Challenges and opportunities in the Polish healthcare sector from the implementation of telemedicine solutions in the field of gerontology and geriatric medicine: own experience.

OBJECTIVE: Aim: To analyze and summarize the implementation of telemedical solutions in geriatrics and gerontology within the Polish healthcare sector, aiming to develop innovative strategies for improving elderly care through telemedical technologies. PATIENTS AND METHODS: Materials and Methods: An interdisciplinary pilot project in geriatrics was implemented, focusing on health, organizational, and technological areas. The project involved continuous monitoring of health parameters, remote consultations, and the use of telemedical devices and platforms. Key data collection tools included digital clinimetric outcomes from the FRA-MNA-SARC model, with data transmitted to a telemedical platform. RESULTS: Results: The pilot project demonstrated significant positive outcomes for senior participants. Continuous monitoring of health parameters allowed for early detection and timely intervention, leading to noticeable improvements in chronic disease management. This proactive approach reduced emergency hospital visits and enhanced overall health stability. The medication adherence support system, with automated reminders, ensured patients took their medications as prescribed, resulting in improved compliance and health outcomes. Telemedical solutions efficiently reduced the need for frequent in-person visits, allowing healthcare providers to monitor progress and adjust therapies in real-time. The project also effectively engaged patients and caregivers, increasing confidence in health management and providing valuable support and real-time information. CONCLUSION: Conclusions: Implementing telemedical solutions in geriatrics within the Polish healthcare sector shows significant potential to improve elderly care. Telemedicine can effectively support chronic disease management, enhance seniors' quality of life through continuous health monitoring, and provide a practical framework for personalized and efficient healthcare delivery.

Unlocking the potential of higher-molecular-weight 5-HT7R ligands: Synthesis, affinity, and ADMET examination.

An increasing number of drugs introduced to the market and numerous repositories of compounds with confirmed activity have posed the need to revalidate the state-of-the-art rules that determine the ranges of properties the compounds should possess to become future drugs. In this study, we designed a series of two chemotypes of aryl-piperazine hydantoin ligands of 5-HT7R, an attractive target in search for innovative CNS drugs, with higher molecular weight (close to or over 500). Consequently, 14 new compounds were synthesised and screened for their receptor activity accompanied by extensive docking studies to evaluate the observed structure-activity/properties relationships. The ADMET characterisation in terms of the biological membrane permeability, metabolic stability, hepatotoxicity, cardiotoxicity, and protein plasma binding of the obtained compounds was carried out in vitro. The outcome of these studies constituted the basis for the comprehensive challenge of computational tools for ADMET properties prediction. All the compounds possessed high affinity to the 5-HT7R (Ki below 250 nM for all analysed structures) with good selectivity over 5-HT6R and varying affinity towards 5-HT2AR, 5-HT1AR and D2R. For the best compounds of this study, the expression profile of genes associated with neurodegeneration, anti-oxidant response and anti-inflammatory function was determined, and the survival of the cells (SH-SY5Y as an in vitro model of Alzheimer's disease) was evaluated. One 5-HT7R agent (32) was characterised by a very promising ADMET profile, i.e. good membrane permeability, low hepatotoxicity and cardiotoxicity, and high metabolic stability with the simultaneous high rate of plasma protein binding and high selectivity over other GPCRs considered, together with satisfying gene expression profile modulations and neural cell survival. Such encouraging properties make it a good candidate for further testing and optimisation as a potential agent in the treatment of CNS-related disorders.

microRNA-449a reduces growth hormone-stimulated senescent cell burden through PI3K-mTOR signaling.

Cellular senescence, a hallmark of aging, has been implicated in the pathogenesis of many major age-related disorders, including neurodegeneration, atherosclerosis, and metabolic disease. Therefore, investigating novel methods to reduce or delay the accumulation of senescent cells during aging may attenuate age-related pathologies. microRNA-449a-5p (miR-449a) is a small, noncoding RNA down-regulated with age in normal mice but maintained in long-living growth hormone (GH)-deficient Ames Dwarf (df/df) mice. We found increased fibroadipogenic precursor cells, adipose-derived stem cells, and miR-449a levels in visceral adipose tissue of long-living df/df mice. Gene target analysis and our functional study with miR-449a-5p have revealed its potential as a serotherapeutic. Here, we test the hypothesis that miR-449a reduces cellular senescence by targeting senescence-associated genes induced in response to strong mitogenic signals and other damaging stimuli. We demonstrated that GH downregulates miR-449a expression and accelerates senescence while miR-449a upregulation using mimetics reduces senescence, primarily through targeted reduction of p16Ink4a, p21Cip1, and the PI3K-mTOR signaling pathway. Our results demonstrate that miR-449a is important in modulating key signaling pathways that control cellular senescence and the progression of age-related pathologies.

Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists.

