Umin was discovered in Curcuma longa L. and/or Curcuma domestica L. C5-curcumin and its derivatives, like synthetic cyclic C5-curcuminoids, are promising anticancer compounds with exceptional pharmacokinetic profiles compared to curcumin. To demonstrate their anticancer activities, we tested six novel synthetic cyclic C5-curcuminoids on HeLa, HEC-1A, and T24 tumor cell lines. This investigation focused on ferroptosis and apoptosis, two types of programmed cell death. Ferroptosis-related genes were investigated using real-time polymerase chain reaction (PCR) and Western blotting. The total iron content, reactive oxygen species (ROS) levels, glutathione peroxidase activity, and thiol concentrations were measured to determine ferroptosis. Cytochrome c levels and caspase-3 activity were measured to monitor the apoptosis. The study of six synthetic cyclic C5-curcuminoids revealed that their effects on HeLa cells differed from those on HEC-1A and T24 cells, indicating distinct mechanisms of action. Compound 4 notably increased iron accumulation and reactive oxygen species (ROS) production, while decreasing antioxidant defenses in all three carcinoma cell lines, suggesting a ferroptotic response. In contrast, compound 9 was successful in activating caspase-3 in carcinoma cells and inducing apoptosis in the COS-1 control cell line. Notably, compound 4 did not enhance caspase-3 activity in the control cell line. These results highlight compound 4 as a possible synthetic cyclic C5-curcuminoid for the three cancerous cell lines tested. Regarding the distinct effects of the examined synthetic cyclic C5-curcuminoids on the three cancer cell types, we hypothesize that their mechanisms of action are different and that divergent target molecules and/or signaling pathways may be involved. However, compounds 4 and 9 were efficient against the three carcinoma cell lines. Further examination of the possible targets could help elucidate which compounds are more suitable for consideration as potential antitumor drug candidates.

Parkinson’s disease (PD) is recognized as one of the most common neurodegenerative disorders globally. The primary factor contributing to this condition is the loss of dopaminergic neurons, which results in both motor and nonmotor symptoms. The etiology of neurodegeneration remains unclear. However, it is characterized by the elevated production of reactive oxygen species, which subsequently leads to oxidative stress, lipid peroxidation, mitochondrial dysfunction, and inflammation. The investigation of the applicability of natural compounds and their derivatives to various diseases is becoming increasingly important. The possible role of curcumin from Curcuma longa L. and its derivatives in the treatment of PD has been partially investigated, but there are no data on the action of synthetic cyclic C5-curcuminoids and chalcones tested in a Parkinson’s model. Two chalcones and five synthetic cyclic C5-curcuminoids with potential antioxidant properties were investigated in an in vitro model of 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in differentiated SH-SY5Y cells. Reactive oxygen species (ROS) production, total antioxidant capacity, antioxidant enzyme activity, thiol and ATP levels, caspase-3 activity, and cytokine release were examined after treatment with the test compounds. Based on these results, one cyclic chalcone (compound 5) and three synthetic cyclic C5-curcuminoids (compounds 9, 12, and 13) decreased oxidative stress and apoptosis in our in vitro model of neurodegeneration. Compounds 5 and 9 were also successful in decreasing the production of pro-inflammatory cytokines (IL-6, IL-8, and TNF-α), while promoting the release of anti-inflammatory cytokines (IL-4 and IL-10). These findings indicate that these two compounds exhibit potential antioxidant, anti-apoptotic, and anti-inflammatory properties, rendering them promising candidates for drug development.

