Search Results (215)

Cervical cancer (CCa) is the fourth leading cause of cancer-related deaths among women worldwide, with nearly 90% of cases in low- and middle-income countries, especially in Sub-Saharan Africa. This study explores the roles of circular ribonucleic acids (circRNAs), hsa_circ_0001038 and circRNA_400029, and the impact of the serine/arginine-rich splicing factor 3 (SRSF3) inhibitor, theophylline, in CCa cell lines. We utilized cell cycle fluorescence-activated cell sorting (FACS) and Annexin V/propidium iodide (PI) assays to evaluate theophylline’s effects on SiHa and C33A cell lines. Results showed S-phase arrest in SiHa and G2/M arrest in C33A, with significant cytotoxic effects indicated by apoptosis analysis. Using CircAtlas, we identified micro ribonucleic acids (miRNAs) binding to hsa_circ_0001038, particularly miR-205-5p, which has a tumour-suppressive role. miRTarBase identified miR-16-5p as a key interacting miRNA for circRNA_400029. We constructed a competing endogenous ribonucleic acid (ceRNA) network, revealing multiple miRNA targets. Pathway analysis via the Kyoto Encyclopedia of Genes and Genomes (KEGG) highlighted critical signalling pathways involved in CCa oncogenesis. In conclusion, theophylline demonstrates cytotoxicity in CCa cells, suggesting its potential for repurposing in CCa theranostics, though further optimization is necessary. Full article

Background/Objectives: Cardiovascular diseases (CVD) remain the leading cause of diet-related mortality, with hepatic overproduction of very-low-density lipoprotein (VLDL) being a central driver of dyslipidemia. The microsomal triglyceride transfer protein (MTP) is essential for this process, and its activity is negatively regulated by cyclic adenosine monophosphate (cAMP). Theophylline, a methylxanthine found in tea, increases intracellular cAMP. This study aimed to evaluate whether physiologically relevant concentrations of theophylline could beneficially modulate lipoprotein secretion in an ex vivo model of diet-induced MTP activation. Methods: Primary hepatocytes were isolated from rats fed a high-fat, high-carbohydrate diet (HFCD). Cells were treated with 100 µM theophylline, and the secretion of triglyceride (TG), total cholesterol (TC), VLDL-cholesterol (VLDL-C), and HDL-cholesterol (HDL-C) was quantified. Hepatocellular MTP activity and atherogenic indices were also assessed. Results: Compared to untreated control cells, theophylline treatment significantly reduced the secretion of TG by 6% and TC by 24%. Specifically, VLDL-C secretion decreased by 6%, while HDL-C secretion increased substantially by 93%. These lipid-modulating effects were correlated with a 6.9% reduction in MTP activity. Consequently, significant improvements were observed in the atherogenic indices TG/HDL-C, TC/HDL-C, and the atherogenic index (AI) (p < 0.01). Conclusions: Our findings demonstrate that physiologically attainable concentrations of theophylline rebalance lipoprotein secretion by suppressing hepatic MTP activity, shifting the lipid profile toward an anti-atherogenic state. These results highlight the potential of theophylline as a functional dietary component for mitigating diet-induced dyslipidemia and reducing cardiovascular risk. Full article

Theophylline represents a significant public health challenge due to its dual acute and chronic toxicity resulting from therapeutic, environmental, and dietary exposures. Effective monitoring across the bio-environmental–food triad requires analytical methods that are highly sensitive, universally applicable, and capable of overcoming complex matrix interferences. This study introduces a flat membrane-based liquid-phase microextraction (LPME) technique combined with LC–MS/MS for the determination of theophylline in diverse matrices. The method eliminates the need for specialized adsorbents or equipment, offering a simple and cost-effective solution for high-throughput sample clean-up. Under optimized conditions, the method demonstrated exceptional sensitivity (LOD: 0.2 ng mL⁻¹) and a wide linear range (0.01–10 μg mL⁻¹). It was successfully applied to plasma, urine, hospital sewage, and green tea, providing accurate (recoveries of 86.7–111.3%) and reproducible (RSD < 10%) results across all matrices. This unified and robust approach effectively addresses matrix interferences and provides a reliable tool for the monitoring and risk assessment of theophylline across multiple domains. Full article

