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)

How does gender influence the recognition of cardiovascular risk and adherence to self-care recommendations? : a study in polish primary care

Background: Studies have shown a correlation between gender and an ability to change lifestyle to reduce the risk of disease. However, the results of these studies are ambiguous, especially where a healthy lifestyle is concerned. Additionally, health behaviors are strongly modified by culture and the environment. Psychological factors also substantially affect engagement with disease-related lifestyle interventions. This study aimed to examine whether there are differences between men and women in the frequency of health care behavior for the purpose of reducing cardiovascular risk (CVR), as well as cognitive appraisal of this type of risk. We also aimed to identify the psychological predictors of engaging in recommended behavior for reducing the risk of cardiovascular disease after providing information about this risk in men and women. Methods: A total of 134 consecutive eligible patients in a family practice entered a longitudinal study. At initial consultation, the individual’s CVR and associated health burden was examined, and preventive measures were recommended by the physician. Self-care behavior, cognitive appraisal of risk, and coping styles were then assessed using psychological questionnaires. Six months after the initial data collection, the frequency of subjects’ self-care behavior was examined. Results: We found an increase in health care behavior after providing information regarding the rate of CVR in both sexes; this increase was greater for women than for men. Women followed self-care guidelines more often than men, particularly for preventive measures and dietary advice. Women were more inclined to recognize their CVR as a challenge. Coping style, cognitive appraisal, age, level of health behaviors at baseline and CVR values accounted for 48% of the variance in adherence to self-care guidelines in women and it was 52% in men. In women, total risk of CVD values were most important, while in men, cognitive appraisal of harm/loss was most important. Conclusions: Different predictors of acquisition of health behavior are encountered in men and women. Our results suggest that gender-adjusted motivation models influencing the recognition process need to be considered to optimize compliance in patients with CVR

CHANGES IN THE MIDDLE SECTION OF THE NAREW RIVER (BETWEEN OSTROŁĘKA AND ŁOMŻA) IN VIEW OF NATURAL FACTORS AND ANTHROPOGENIC PRESSURES

Contemporary and archive cartographic materials illustrating horizontal profile of the middle channel of the Narew River (between Ostrołęka and Łomża) were compared in the GeoMedia application. The results of the analysis revealed that natural and anthropogenic factors had not significantly contributed to changes in the channel profile over a period of two centuries. Narew is a meandering river, and its activity is associated with intensified erosion of right-bank bends and lateral movement along its flat-bed channel. The most noticeable changes include reduced area of oxbow lakes, mainly due to succession, and suburban settlement in floodplains that had been regarded as unfit for development in the 20th century

INFLUENCE OF THE CHANGE OF USING SOIL TO THE WATER QUALITY ON THE DRAINAGE SYSTEMS IN OBJECT LIDZBARK WARMIŃSKI

The study included groundwater outflow drainage systems and collected in the pond located at the agricultural use area in the portion of the drainage facility Lidzbark Warminski located on the Sępopolska Plain. The study was performed in two periods: the first one was in 1998–2000 (just after was made drainage), in which the discussed area was used as pasture, and the second in 2008–2010, in which after plowed of the soil was cultivated winter wheat. The aim of the study was to determine changes in water quality after the change of the way of land use. Examinations showed that as a result of the change of the way of using the area and ceasing of mineral fertilizing in waters of the pond was a reduction in the concentrations of the most mineral components, but an increase of pH reaction and concentrations of potassium, magnesium of sulfates and bicarbonates. In groundwaters observed increased the content of concentrations of mineral forms of nitrogen, phosphatic phosphorus, potassium, magnesium, general iron and bicarbonates, and a reduction in the concentrations of calcium, sodium, sulfates and chlorides. However in the water which outflow from drainage pipelines system from the research area was an increase of concentrations most of the determined substances, apart from ammonia nitrogen and chlorides

Heavy Metal Contamination in the Surface Layer of Bottom Sediments in a Flow-Through Lake: A Case Study of Lake Symsar in Northern Poland