TrkB is a tyrosine kinase receptor that is activated upon binding to brain-derived neurotrophic factor (BDNF). To date, the search for low-molecular-weight molecules mimicking BDNF's action has been unsuccessful. Several molecules exerting antidepressive effects in vivo, such as 7,8-DHF, have been suggested to be TrkB agonists. However, more recent publications question this hypothesis. In this study, we developed a set of experimental procedures including the evaluation of direct interactions, dimerization, downstream signaling, and cytoprotection in parallel with physicochemical and ADME methods to verify the pharmacology of 7,8-DHF and other potential reference compounds, and perform screening for novel TrkB agonists. 7,8 DHF bound to TrkB with Kd = 1.3 µM; however, we were not able to observe any other activity against the TrkB receptor in SN56 T48 and differentiated SH-SY5Y cell lines. Moreover, the pharmacokinetic and pharmacodynamic effects of 7,8-DHF at doses of 1 and 50 mg/kg were examined in mice after i.v and oral administration, respectively. The poor pharmacokinetic properties and lack of observed activation of TrkB-dependent signaling in the brain confirmed that 7,8-DHF is not a relevant tool for studying TrkB activation in vivo. The binding profile for 133 molecular targets revealed a significant lack of selectivity of 7,8-DHF, suggesting a distinct functional profile independent of interaction with TrkB. Additionally, a compound library was screened in search of novel low-molecular-weight orthosteric TrkB agonists; however, we were not able to identify reliable drug candidates. Our results suggest that published reference compounds including 7,8-DHF do not activate TrkB, consistent with canonical dogma, which indicates that the reported pharmacological activity of these compounds should be interpreted carefully in a broad functional context.

IntelliCage as a tool for measuring mouse behavior - 20 years perspective.

Since the 1980s, we have witnessed the rapid development of genetically modified mouse models of human diseases. A large number of transgenic and knockout mice have been utilized in basic and applied research, including models of neurodegenerative and neuropsychiatric disorders. To assess the biological function of mutated genes, modern techniques are critical to detect changes in behavioral phenotypes. We review the IntelliCage, a high-throughput system that is used for behavioral screening and detailed analyses of complex behaviors in mice. The IntelliCage was introduced almost two decades ago and has been used in over 150 studies to assess both spontaneous and cognitive behaviors. We present a critical analysis of experimental data that have been generated using this device.

A generalised framework for detailed classification of swimming paths inside the Morris Water Maze.

The Morris Water Maze is commonly used in behavioural neuroscience for the study of spatial learning with rodents. Over the years, various methods of analysing rodent data collected during this task have been proposed. These methods span from classical performance measurements to more sophisticated categorisation techniques which classify the animal swimming path into behavioural classes known as exploration strategies. Classification techniques provide additional insight into the different types of animal behaviours but still only a limited number of studies utilise them. This is primarily because they depend highly on machine learning knowledge. We have previously demonstrated that the animals implement various strategies and that classifying entire trajectories can lead to the loss of important information. In this work, we have developed a generalised and robust classification methodology to boost classification performance and nullify the need for manual tuning. We have also made available an open-source software based on this methodology.

Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons.

Decreased rRNA synthesis and nucleolar disruption, known as nucleolar stress, are primary signs of cellular stress associated with aging and neurodegenerative disorders. Silencing of rDNA occurs during early stages of Alzheimer's disease (AD) and may play a role in dementia. Moreover, aberrant regulation of the protein synthesis machinery is present in the brain of suicide victims and implicates the epigenetic modulation of rRNA. Recently, we developed unique mouse models characterized by nucleolar stress in neurons. We inhibited RNA polymerase I by genetic ablation of the basal transcription factor TIF-IA in adult hippocampal neurons. Nucleolar stress resulted in progressive neurodegeneration, although with a differential vulnerability within the CA1, CA3, and dentate gyrus (DG). Here, we investigate the consequences of nucleolar stress on learning and memory. The mutant mice show normal performance in the Morris water maze and in other behavioral tests, suggesting the activation of adaptive mechanisms. In fact, we observe a significantly enhanced learning and re-learning corresponding to the initial inhibition of rRNA transcription. This phenomenon is accompanied by aberrant synaptic plasticity. By the analysis of nucleolar function and integrity, we find that the synthesis of rRNA is later restored. Gene expression profiling shows that 36 transcripts are differentially expressed in comparison to the control group in absence of neurodegeneration. Additionally, we observe a significant enrichment of the putative serum response factor (SRF) binding sites in the promoters of the genes with changed expression, indicating potential adaptive mechanisms mediated by the mitogen-activated protein kinase pathway. In the DG a neurogenetic response might compensate the initial molecular deficits. These results underscore the role of nucleolar stress in neuronal homeostasis and open a new ground for therapeutic strategies aiming at preserving neuronal function.