Additive manufacturing using fused deposition modelling (FDM) is increasingly explored for personalised drug delivery, but the lack of suitable biodegradable and printable filaments limits its pharmaceutical application. In this study, we investigated the influence of formulation and structural design on the performance of polyvinyl alcohol (PVA)-based filaments doped with theophylline anhydrous for 3D printing. To address the intrinsic brittleness and poor printability of PVA, cassava pulp-derived fibres—a sustainable and underutilised agricultural by-product—were incorporated together with polyethylene glycol (PEG 400), Eudragit^® NE 30 D, and calcium stearate. The addition of fibres modified the mechanical properties of PVA filaments through hydrogen bonding, improving flexibility but increasing surface roughness. This drawback was mitigated by Eudragit^® NE 30 D, which enhanced surface smoothness and drug distribution uniformity. The optimised composite formulation (P₁₀F₅E₅T₅) was successfully extruded and used to fabricate 3D-printed constructs. Release studies demonstrated that drug release could be modulated by pore geometry and construct thickness: wider pores enabled rapid Fickian diffusion, while narrower pores and thicker constructs shifted release kinetics toward anomalous transport governed by polymer swelling. These findings demonstrate, for the first time, the potential of cassava fibre as a functional additive in pharmaceutical FDM and provide a rational formulation–structure–performance framework for developing sustainable, geometry-tuneable drug delivery systems. Full article

Background: Theophylline, which is biologically important and found in tea, coffee, and cocoa beans, can be synthesized chemically or by direct extraction and concentration from natural sources. Theophylline derivatives have garnered attention in recent years for their potential therapeutic effects on Mycobacterium tuberculosis, antihistaminic, anti-inflammatory, and anticancer. Also, trifluoromethyl (CF₃) group has also been widely used in drug and agrochemical design. Methods: In this study, a series of new theophylline derivatives containing substituted trifluoromethyl and trifluoromethoxy groups were synthesized. The structures of these new compounds were confirmed by NMR, FT-IR, and elemental analyses. Additionally, the anticancer activities of the molecules were analyzed against VEGFR-2, CYP P450, and estrogen receptor by molecular docking method. Furthermore, in vitro biological effects of the compounds were comprehensively evaluated in cancer (A549 and HeLa) and normal (BEAS-2B) cells. Cell viability was assessed by MTT assay, and selectivity index (SI) values were calculated to determine tumor-specific toxicity. Results: N(7)-substituted theophyllines were prepared by the reaction of 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (theophylline) and trifluoromethyl substituted benzyl halide compounds. The synthesized N(7)-substituted theophyllines were obtained as white powder in high yield. The structure of synthesized compounds was confirmed by various spectroscopic techniques such as ¹H, ¹³C, ¹⁹F NMR, and FT-IR spectroscopy, and elemental analysis. The highest interaction was recorded as −5.69 kcal/mol for 3-CF₃ substituted against VEGFR-2 structure while the best binding affinity was determined for 4-OCF₃ substituted with −6.69 kcal/mol against Human Cytochrome P450 with in silico analysis. The in vitro anticancer activities of the molecules were also evaluated against A549 and HeLa cells, and displayed considerably higher cytotoxicity with 2-CF₃, 3-CF_3, and 4-CF₃ substituted molecules in Hela and A549 cell line. To elucidate the molecular mechanism, apoptosis-related gene expression changes were analyzed by RT-qPCR in A549 and HeLa cells treated with compound 2-CF₃. Significant upregulation of pro-apoptotic markers and downregulation of anti-apoptotic genes were observed. Consistently, ELISA-based quantification confirmed increased protein levels of Caspase-3, BAX, and Cytochrome C, and decreased BCL-2, validating the apoptotic mechanism at the protein level. Also, the antibacterial and antibiofilm activity details of the molecules were evaluated against DNA Gyrase, and SarA crystal structures by molecular docking method. The highest interaction was recorded as −5.56 kcal/mol for 2-CF₃ substituted with H-bonds with Asn46, Val71, Asp73, and Thr165 against DNA Gyrase crystal structure while 3-CF₃ substituted has the best binding affinity against SarA. The in vitro antimicrobial effects of the molecules were also evaluated. Conclusions: The synthesized molecules may provide insight into the development of potential therapeutic agents to the increasing antimicrobial resistance and biofilm-forming capacity of microorganisms. Additionally, compound 2-CF₃ substituted exhibited promising and selective anticancer activity through apoptosis induction, supported by gene and protein level evidence. Full article

