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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.

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Aclarubicin (aclacinomycin A) is one of the anthracycline antineoplastic antibiotics with a multifaceted mechanism of antitumor activity. As a second-generation drug, it offers several advantages compared to standard anthracycline drugs such as doxorubicin or daunorubicin, which could position it as a potential blockbuster drug in antitumor therapy. Key mechanisms of action for aclarubicin include the inhibition of both types of topoisomerases, suppression of tumor invasion processes, generation of reactive oxygen species, inhibition of chymotrypsin-like activity, influence on cisplatin degradation, and inhibition of angiogenesis. Therefore, aclarubicin appears to be an ideal candidate for antitumor therapy. However, despite initial interest in its clinical applications, only a limited number of high-quality trials have been conducted thus far. Aclarubicin has primarily been evaluated as an induction therapy in acute myeloid and lymphoblastic leukemia. Studies have indicated that aclarubicin may hold significant promise for combination therapies with other anticancer drugs, although further research is needed to confirm its potential. This paper provides an in-depth exploration of aclarubicin's diverse mechanisms of action, its pharmacokinetics, potential toxicity, and the clinical trials in which it has been investigated.

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PURPOSE: Molecular oxygen, besides a photosensitizer and light of appropriate wavelength, is one of the three factors necessary for photodynamic therapy (PDT). In tumor tissue, PDT leads to the killing of tumor cells, destruction of endothelial cells and vasculature collapse, and the induction of strong immune responses. All these effects may influence the oxygenation levels, but it is the vasculature changes that have the main impact on pO2. The purpose of our study was to monitor changes in tumor oxygenation after PDT and explore its significance for predicting long-term treatment response. PROCEDURES: Electron paramagnetic resonance (EPR) spectroscopy enables direct, quantitative, and sequential measurements of partial pressure of oxygen (pO2) in the same animal. The levels of chlorophyll derived photosensitizers in tumor tissue were determined by transdermal emission measurements. RESULTS: The noninvasive monitoring of pO2 in the tumor tissue after PDT showed that the higher ΔpO2 (pO2 after PDT minus pO2 before PDT), the greater the inhibition of tumor growth. ΔpO2 also correlated with higher levels of the photosensitizers in the tumor and with the occurrence of a severe edema/erythema after PDT. CONCLUSION: Monitoring of PDT-induced changes in tumor oxygenation is a valuable prognostic factor and could be also used to identify potentially resistant tumors, which is important in predicting long-term treatment response.

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PURPOSE: The goal of this work was to compare pO2 measured using both continuous wave (CW) and pulse electron paramagnetic resonance (EPR) spectroscopy. The Oxychip particle spin probe enabled longitudinal monitoring of pO2 in murine pancreatic tumor treated with gemcitabine during the course of therapy. PROCEDURES: Pancreatic PanO2 tumors were growing in the syngeneic mice, in the leg. Five doses of saline in control animals or gemcitabine were administered every 3 days, and pO2 was measured after each dose at several time points. Oxygen partial pressure was determined from the linewidth of the CW EPR signal (Bruker E540L) or from the T2 measured using the electron spin echo sequence (Jiva-25™). RESULTS: The oxygen sensitivity was determined from a calibration curve as 6.1 mG/mm Hg in CW EPR and 68.5 ms-1/mm Hg in pulse EPR. A slight increase in pO2 of up to 20 mm Hg was observed after the third dose of gemcitabine compared to the control. The maximum delta pO2 during the therapy correlated with better survival. CONCLUSIONS: Both techniques offer fast and reliable oximetry in vivo, allowing to follow the effects of pharmaceutic intervention.

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The growing consumption of antidepressant pharmaceuticals has resulted in their widespread occurrence in the environment, particularly in waterways with a typical concentration range from ng L-1 to µg L-1. An increasing number of studies have confirmed the ecotoxic potency of antidepressants, not only at high concentrations but also at environmentally relevant levels. The present review covers literature from the last decade on the individual-level ecotoxicological effects of the most commonly used antidepressants, including their impact on behavior, growth, and survival. We focus on the relationship between antidepressants physico-chemical properties and dynamics in the environment. Furthermore, we discuss the advantages of considering behavioral changes as sensitive endpoints in ecotoxicology, as well as some current methodological shortcomings in the field, including low standardization, reproducibility and context-dependency.

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Cancer is one of the leading causes of death in humans. Despite the progress in cancer treatment, and an increase in the effectiveness of diagnostic methods, cancer is still highly lethal and very difficult to treat in many cases. Combination therapy, in the context of cancer treatment, seems to be a promising option that may allow minimizing treatment side effects and may have a significant impact on the cure. It may also increase the effectiveness of anti-cancer therapies. Moreover, combination treatment can significantly increase delivery of drugs to cancerous tissues. Photodynamic therapy and hyperthermia seem to be ideal examples that prove the effectiveness of combination therapy. These two kinds of therapy can kill cancer cells through different mechanisms and activate various signaling pathways. Both PDT and hyperthermia play significant roles in the perfusion of a tumor and the network of blood vessels wrapped around it. The main goal of combination therapy is to combine separate mechanisms of action that will make cancer cells more sensitive to a given therapeutic agent. Such an approach in treatment may contribute toward increasing its effectiveness, optimizing the cancer treatment process in the future.