River-lake systems most often behave as hydrographic units, which undergo complex interactions, especially in the contact zone. One such interaction pertains to the role of a river in the dispersal of trace elements carried into and out of a lake. In this study, we aimed to assess the impact of rivers on the accumulation of heavy metals in bottom sediments of natural lakes comprised in postglacial river-lake systems. The results showed that a river flowing through a lake is a key factor responsible for the input of the majority of available fraction of heavy metals (Zn, Mn, Cd and Ni) into the water body and for their accumulation along the flow of river water in the lake. The origin of other accumulated elements were the linear and point sources in catchments. In turn, the Pb content was associated with the location of roads in the direct catchment, while the sediment structure (especially size of fraction and density) could have affected the accumulation of Cr and Zn, which indicated correlations between these metals and fine fraction. Our results suggest that lakes act as filters and contribute to the self-purification of water that flows through them. As a result, the content of most metals in lake sediments showed a decrease by approx. 75% between the upstream (inflow) and downstream (outflow) sections. The increased content of two metals only, such as chromium and cadmium (higher by 2.0 and 2.5 times, respectively, after passing through the lake), was due to the correlation of the metals with fine sand. Both the content and distribution pattern of heavy metals in lake sediments are indicative of the natural response of aquatic ecosystems to environmental stressors, such as pollutant import with river water or climate change. The complex elements creating the water ecosystem of each lake can counteract stress by temporarily removing pollutants such as toxic metals form circulation and depositing them mostly around the delta

Discovery of New Cyclopentaquinoline Analogues as Multifunctional Agents for the Treatment of Alzheimer’s Disease

Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride (3e) as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, 3e compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase’s inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of 3e compound. A LogP assay confirmed that 3e compound fulfills Lipinsky’s rule of fiv

New cyclopentaquinoline and 3,5-dichlorobenzoic acid hybrids with neuroprotection against oxidative stress for the treatment of Alzheimers disease

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disease. Thus, drugs including donepezil, rivastigmine, and galantamine are not entirely effective in the treatment of this multifactorial disease. The present study evaluates eight derivatives (3a–3h) as candidates with stronger anti-AD potential but with less side effects. Reactive oxygen species (ROS) assays were used to assess oxidative stress which involve in the neurodegeneration. The neuroprotective properties of 3e against oxidative stress were done in three experiments using MTT test. The anti-AD potential was determined based on their anticholinesterase inhibition ability, determined using Ellman’s method, Aβ aggregation potential according to thioflavin (Th) fluorescence assay, and their antioxidative and anti-inflammatory activities. Compound 3e exhibited moderate cholinesterase inhibition activity (AChE, IC(50) = 0.131 µM; BuChE, IC(50) = 0.116 µM; SI = 1.13), significant inhibition of Aβ(1–42) aggregation (55.7%, at 5 µM) and acceptable neuroprotective activity. Extensive analysis of in vitro and in vivo assays indicates that new cyclopentaquinoline derivatives offer promise as candidates for new anti-AD drugs

New cyclopentaquinoline and 3,5-dichlorobenzoic acid hybrids with neuroprotection against oxidative stress for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative brain disease. Thus, drugs including donepezil, rivastigmine, and galantamine are not entirely effective in the treatment of this multifactorial disease. The present study evaluates eight derivatives (3a-3h) as candidates with stronger anti-AD potential but with less side effects. Reactive oxygen species (ROS) assays were used to assess oxidative stress which involve in the neurodegeneration. The neuroprotective properties of 3e against oxidative stress were done in three experiments using MTT test. The anti-AD potential was determined based on their anticholinesterase inhibition ability, determined using Ellman's method, Aβ aggregation potential according to thioflavin (Th) fluorescence assay, and their antioxidative and anti-inflammatory activities. Compound 3e exhibited moderate cholinesterase inhibition activity (AChE, IC50 = 0.131 µM; BuChE, IC50 = 0.116 µM; SI = 1.13), significant inhibition of Aβ(1-42) aggregation (55.7%, at 5 µM) and acceptable neuroprotective activity. Extensive analysis of in vitro and in vivo assays indicates that new cyclopentaquinoline derivatives offer promise as candidates for new anti-AD drugs