Background: Understanding interactions between cytokine antagonists and drugs is essential for effective medication management in inflammatory conditions. Recent regulatory authority guidelines emphasise a systematic, risk-based approach to evaluating these interactions, underscoring the need for mechanistic insight. Proinflammatory cytokines, such as interleukin-6 (IL-6), modulate cytochrome P450 (CYP) enzymes, reducing the metabolism of CYP substrates. Cytokine antagonists (such as IL-6 receptor antagonists) can counteract this effect, restoring CYP activity and increasing drug clearance. However, quantitative prediction of cytokine-mediated drug interactions remains challenging, as existing models often lack the mechanistic detail needed to capture the dynamic relationship between cytokine signalling, receptor engagement, and downstream modulation of drug metabolism. Methods: A physiologically based pharmacokinetic (PBPK) framework incorporating cytokine–receptor binding, subsequent downregulation of CYP expression, and blockade of the cytokine signalling by a therapeutic protein antagonist was developed to simulate and investigate cytokine antagonist-drug interactions. Tocilizumab, a humanised IL-6 receptor antagonist used to treat several inflammatory conditions associated with elevated IL-6 levels, was selected as a model drug to demonstrate the utility of the framework. Results: The developed PBPK model accurately predicted the pharmacokinetics profiles of tocilizumab and captured clinically observed dynamic changes in simvastatin exposure before and after tocilizumab treatment in rheumatoid arthritis (RA) patients. Simulated IL-6 dynamics aligned with observed clinical profiles, showing transient elevation following receptor blockade and associated restoration of CYP3A4 activity. Prospective simulations with commonly co-administered CYP substrates (celecoxib, chloroquine, cyclosporine, ibuprofen, prednisone, simvastatin, and theophylline) in RA patients revealed dose regimen- and drug-dependent differences in interaction magnitude. Conclusions: This study demonstrated the utility of PBPK models in providing a mechanistic understanding of cytokine antagonist-drug interactions, supporting enhanced therapeutic decision-making and optimising patient care in inflammatory conditions. Full article

The use of pharmaceuticals and personal care products (PPCPs) is steadily growing as the world’s population both increases and ages. Many of these products are released into the environment via municipal wastewater treatment plants and onsite wastewater treatment systems (septic tanks). Consequently, it is essential to ascertain whether these contaminants pose any risk to aquatic organisms who live in the water bodies receiving this waste. Risk quotients (RQ) are a commonly used method to do so. For our pilot study, we undertook such analysis for three trophic levels: algae, crustaceans, and fish from two small lakes, one fed by septic tanks and the other not. This research was conducted in 2021 from the end of the dry season and through most of the wet season in west central Florida, USA. Of the 14 PPCPs measured, six had RQs that posed a risk to all three trophic levels. This risk increased during the wet season. Both lakes, regardless of whether they directly received PPCPs from septic tanks or not, had some level of risk. However, the lake without septic tanks had a smaller risk, both in elevated RQs and the occurrence to the various species. Of the PPCPs measured, DEET, caffeine, and theophylline posed the greatest risk. Full article

Shallow lakes are highly vulnerable to pollution due to their small water volume. Those that receive effluent from the drainfields of onsite wastewater treatment systems (septic tanks) may contain pharmaceuticals and personal care products (PPCPs) that escaped removal during treatment. This study examined the effects of seasonal rainfall variability on the assemblages and concentrations of fourteen PPCPs in two shallow lakes in West–Central Florida, USA: one surrounded by residents equipped with septic tanks and the other located within a nature preserve. Water samples were collected weekly during an 18-week interval from April to August 2021. Liquid chromatography–mass spectrometry analyses revealed the omnipresence of five PPCPs: theophylline, caffeine, cotinine, DEET, and testosterone, although acetaminophen, ibuprofen, and sulfamethoxazole were also common. Of all the PPCPs detected, theophylline, DEET, and acetaminophen concentrations were higher during the wet season in the septic tank-influenced lake, while caffeine, cotinine, and testosterone concentrations decreased. In the lake located in the nature preserve, theophylline, caffeine, and acetaminophen levels increased in the wet season. In contrast, cotinine, DEET, and testosterone levels decreased. Overall, more compounds were detected during the wet season, with highly hydrophobic PPCPs (fluoxetine, atorvastatin, and octocrylene) only present during this period. Full article

