AIMS: The aim of this study was to compare the clinical decision-making for benzodiazepine deprescribing between a healthcare provider (HCP) and an artificial intelligence (AI) chatbot GPT4 (ChatGPT-4). METHODS: We analysed real-world data from a Croatian cohort of community-dwelling benzodiazepine patients (n = 154) within the EuroAgeism H2020 ESR 7 project. HCPs evaluated the data using pre-established deprescribing criteria to assess benzodiazepine discontinuation potential. The research team devised and tested AI prompts to ensure consistency with HCP judgements. An independent researcher employed ChatGPT-4 with predetermined prompts to simulate clinical decisions for each patient case. Data derived from human-HCP and ChatGPT-4 decisions were compared for agreement rates and Cohen's kappa. RESULTS: Both HPC and ChatGPT identified patients for benzodiazepine deprescribing (96.1% and 89.6%, respectively), showing an agreement rate of 95% (κ = .200, P = .012). Agreement on four deprescribing criteria ranged from 74.7% to 91.3% (lack of indication κ = .352, P < .001; prolonged use κ = .088, P = .280; safety concerns κ = .123, P = .006; incorrect dosage κ = .264, P = .001). Important limitations of GPT-4 responses were identified, including 22.1% ambiguous outputs, generic answers and inaccuracies, posing inappropriate decision-making risks. CONCLUSIONS: While AI-HCP agreement is substantial, sole AI reliance poses a risk for unsuitable clinical decision-making. This study's findings reveal both strengths and areas for enhancement of ChatGPT-4 in the deprescribing recommendations within a real-world sample. Our study underscores the need for additional research on chatbot functionality in patient therapy decision-making, further fostering the advancement of AI for optimal performance.

• MeSH
• benzodiazepiny škodlivé účinky   MeSH
• depreskripce * MeSH
• klinické rozhodování MeSH
• lidé MeSH
• umělá inteligence * MeSH
• zdravotnický personál MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Imiquimod (IMQ) is a potent immune response modifier with antiviral and antitumor properties. IMQ's low aqueous solubility and unsatisfactory cutaneous permeability limit its formulation into effective dosage forms. This work aimed to develop IMQ-loaded microemulsions (MEs) based on phospholipids and oleic acid to improve IMQ penetration into the epidermis. A pseudo-ternary phase diagram was constructed, and the microstructure of the formulations was examined by measuring the conductivity values. Selected MEs were characterized and studied for their ability to deliver IMQ into and through ex vivo human skin. ME1 with 1% IMQ (bicontinuous ME with Bingham rheology) delivered similar IMQ quantities to the human epidermis ex vivo as the commercial product while having a 5-fold lower IMQ dose. IMQ was not detected in the acceptor phase after the permeation experiment, suggesting a lower systemic absorption risk than the established product. Infrared spectroscopy of the stratum corneum revealed less ordered and less tightly packed lipids after ME1 application. The ME1-induced barrier disruption recovered within less than 5 h after the formulation removal, as detected by transepidermal water loss measurements. In conclusion, our findings demonstrate that phospholipid and oleic acid-based MEs could become a promising alternative for topical IMQ administration.

• Publikační typ
• časopisecké články MeSH

The search for novel antimycobacterial drugs is a matter of urgency, since tuberculosis is still one of the top ten causes of death from a single infectious agent, killing more than 1.4 million people worldwide each year. Nine Amaryllidaceae alkaloids (AAs) of various structural types have been screened for their antimycobacterial activity. Unfortunately, all were considered inactive, and thus a pilot series of aromatic esters of galanthamine, 3-O-methylpancracine, vittatine and maritidine were synthesized to increase biological activity. The semisynthetic derivatives of AAs were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra and two other mycobacterial strains (M. aurum, M. smegmatis) using a modified Microplate Alamar Blue Assay. The most active compounds were also studied for their in vitro hepatotoxicity on the hepatocellular carcinoma cell line HepG2. In general, the derivatization of the original AAs was associated with a significant increase in antimycobacterial activity. Several pilot derivatives were identified as compounds with micromolar MICs against M. tuberculosis H37Ra. Two derivatives of galanthamine, 1i and 1r, were selected for further structure optimalization to increase the selectivity index.

