zależnościami.The aim of this research is to verify if there is connection between attitude towards body, tie strength and attachment style in group of young women (age 19-30). Previous research shows differences i.a. in body image among women with different attachment styles and connection between body esteem and trust and jealousy in close relationship. In the final analyses 124 women were taken into account and matched to four groups given attachment style. The following questionnaires were used to verify hypothesis: Tie Strength Scale (TSS), Experiences in Close Relationships (ECR), Eating Disorder Inventory (EDI) subscale: body dissatisfaction, Contour Drawing Rating Scale (CDRS), Behaviors Towards Body Questionnaire (KZWC), Sociocultural Attitudes Towards Appearance Scale (SATAQ-3), Body Esteem Scale (BES), Including other in Self (IOS). No one of the hypotheses were completely confirmed. Statistical analysis shows weak connection between body esteem in the context of sexual attractiveness, body dissatisfaction and intimacy in close relationship, as well as between body esteem considering sexual attractiveness and perceived resemblance. In the case of attachment style, there were differences between secure and anxious attachment considering internalization of sociocultural standards and body esteem in context of sexual attractiveness. Considering second indicator there were difference between secure and avoidant attachment. It has been shown that perceived support were also statistically important and can mediate in this connections

Aspartame—True or False? Narrative Review of Safety Analysis of General Use in Products

Aspartame is a sweetener introduced to replace the commonly used sucrose. It was discovered by James M. Schlatter in 1965. Being 180–200 times sweeter than sucrose, its intake was expected to reduce obesity rates in developing countries and help those struggling with diabetes. It is mainly used as a sweetener for soft drinks, confectionery, and medicines. Despite its widespread use, its safety remains controversial. This narrative review investigates the existing literature on the use of aspartame and its possible effects on the human body to refine current knowledge. Taking to account that aspartame is a widely used artificial sweetener, it seems appropriate to continue research on safety. Studies mentioned in this article have produced very interesting results overall, the current review highlights the social problem of providing visible and detailed information about the presence of aspartame in products. The studies involving the impact of aspartame on obesity, diabetes mellitus, children and fetus, autism, neurodegeneration, phenylketonuria, allergies and skin problems, its cancer properties and its genotoxicity were analyzed. Further research should be conducted to ensure clear information about the impact of aspartame on health

Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional, Potent Drug Candidates in Alzheimer’s Disease

A series of new cyclopentaquinoline derivatives with 9-acridinecarboxylic acid and a different alkyl chain length were synthesized, and their ability to inhibit cholinesterases was evaluated. All designed compounds, except derivative 3f, exhibited a selectivity for butyrylcholinesterase (BuChE) with IC50 values ranging from 103 to 539 nM. The 3b derivative revealed the highest inhibitory activity towards BuChE (IC50 = 103.73 nM) and a suitable activity against AChE (IC50 = 272.33 nM). The 3f derivative was the most active compound to AChE (IC50 = 113.34 nM) with satisfactory activity towards BuChE (IC50 = 203.52 nM). The potential hepatotoxic effect was evaluated for both 3b and 3f compounds. The 3b and 3f potential antioxidant activity was measured using the ORAC-FL method. The 3b and 3f derivatives revealed a significantly higher antioxidant potency, respectively 35 and 25 higher than tacrine. Theoretical, physicochemical, and pharmacokinetic properties were calculated using ACD Labs Percepta software. Molecular modeling and kinetic study were used to reveal the mechanism of cholinesterase inhibition in the most potent compounds: 3b and 3f