BackgroundOver the past 4 decades, obesity has escalated into a global epidemic, with its worldwide prevalence nearly tripling. Pharmacological treatments have evolved with the recent development of glucagon-like peptide 1 agonists, such as semaglutide. However, off-label use of drugs such as Ozempic for cosmetic weight loss has surged in popularity, raising concerns about potential misuse and the emergence of substandard and falsified products in the unregulated supply chain. ObjectiveThis study aims to conduct a multifactor investigation of product quality and patient safety risks associated with the unregulated online sale of semaglutide by examining product availability and vendor characteristics and assessing product quality through test purchases. MethodsWe used a complex risk and quality assessment methodology combining online market surveillance, search engine results page analysis, website content assessment, domain traffic analytics, conducting targeted product test purchases, visual quality inspection of product packaging, microbiological sterility and endotoxin contamination evaluation, and quantitative sample analysis using liquid chromatography coupled with mass spectrometry. ResultsWe collected and evaluated 1080 links from search engine results pages and identified 317 (29.35%) links belonging to online pharmacies, of which 183 (57.7%) led to legal pharmacies and 134 (42.3%) directed users to 59 unique illegal online pharmacy websites. Web traffic data for the period between July and September 2023 revealed that the top 30 domains directly or indirectly affiliated with illegal online pharmacies accumulated over 4.7 million visits. Test purchases were completed from 6 illegal online pharmacies with the highest number of links offering semaglutide products for sale without prescription at the lowest price range. Three injection vial purchases were delivered; none of the 3 Ozempic prefilled injection pens were received due to nondelivery e-commerce scams. All purchased vials were considered probable substandard and falsified products, as visual inspection indicated noncompliance in more than half (59%-63%) of the evaluated criteria. The semaglutide content of samples substantially exceeded labeled amounts by 28.56%-38.69%, although no peptide-like impurities were identified. The lyophilized peptide samples were devoid of viable microorganisms at the time of testing; however, endotoxin was detected in all samples with levels ranging between 2.1645 EU/mg and 8.9511 EU/mg. Furthermore, the measured semaglutide purity was significantly low, ranging between 7.7% and 14.37% and deviating from the 99% claimed on product labels by manufacturers. ConclusionsGlucagon-like peptide 1 agonist drugs promoted for weight loss, similar to erectile dysfunction medications more than 2 decades ago, are becoming the new blockbuster lifestyle medications for the illegal online pharmacy market. Protecting the pharmaceutical supply chain from substandard and falsified weight loss products and raising awareness regarding online medication safety must be a public health priority for regulators and technology platforms alike.

This qualitative study assesses the quality, amount of active ingredient, and characteristics associated with counterfeiting of semaglutide purchased from illegal online pharmacies without a prescription.

The phenolic drug molecules can be metabolized, among others, by the small intestine's enterocytes. The conjugation reactions (glucuronidation and sulfation) show great importance in these transformations, although the oxidation reactions can be significant. These processes are dependent on the substituents of the phenolic compounds or the reacting functional groups (hydroxyl or carboxyl). Pathologic conditions, e.g., permanent hyperglycemia and diabetes, can alter the activities of the conjugative and possibly the oxidative enzymes, thus forming a change in the metabolic pattern and eventually provoking oxidative stress. A rat intestinal perfusion model was used to investigate the way in which experimental hyperglycemia affects the paracetamol's intestinal elimination and metabolism. Hyperglycemia was induced by the administration of streptozotocin. Two hundred and fifty µM paracetamol was used in the intestinal perfusion solution. For the quantitation of the paracetamol and its major metabolites in the intestinal perfusate, an isocratic high-performance liquid chromatography method with UV-Vis detection was developed. The results revealed that quantities of all of the measured metabolites (glucuronide, sulfate, cysteine, and mercapturic acid conjugates) increased as the effect of the streptozotocin-induced hyperglycemia also did. In the small intestine's homogenate, the glutathione levels showed that there was a decrease in the hyperglycemia levels after the paracetamol administration. In contrast, the tissue levels of the cysteine were lower in the streptozotocin-induced hyperglycemia and increased after the administration of the paracetamol. The changes in the activity of the intestinal CYP 3A4, CYP 2E1, and cyclooxygenase (COX) enzymes were determined in the control and the hyperglycemic cases. Still, there was a significant observable enzyme activity elevation in the intestinal COX enzymes, but there was a decrease in the amount of activity of the intestinal CYP3A4 enzymes, and the CYP2E1 enzyme activity was practically changeless. The results on the cysteine levels in the intestinal homogenate, at least partly, can be explained by the regulation function of the cysteine during the occurrence of oxidative stress.

One of the negative consequences of the increased use of medicines is the potential reason for releasing various pharmaceutical residues into the environment. Continuous development of analytical methodologies to identify and quantify such chemicals in natural waters is of major importance to public health. This study aimed to set up a sufficiently sensitive LC-MS method to quantitate targeted androgens and estrogens in water samples. Method development was based on the official EPA Method 539:2010. In our experiments, estrogens were analyzed in the form of their dansyl derivatives. Such derivatization, using multiple reaction monitoring (MRM) mode, improved sensitivity of the original method for estrogens by one or two orders of magnitude. Using electrospray in positive ionization (HESI+) mode resulted in a robust, selective, and sensitive to quantify the targeted steroids with 10 pg L -1 method detection limit (MDL). The linearity of the method was good with correlation coefficients (R) in the range of 0.997-1.000 and with a calibration range of 5-1000 pg L -1 in drinking water. The method was successfully applied to analyze drinking water and mineral water samples collected in the area of Pécs (Baranya County, Hungary).