• MeSH
• alkaloidy amarylkovitých škodlivé účinky   chemická syntéza   farmakologie   MeSH
• antibakteriální látky škodlivé účinky   chemická syntéza   farmakologie   MeSH
• buňky Hep G2 MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Pancracine, a montanine-type Amaryllidaceae alkaloid (AA), is one of the most potent compounds among natural isoquinolines. In previous studies, pancracine exhibited cytotoxic activity against diverse human cancer cell lines in vitro. However, further insight into the molecular mechanisms that underlie the cytotoxic effect of pancracine have not been reported and remain unknown. To fill this void, the cell proliferation and viability of cancer cells was explored using the Trypan Blue assay or by using the xCELLigence system. The impact on the cell cycle was determined by flow cytometry. Apoptosis was evaluated by Annexin V/PI and by quantifying the activity of caspases (-3/7, -8, and -9). Proteins triggering growth arrest or apoptosis were detected by Western blotting. Pancracine has strong antiproliferative activity on A549 cells, lasting up to 96 h, and antiproliferative and cytotoxic effects on MOLT-4 cells. The apoptosis-inducing activity of pancracine in MOLT-4 cells was evidenced by the significantly higher activity of caspases. This was transmitted through the upregulation of p53 phosphorylated on Ser392, p38 MAPK phosphorylated on Thr180/Tyr182, and upregulation of p27. The pancracine treatment negatively altered the proliferation of A549 cells as a consequence of an increase in G1-phase accumulation, associated with the downregulation of Rb phosphorylated on Ser807/811 and with the concomitant upregulation of p27 and downregulation of Akt phosphorylated on Thr308. This was the first study to glean a deeper mechanistic understanding of pancracine activity in vitro. Perturbation of the cell cycle and induction of apoptotic cell death were considered key mechanisms of pancracine action.

• MeSH
• adenokarcinom plic patologie   MeSH
• alkaloidy izolace a purifikace   farmakologie   MeSH
• Amaryllidaceae chemie   MeSH
• apoptóza účinky léků   MeSH
• buňky A549 MeSH
• buňky Hep G2 MeSH
• fytogenní protinádorové látky izolace a purifikace   farmakologie   MeSH
• heterocyklické sloučeniny tetra- a více cyklické izolace a purifikace   farmakologie   MeSH
• leukemie patologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• nádory plic patologie   MeSH
• proliferace buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Mitochondria play an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Previously, we found that succinate-activated respiration was the most affected mitochondrial parameter in mice with mild NAFLD. In this study, we focused on the role of succinate dehydrogenase (SDH) in NAFLD pathogenesis. To induce the progression of NAFLD to nonalcoholic steatohepatitis (NASH), C57BL/6J mice were fed a Western-style diet (WD) or control diet for 30 weeks. NAFLD severity was evaluated histologically and the expression of selected proteins and genes was assessed. Mitochondrial respiration was measured by high-resolution respirometry. Liver redox status was assessed using glutathione, malondialdehyde, and mitochondrial production of reactive oxygen species (ROS). Metabolomic analysis was performed by GC/MS. WD consumption for 30 weeks led to reduced succinate-activated respiration. We also observed decreased SDH activity, decreased expression of the SDH activator sirtuin 3, decreased gene expression of SDH subunits, and increased levels of hepatic succinate, an important signaling molecule. Succinate receptor 1 (SUCNR1) gene and protein expression were reduced in the livers of WD-fed mice. We did not observe signs of oxidative damage compared to the control group. The changes observed in WD-fed mice appear to be adaptive to prevent mitochondrial respiratory chain overload and massive ROS production.

• MeSH
• apoptóza MeSH
• biologické markery MeSH
• buněčné dýchání MeSH
• fibróza MeSH
• jaterní mitochondrie metabolismus   MeSH
• kyselina jantarová metabolismus   MeSH
• metabolom MeSH
• metabolomika metody   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• náchylnost k nemoci MeSH
• nealkoholová steatóza jater etiologie   metabolismus   patologie   MeSH
• oxidace-redukce * MeSH
• oxidační stres * MeSH
• sukcinátdehydrogenasa metabolismus   MeSH
• západní dieta * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The prevalence rates of the use of Complementary and Alternative Medicine (CAM) in allergy patients range from 42% in the United States up to 50% in Europe. In the Czech Republic, no such data exists. Our aim was to examine patterns in CAM use in populations with self-reported allergies in the Czech Republic. METHODS: A cross-sectional survey was conducted. A sample of citizens aged 15 years and older, sex, age, and region-stratified, was randomly selected from the 2014 voter registration lists (n = 8,395,132). Respondents with self-reported allergies were further analyzed. RESULTS: Overall, 93% of the respondents with self-reported allergies reported the use of 1 or more CAM modalities during the past 30 days. Herbal teas, relaxation techniques, a detoxifying diet, dietary supplements (excluding vitamins and minerals), and reflexology were used in respondents with allergies. Females, under age 30, with higher education, higher income, and self-reported poor health, were significantly associated with the use of CAM among respondents with allergies. CONCLUSIONS: The prevalence of CAM use among people with self-reported allergies in the Czech Republic is higher compared to other countries, with determinants of CAM varying across specific CAM categories. More attention to existing use is needed to promote the healthy adoption of CAM by raising awareness of its safe and effective use, both for CAM users as well as for health care providers.

