This study demonstrated the anticancer efficacy of chalcones with indole moiety (MIPP, MOMIPP) in fibrosarcoma cells for the first time. The results showed that MIPP and MOMIPP reduced the viability ...of HT-1080 cells in a concentration-dependent manner. MOMIPP was more active than MIPP in HT-1080 cells, showing lower IC50 values (3.67 vs. 29.90 μM). Both compounds at a concentration of 1 μM induced apoptosis in HT-1080 cells, causing death strictly related to caspase activation, as cell viability was restored when the caspase inhibitor Z-VAD was added. Reactive oxygen species production was approximately 3-fold higher than in control cells, and cotreatment with the inhibitor of mitochondrial ATPase oligomycin diminished this effect. Such effects were also reflected in mitochondrial dysfunction, including decreased membrane potential. Interestingly, the compounds that were studied caused massive vacuolization in HT-1080 cells. Immunocytochemical staining and TEM analysis showed that HT-1080 cells exhibited increased expression of the LC3-II protein and the presence of autophagosomes with a double membrane, respectively. Both compounds induced apoptosis, highlighting a promising link between autophagy and apoptosis. This connection could be a new target for therapeutic strategies to overcome chemoresistance, which is a significant cause of treatment failure and tumour recurrence in fibrosarcoma following traditional chemotherapy.
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Alzheimer’s disease (AD) is a neurodegenerative disorder, for which there is no effective cure. Current drugs only slow down the course of the disease, and, therefore, there is an urgent need to find ...effective therapies that not only treat, but also prevent it. Acetylcholinesterase inhibitors (AChEIs), among others, have been used for years to treat AD. Histamine H3 receptors (H3Rs) antagonists/inverse agonists are indicated for CNS diseases. Combining AChEIs with H3R antagonism in one structure could bring a beneficial therapeutic effect. The aim of this study was to find new multitargetting ligands. Thus, continuing our previous research, acetyl- and propionyl-phenoxy-pentyl(-hexyl) derivatives were designed. These compounds were tested for their affinity to human H3Rs, as well as their ability to inhibit cholinesterases (acetyl- and butyrylcholinesterases) and, additionally, human monoamine oxidase B (MAO B). Furthermore, for the selected active compounds, their toxicity towards HepG2 or SH-SY5Y cells was evaluated. The results showed that compounds 16 (1-(4-((5-(azepan-1-yl)pentyl)oxy)phenyl)propan-1-one) and 17 (1-(4-((6-(azepan-1-yl)hexyl)oxy)phenyl)propan-1-one) are the most promising, with a high affinity for human H3Rs (Ki: 30 nM and 42 nM, respectively), a good ability to inhibit cholinesterases (16: AChE IC50 = 3.60 µM, BuChE IC50 = 0.55 µM; 17: AChE IC50 = 1.06 µM, BuChE IC50 = 2.86 µM), and lack of cell toxicity up to 50 µM.
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Chronic inflammation plays an important role in the development of neurodegenerative diseases, such as Parkinson’s disease (PD). In the present study, we synthesized 25 novel xanthine derivatives ...with variable substituents at the N1-, N3- and C8-position as adenosine receptor antagonists with potential anti-inflammatory activity. The compounds were investigated in radioligand binding studies at all four human adenosine receptor subtypes, A1, A2A, A2B and A3. Compounds showing nanomolar A2A and dual A1/A2A affinities were obtained. Three compounds, 19, 22 and 24, were selected for further studies. Docking and molecular dynamics simulation studies indicated binding poses and interactions within the orthosteric site of adenosine A1 and A2A receptors. In vitro studies confirmed the high metabolic stability of the compounds, and the absence of toxicity at concentrations of up to 12.5 µM in various cell lines (SH-SY5Y, HepG2 and BV2). Compounds 19 and 22 showed anti-inflammatory activity in vitro. In vivo studies in mice investigating carrageenan- and formalin-induced inflammation identified compound 24 as the most potent anti-inflammatory derivative. Future studies are warranted to further optimize the compounds and to explore their therapeutic potential in neurodegenerative diseases.
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The multitarget-directed ligands demonstrating affinity to histamine H3 receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective ...treatment of Alzheimer’s disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H3R (Ki = 8 nM) and significant inhibitory activity toward BuChE (IC50 = 172 nM and 1.16 µM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (Pe) of 6.3 × 10−6 cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED50 = 20.9 mg/kg) and inflammatory (ED50 = 17.5 mg/kg) pain.