A Gyógyszerészi Kémiai Intézet 2002. január 1-én alakult, mint a Pécsen 2000-ben indult gyógyszerészképzés egyik szakintézete. Az intézet végleges helyének kialakítása 2003. októberétől kezdődhetett meg. Az adminisztratív ügyek intézésére és az oktatással kapcsolatos feladatainak ellátására - 2002. augusztusától – 2003. októberéig – a PTE Egyetemi Gyógyszertár két helyiségében kapott ideiglenes elhelyezést. A munkatársak 2003. november elején foglalták el a Rókus utcai épület földszinti helyiségeit. Ezt követően kezdődött meg az intézet kutató laboratóriumainak és kutatási profiljainak kialakítása. Az intézetben jelenleg két egymással szorosan kapcsolódó, de tematikusan különböző területen – szerkezet-reaktivitás és szerkezet-hatás vizsgálatok, valamint in vitro és in vivo gyógyszermetabolizmus vizsgálatok – folyik kutatómunka. Jelen közlemény az előbbi területen folytatott vizsgálatok néhány fontosabb eredményeit mutatja be.

Novel series of cyclic C5-curcuminoids 17a-j and 19-22 were prepared as cytotoxic agents and evaluated against human neuroblastoma (SH-SY5Y) or human grade IV astrocytoma (CCF-STTG1) cell lines in low (∼0.1 nM - 10 nM) concentrations. Among the tested 21 derivatives, 16 displayed potent antiproliferative activity with IC50 values in the low nanomolar to picomolar range (IC50 = 7.483-0.139 nM). Highly active compounds like N-monocarboxylic derivative 19b with IC50 = 0.139 nM value against neuroblastoma and N-alkyl substituted 11 with IC50 = 0.257 nM against astrocytoma proved some degree of selectivity toward non-cancerous astrocytes and kidney cells. This potent anticancer activity did not show a strong correlation with experimental logPTLC values, but the most potent antiproliferative molecules 11-13 and 19-22 are belonging to discrete subgroups of the cyclic C5-curcuminoids. Compounds 12, 17c and 19b were subjected to blood-brain barrier (BBB) penetration studies, too. The BBB was revealed to be permeable for all of them but, as the apparent permeability coefficient (Papp) values mirrored, in different ratios. Lower toxicity of 12, 17c and 19b was observed toward primary rat brain endothelial cells of the BBB model, which means they remained undamaged under 10 µM concentrations. Penetration depends, at least in part, on albumin binding of 12, 17c and 19b and the presence of monocarboxylic acid transporters in the case of 19b. Permeation through the BBB and albumin binding, we described here, is the first example of cyclic C5-curcuminoids as to our knowledge.

Increased activation of poly(ADP-ribose) polymerase (PARP) enzyme has been implicated in the pathogenesis of acute and chronic myocardial dysfunction. We have demonstrated the protective effect of PARP inhibitors against postinfarction myocardial remodeling and heart failure. The primary aim of our recent work was to compare the effect and efficacy of a potent PARP-inhibitor (L-2286) to enalapril, a widely used angiotensin-converting enzyme (ACE) inhibitor in experimental heart failure model. Both L-2286 and enalapril were tested in a rat model of chronic heart failure after isoproterenol-induced myocardial infarction. After a 12-week treatment period, echocardiography was performed, cardiac hypertrophy and interstitial collagen deposition were assessed, and the phosphorylation state of Akt-1/GSK-3 beta pathway as well as the PKC and MAPK kinases were determined. Both PARP and ACE inhibition reduced the progression of postinfarction heart failure by attenuating cardiac hypertrophy and interstitial fibrosis. More importantly, PARP inhibition increased the activity of the prosurvival signal transduction factors (Akt-1/GSK-3 beta pathway, PKCE). Due to these effects, L-2286 improved the systolic left ventricular function. Enalapril treatment exerted a similar, but weaker protective effect against postinfarction myocardial remodeling and heart failure. In conclusion, we demonstrated in an experimental heart failure model that L-2286 decreased the postinfarction myocardial remodeling more effectively than enalapril treatment.