• MeSH
• alergie epidemiologie   terapie   MeSH
• dospělí MeSH
• komplementární terapie statistika a číselné údaje   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• pacientův souhlas se zdravotní péčí statistika a číselné údaje   MeSH
• průřezové studie MeSH
• průzkumy a dotazníky MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra‑S or G2/M checkpoints has also been extensively pursued. This review focuses on clinical candidates that target the kinases involved in intra‑S and G2/M checkpoints, namely, ATR, CHK1, and WEE1 inhibitors. It provides insight into their current status and future perspectives for anticancer treatment. Overall, even though CHK1 inhibitors are still far from clinical establishment, promising accomplishments with ATR and WEE1 inhibitors in phase II trials present a positive outlook for patient survival.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Olaparib is a potent poly (ADP-ribose) polymerase inhibitor currently used in targeted therapy for treating cancer cells with BRCA mutations. Here we investigate the possible interference of olaparib with daunorubicin (Daun) metabolism, mediated by carbonyl-reducing enzymes (CREs), which play a significant role in the resistance of cancer cells to anthracyclines. Incubation experiments with the most active recombinant CREs showed that olaparib is a potent inhibitor of the aldo-keto reductase 1C3 (AKR1C3) enzyme. Subsequent inhibitory assays in the AKR1C3-overexpressing cellular model transfected human colorectal carcinoma HCT116 cells, demonstrating that olaparib significantly inhibits AKR1C3 at the intracellular level. Consequently, molecular docking studies have supported these findings and identified the possible molecular background of the interaction. Drug combination experiments in HCT116, human liver carcinoma HepG2, and leukemic KG1α cell lines showed that this observed interaction can be exploited for the synergistic enhancement of Daun's antiproliferative effect. Finally, we showed that olaparib had no significant effect on the mRNA expression of AKR1C3 in HepG2 and KG1α cells. In conclusion, our data demonstrate that olaparib interferes with anthracycline metabolism, and suggest that this phenomenon might be utilized for combating anthracycline resistance.

• Publikační typ
• časopisecké články MeSH

Plants of the Amaryllidaceae family are promising therapeutic tools for human diseases and have been used as alternative medicines. The specific secondary metabolites of this plant family, called Amaryllidaceae alkaloids (AA), have attracted considerable attention due to their interesting pharmacological activities. One of them, galantamine, is already used in the therapy of Alzheimer's disease as a long acting, selective, reversible inhibitor of acetylcholinesterase. One group of AA is the montanine-type, such as montanine, pancracine and others, which share a 5,11-methanomorphanthridine core. So far, only 14 montanine-type alkaloids have been isolated. Compared with other structural-types of AA, montanine-type alkaloids are predominantly present in plants in low concentrations, but some of them display promising biological properties, especially in vitro cytotoxic activity against different cancerous cell lines. The present review aims to summarize comprehensively the research that has been published on the Amaryllidaceae alkaloids of montanine-type.

• MeSH
• alkaloidy amarylkovitých chemie   izolace a purifikace   farmakologie   MeSH
• Amaryllidaceae chemie   metabolismus   MeSH
• antiprotozoální látky chemie   izolace a purifikace   farmakologie   MeSH
• cholinesterasové inhibitory chemie   izolace a purifikace   farmakologie   MeSH
• fenantridiny chemie   izolace a purifikace   farmakologie   MeSH
• fytogenní protinádorové látky chemie   izolace a purifikace   farmakologie   MeSH
• galantamin chemie   izolace a purifikace   farmakologie   MeSH
• heterocyklické sloučeniny tetra- a více cyklické chemie   izolace a purifikace   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• isochinoliny chemie   izolace a purifikace   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nootropní látky chemie   izolace a purifikace   farmakologie   MeSH
• rostlinné extrakty chemie   MeSH
• sekundární metabolismus MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Bersavine is the new bisbenzylisoquinoline alkaloid isolated from the Berberis vulgaris L.(Berberidaceae) plant. The results of cytotoxicity screening 48 h post-treatment showed thatbersavine considerably inhibits the proliferation and viability of leukemic (Jurkat, MOLT-4), colon(HT-29), cervix (HeLa) and breast (MCF-7) cancer cells with IC50 values ranging from 8.1 to 11 μM.The viability and proliferation of leukemic Jurkat and MOLT-4 cells were decreased after bersavinetreatment in a time- and dose-dependent manner. Bersavine manifested concentration-dependentantiproliferative activity in human lung, breast, ovarian and hepatocellular carcinoma cell linesusing a xCELLigence assay. Significantly higher percentages of MOLT-4 cells exposed to bersavineat 20 μM for 24 h were arrested in the G1 phase of the cell cycle using the flow cytometry method.The higher percentage of apoptotic cells was measured after 24 h of bersavine treatment. Theupregulation of p53 phosphorylated on Ser392 was detected during the progression of MOLT-4 cellapoptosis. Mechanistically, bersavine-induced apoptosis is an effect of increased activity ofcaspases, while reduced proliferation seems dependent on increased Chk1 Ser345 phosphorylationand decreased Rb Ser807/811 phosphorylation in human leukemic cells.

• MeSH
• alkaloidy * chemie   izolace a purifikace   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• Berberis chemie   MeSH
• buňky Hep G2 MeSH
• buňky HT-29 MeSH
• cytotoxiny * chemie   izolace a purifikace   farmakologie   MeSH
• fytogenní protinádorové látky * chemie   izolace a purifikace   farmakologie   MeSH
• G1 fáze účinky léků   MeSH
• HeLa buňky MeSH
• Jurkat buňky MeSH
• leukemie farmakoterapie   metabolismus   patologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• screeningové testy protinádorových léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH