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.

Adipose Tissue-Derived Stromal Cells in Matrigel Impacts the Regeneration of Severely Damaged Skeletal Muscles.

In case of large injuries of skeletal muscles the pool of endogenous stem cells, i.e., satellite cells, might be not sufficient to secure proper regeneration. Such failure in reconstruction is often associated with loss of muscle mass and excessive formation of connective tissue. Therapies aiming to improve skeletal muscle regeneration and prevent fibrosis may rely on the transplantation of different types of stem cell. Among such cells are adipose tissue-derived stromal cells (ADSCs) which are relatively easy to isolate, culture, and manipulate. Our study aimed to verify applicability of ADSCs in the therapies of severely injured skeletal muscles. We tested whether 3D structures obtained from Matrigel populated with ADSCs and transplanted to regenerating mouse gastrocnemius muscles could improve the regeneration. In addition, ADSCs used in this study were pretreated with myoblasts-conditioned medium or anti-TGFß antibody, i.e., the factors modifying their ability to proliferate, migrate, or differentiate. Analyses performed one week after injury allowed us to show the impact of 3D cultured control and pretreated ADSCs at muscle mass and structure, as well as fibrosis development immune response of the injured muscle.

New cyclopentaquinoline hybrids with multifunctional capacities for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common progressive form of brain neurodegeneration and the most prevailing cause of dementia. Unfortunately, the aetiology of AD is not completely studied but different factors are associated with the development of AD such as among others low level of acetylcholine, aggregation of ß-amyloid (Aß), hyperphosphorylated tau protein, oxidative stress, and inflammation. The study encompass organic syntheses of 2,3-dihydro-1H-cyclopenta[b]quinoline with 5,6-dichloronicotinic acid and suitable linkers derivatives as multifunctional agents for AD treatment. Afterwards self-induced amyloid beta aggregation, inhibition studies of acetylcholinesterase and butyrylcholinesterase and molecular docking studies were performed. The results showed that 3b compound exhibited the best acetylcholinesterase inhibitory activity, with IC50 value of 0.052 µM which is lower compared to references. Besides, all synthesised compounds showed good butyrylcholinesterase inhibitory activity with IC50 values from 0.071 to 0.797 µM. Compound 3b exhibited strong Aß1-42 aggregation inhibitory effect with 25.7% at 5 µM to 92.8% at 100 µM as well as good anti-inflammatory effect. Thus, new compounds could create new perspectives for further development as a multi-target-directed agent for AD treatment.

Extended Reality in Diagnostic Imaging-A Literature Review.

The utilization of extended reality (ER) has been increasingly explored in the medical field over the past ten years. A comprehensive analysis of scientific publications was conducted to assess the applications of ER in the field of diagnostic imaging, including ultrasound, interventional radiology, and computed tomography. The study also evaluated the use of ER in patient positioning and medical education. Additionally, we explored the potential of ER as a replacement for anesthesia and sedation during examinations. The use of ER technologies in medical education has received increased attention in recent years. This technology allows for a more interactive and engaging educational experience, particularly in anatomy and patient positioning, although the question may be asked: is the technology and maintenance cost worth the investment? The results of the analyzed studies suggest that implementing augmented reality in clinical practice is a positive phenomenon that expands the diagnostic capabilities of imaging studies, education, and positioning. The results suggest that ER has significant potential to improve diagnostic imaging procedures' accuracy and efficiency and enhance the patient experience through increased visualization and understanding of medical conditions. Despite these promising advancements, further research is needed to fully realize the potential of ER in the medical field and to address the challenges and limitations associated with its integration into clinical practice.

A review of the mechanisms underlying selected comorbidities in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) leading to mental deterioration and devastation, and eventually a fatal outcome. AD affects mostly the elderly. AD is frequently accompanied by hypercholesterolemia, hypertension, atherosclerosis, and diabetes mellitus, and these are significant risk factors of AD. Other conditions triggered by the progression of AD include psychosis, sleep disorders, epilepsy, and depression. One important comorbidity is Down's syndrome, which directly contributes to the severity and rapid progression of AD. The development of new therapeutic strategies for AD includes the repurposing of drugs currently used for the treatment of comorbidities. A better understanding of the influence of comorbidities on the pathogenesis of AD, and the medications used in its treatment, might allow better control of disease progression, and more effective pharmacotherapy.

Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer's disease treatment.

A novel series of 9-amino-1,2,3,4-tetrahydroacridine and 5,6-dichloronicotinic acid moiety were conjugated with different linkers. Afterwards new derivatives were evaluated as potential multifunctional acetylcholinesterase inhibitors (AChEIs), anti-Alzheimer's disease (AD) drug candidates. All the compounds were synthesized and tested for capacity for the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Specifically, the most promising derivative 3b (IC50 = 1.02 nM) had higher inhibitory potency compared to the reference drug, tacrine. Consequently, kinetic studies of 3b compound showed a mixed-type inhibition of both AChE and BuChE. Afterwards the best potent AChE inhibitor has been examined on amyloid ß (Aß) self-induced aggregation. Furthermore, 3b compound was tested in various concentrations and had moderate activity against Aß aggregation. Inhibition of Aß aggregation was 46.63% and 19.41% at 50 µM and 5  µM concentrations, respectively. Moreover, no cytotoxicity was observed for the mentioned concentrations. Therefore, 3b compound is a promising multipotent agent for the treatment of AD.