The inhibition of glycogen synthase kinase-3beta (GSK-3beta) via phosphorylation by Akt or protein kinase C (PKC), or the activation of mitogen-activated protein kinase (MAPK) cascades can play a pivotal role in left ventricular remodeling following myocardial infarction. Our previous data showed that MAPK and phosphatidylinositol-3-kinase/Akt pathways could be modulated by poly(ADP-ribose)polymerase (PARP) inhibition raising the possibility that cardiac hypertrophic signaling responses may be favorably influenced by PARP inhibitors. A novel PARP inhibitor (L-2286) was tested in a rat model of chronic heart failure following isoproterenol-induced myocardial infarction. Subsequently, cardiac hypertrophy and interstitial collagen deposition were assessed; additionally, mitochondrial enzyme activity and the phosphorylation state of GSK-3beta, Akt, PKC and MAPK cascades were monitored. PARP inhibitor (L-2286) treatment significantly reduced the progression of postinfarction heart failure attenuating cardiac hypertrophy and interstitial fibrosis, and preserving the integrity of respiratory complexes. More importantly, L-2286 repressed the hypertrophy-associated increased phosphorylation of panPKC, PKC alpha/betaII, PKC delta and PKC epsilon, which could be responsible for the activation of the antihypertrophic GSK-3beta. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3beta intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure.

Blocking poly(ADP-ribosyl)ation of nuclear proteins protects the heart from ischemia-reperfusion injury. In addition, activation of Akt and mitogen-activated protein kinase (MAPK) cascades also plays a pivotal role in the survival of cardiomyocytes during ischemia-reperfusion; however, the potential interplay between these pathways is yet to be elucidated. We therefore tested the hypothesis whether poly(ADP-ribose) polymerase (PARP) inhibition can modulate Akt and MAPK signaling of ischemic-reperfused rat hearts. A novel PARP inhibitor, L-2286 [2-[(2-piperidin-1-yletil)thio]quinazolin-4(3H)-one] was administered during ischemia-reperfusion in Langendorff perfused rat hearts and in isoproterenol-induced myocardial infarction. Thereafter, the cardiac energy metabolism, oxidative damage, and the phosphorylation state of Akt and MAPK cascades were monitored. L-2286 exerted significant protective effect against ischemia-reperfusion-induced myocardial injury in both experimental models. More importantly, L-2286 facilitated the ischemia-reperfusion-induced activation of Akt, extracellular signal-regulated kinase, and p38-MAPK in both isolated hearts and in vivo cardiac injury. By contrast, isoproterenol-induced rapid c-Jun N-termainal kinase activation was repressed by L-2286. Here, we provide evidence for the first time that PARP inhibition beneficially modulates the cardiac Akt and MAPK signaling in ex vivo and in vivo ischemia-reperfusion models. We therefore propose that this novel mechanism may contribute to the cardioprotective properties of PARP inhibitors.

Starting from paramagnetic benzaldehyde, a benzophenone-type photoactivable spin label, paramagnetic warfarin and phenindiore were synthesized. Nitration of protected benzylic alcohol led to 2-nitrobenzylmethanethiosulfonate, a thiol specific spin label, and 2-nitroaldehyde, which was a key compound for paramagnetic indigo, salicylic acid and nifedipine.

Paramagnetic and diamagnetic flavone and flavanone derivatives modified on the C or B rings were synthesized by condensation, Sonogashira reaction, lithiation, and the Baker-Venkataraman procedure.

4-Quinazolinones modified with 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole or 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine rings and their N-oxyl derivatives were synthesized and some of them evaluated for protecting activity against H2O2 induced cell death on WRL-68 human liver cell line. Compounds 15a, 15c and 15d exhibited remarkably inhibitory effects on PARP enzyme in vitro.

Starting from paramagnetic β-bromo-α,β-unsaturated aldehyde 1, β-bromo-α,β-unsaturated nitrile 2 and diene 3 heterocycles 4-10 and carbocycles 12-14, 16, and 17 were synthesized with simple procedures in the presence of a nitroxide moiety. A complex-forming paramagnetic phenanthroline 19 is also described.