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Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It ...is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H3 receptors (H3Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H3R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H3R ligands. Most of these compounds show high affinity for human H3R (Ki < 150 nM) and submicromolar inhibition of BuChE (IC50 < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-(1,1′-biphenyl-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H3R, with a Ki value of 33.9 nM, and for equine serum BuChE, with an IC50 of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC50 of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.
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Dual target ligands are a promising concept for the treatment of Parkinson’s disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H3 receptor (H3R) antagonism could ...have positive effects on dopamine regulation. Thus, a series of twenty-seven 4-tert-butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4-tert-butylphenoxy)propyl)piperidine (DL76). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H3R (hH3R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH3R affinities with Ki values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH3R: Ki = 38 nM and hMAO B: IC50 = 48 nM). Thus, DL76 was chosen for further studies, revealing the nontoxic nature of DL76 in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for DL76 in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of DL76 in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight.
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Cel pracy
Celem pracy jest analiza wpływu interwencji poznawczo-behawioralnej (CBI- cognitive-behavioral intervention) u pacjentów poddawanych implantacji urządzeń do elektroterapii na jakość życia ...po zabiegu oraz na stopień akceptacji choroby.
Metoda
Grupę badaną stanowili pacjenci poddani standardowej opiece medycznej związanej z implantacją urządzenia do elektroterapii serca oraz u których dodatkowo zastosowano CBI. Pacjenci objęci jedynie standardową opieką medyczną związaną z implantacją urządzenia do elektroterapii serca stanowili grupę kontrolną. CBI składała się z czterech sesji przeprowadzonych w ciągu 30 dni (± 3 dni) od implantacji. Oceniano czynniki demograficzne, kliniczne i psychologiczne. Zastosowano m.in. Skalę Akceptacji Choroby (AIS) i kwestionariusz oceniający jakość życia EuroQol-5D (EQ-5D).
Wyniki
Do badania włączono ostatecznie 128 pacjentów (36,7% kobiet, średni wiek 64,5 ± 8,9). Proponowany cykl czterech ustrukturalizowanych spotkań CBI był dobrze akceptowany przez pacjentów, co zostało potwierdzone wysoką częstotliwością uczestnictwa w sesjach podczas terapii. Po sześciu miesiącach obserwowano wyższą jakość życia u pacjentów objętych CBI w porównaniu z grupą kontrolną, w tym w zakresie Wizualnej Skali Analogowej EQ-5D 80,2 ± 11,8 vs 64,9 ± 14,3 (p <0,0001) oraz obserwowano lepszą akceptację choroby AIS: 35,6 ± 4,3 vs 28,7 ± 6,1 (p <0,0001).
Wnioski
Zastosowanie CBI u pacjentów po implantacji urządzeń do elektroterapii serca wiązało się z istotną poprawą jakości życia oraz wyższą akceptacją choroby w porównaniu do grupy pacjentów objętych standardową opieką po zabiegu elektroterapii. CBI ma wiele zalet w tej grupie pacjentów, a także zapewnia spełnienie oczekiwanego efektu terapeutycznego, podczas gdy krótki czas trwania interwencji nie wydłużał czasu trwania samej hospitalizacji.
Objectives
This study is an attempt to provide an analysis of the influence of implementation of cognitive behavioral intervention (CBI) in patients after cardiovascular implantable electronic device (CIED) implantation on the quality of life following the procedure as well as the level of illness acceptance.
Methods
The study group consisted of patients who underwent standard medical care related to CIED implantation and who additionally received CBI. Patients who received only standard medical care related to CIED implantation constituted a control group. CBI consisted of four sessions conducted over 30 (±3) days after the implantation. Demographic, clinicaland psychological factors were assessed.The Acceptance of Illness Scale (AIS) and EuroQol-5D (EQ-5D) were applied.
Results
In total, 128 patients (women: 36.7%, mean age 64.5 ± 8.9) were included in the study. The proposed cycle of four structured CBI meetings was well accepted by the patients, which is confirmed by their high turnout for these meetings. After six months, quality of life indices were significantly improved in cardiac electrotherapy recipients assigned to CBI, including: Visual Analogue Scale EQ-5D (80.2 ± 11.8 vs. 64.9 ± 14.3; p < 0.0001) and better acceptance of illness (AIS: 35.6 ± 4.3 vs. 28.7 ± 6.1; p < 0.0001).
Conclusions
Implementation of CBI in patients after CIED implantation significantly improved indices of quality of life as well as illness acceptance, when compared to the control group of patients in standard care following electrotherapy. CBI showed multiple benefits in this population, as well as ensures the fulfilment of its expected therapeutic effect, while short duration of the intervention did not prolong the hospitalization itself.
Moderate physical activity has a positive impact on health, although extreme forms of sport such as marathon running may trigger exercise-induced cardiac fatigue. The explicit distinction between the ...right ventricular (RV) physiological response to training and maladaptive remodeling has not yet been determined. In this study, we aimed to analyze the impact of running a marathon on RV mechanics in amateur athletes using three-dimensional (3D) echocardiography (ECHO) and the ReVISION method (RV separate wall motion quantification). A group of 34 men with a mean age of 40 ± 8 years who successfully finished a marathon underwent ECHO three times, i.e., 2 weeks before the marathon (stage I), at the marathon finish line (stage II), and 2 weeks after the marathon (stage III). The ECHO findings were then correlated with the concentrations of biomarkers related to myocardial injury and overload and also obtained at the three stages. On finishing the marathon, the amateur athletes were found to have a significant (
< 0.05) increase in end-diastolic (with a median of 51.4 vs. 57.0 ml/m
) and end-systolic (with a median of 24.9 vs. 31.5 ml/m
) RV volumes indexed to body surface area, reduced RV ejection fraction (RVEF) (with a median of 51.0% vs. 46.0%), and a decrease in RV radial shortening i.e., radial EF (REF) (with a mean of 23.0 ± 4.5% vs. 19.3 ± 4.2%), with other RV motion components remaining unchanged. The post-competition decrease in REF was more evident in runners with larger total volume of trainings (
= 0.4776,
= 0.0002) and higher concentrations of high-sensitivity cardiac troponin I (
= 0.43,
< 0.05) during the preparation period. The decrease in REF was more prominent in the training of marathoners more than 47 km/week. At stage II, marathoners with a more marked decrease in RVEF and REF had higher galectin-3 (Gal-3) levels (
= -0.48 and
= -0.39, respectively;
< 0.05). Running a marathon significantly altered the RV performance of amateur athletes. Transient impairment in RV systolic function resulted from decreased radial shortening, which appeared in those who trained more extensively. Observed ECHO changes correlated with the concentrations of the profibrotic marker Gal-3.
Alzheimer's disease (AD) is a neurodegenerative disorder, for which there is no effective cure. Current drugs only slow down the course of the disease, and, therefore, there is an urgent need to find ...effective therapies that not only treat, but also prevent it. Acetylcholinesterase inhibitors (AChEIs), among others, have been used for years to treat AD. Histamine Hsub.3 receptors (Hsub.3Rs) antagonists/inverse agonists are indicated for CNS diseases. Combining AChEIs with Hsub.3R antagonism in one structure could bring a beneficial therapeutic effect. The aim of this study was to find new multitargetting ligands. Thus, continuing our previous research, acetyl- and propionyl-phenoxy-pentyl(-hexyl) derivatives were designed. These compounds were tested for their affinity to human Hsub.3Rs, as well as their ability to inhibit cholinesterases (acetyl- and butyrylcholinesterases) and, additionally, human monoamine oxidase B (MAO B). Furthermore, for the selected active compounds, their toxicity towards HepG2 or SH-SY5Y cells was evaluated. The results showed that compounds 16 (1-(4-((5-(azepan-1-yl)pentyl)oxy)phenyl)propan-1-one) and 17 (1-(4-((6-(azepan-1-yl)hexyl)oxy)phenyl)propan-1-one) are the most promising, with a high affinity for human Hsub.3Rs (Ki: 30 nM and 42 nM, respectively), a good ability to inhibit cholinesterases (16: AChE ICsub.50 = 3.60 µM, BuChE ICsub.50 = 0.55 µM; 17: AChE ICsub.50 = 1.06 µM, BuChE ICsub.50 = 2.86 µM), and lack of cell toxicity up to 50 µM.
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