Background: Nedaplatin is a platinum-based anticancer drug that combines the benefits of Cisplatin and Carboplatin, retaining Cisplatin’s anticancer activity while reducing toxicity similar to Carboplatin. After hydrolysis, Nedaplatin targets purines in DNA and forms cross-links that induce cell death via apoptosis. However, it is important to consider how the presence of other chemical compounds with structural similarities to Adenine or Guanine, such as aromatic, purine, or pyrimidine compounds containing a nitrogen atom with a free electron pair, might influence its activity at the cellular level. Alkaloids with structures similar to DNA nucleobases are common, and their influence on Nedaplatin’s activity requires investigation. Methods: In this study, the interactions between Nedaplatin (including its hydrolyzed forms, such as [Pt(NH₃)₂(H₂O)₂]²⁺ and [Pt(NH₃)₂(H₂O)(OH)]⁺) and nucleobases (Adenine and Guanine) and purine alkaloids (Caffeine, Theobromine and Theophylline) were thoroughly investigated using theoretical (density functional theory, DFT) and experimental (UV-Vis spectroscopy) methods. DFT calculations were performed at the B3LYP/6-31G(d,p)/LANL2DZ and MN15/def2-TZVP levels, with structure optimization and harmonic analysis in the gas phase and aqueous solution (modeled using IEF-PCM). UV-Vis spectroscopy was used to verify theoretical findings by examining changes in absorption spectra. Results: Both theoretical and experimental studies confirmed that Nedaplatin forms complexes with both nucleobases and purine alkaloids. Nedaplatin was found to exhibit a higher affinity for nucleobases than for purine alkaloids. Furthermore, this affinity was dependent on the computational method used and on the hydrolyzed form of Nedaplatin. Theoretical calculations showed the formation of stable complexes through bonding with nitrogen atoms in the ligand molecules, which was confirmed by changes in UV-Vis spectra, indicating adduct formation. Conclusions: The results indicate that Nedaplatin readily forms complexes with both nucleobases and purine alkaloids, showing a stronger affinity for nucleobases. This finding highlights the potential importance of Nedaplatin’s interactions with other compounds present in the body, which may influence its effectiveness and mechanism of action in cancer therapy. These studies provide new insights into the molecular mechanisms of Nedaplatin’s action and may contribute to a better understanding of its pharmacological interactions. However, research requires confirmation not only in in vivo studies but also in clinical trials. Full article

In this study, we analysed cocoa (a dried and fully fermented seed of Theobroma cacao L.) from two Amazonian cultivars and a commercial sample of the Amazonian variety EETP801, grown under sustainable organic conditions, in comparison to CCN51 cocoa grown on a neighbouring commercial farm using standard practises and a European commercial cacao powdered beverage. The overall metabolite profile of the 70% aq acetone sample cocoa extracts was analysed using high-performance TLC analyses (HPTLC), and the xanthine alkaloids were analysed using quantitative liquid chromatography–UV photodiode array (HPLC-DAD) analyses. The volatile fraction in the headspace of the freshly ground cocoa was subjected to solid phase micro-extraction and analysed by gas chromatography–mass spectrometry (HS-SPME/GC-MS). Total polyphenol content was determined by the Folin–Ciocalteu method. Despite the reduced production of cocoa by the EETP801 cultivar in comparison with the CCN51 cultivar, the obtained produce is significantly richer in theobromine (130 mg vs. 170 mg per g of cacao), with CCN51 having a double concentration of theophylline (12.6 vs. 6.5 mg per g of cacao). Qualitatively, the two Amazonian cocoa samples had a similar polyphenolic composition (per the HPTLC fingerprint). HS-SPME/GC-MS analyses revealed that all the samples show a spontaneous emission profile mainly rich in non-terpene derivatives, of which hydrocarbons and pyrazines are the most abundant groups. The most represented volatile organic compound is n-tridecane for both EETP801 and CCN51. The variability in the artisan fermentation and roasting processes influenced certain aspects of the volatile composition as reflected by the trimethyl pyrazine/tetramethyl pyrazine ratio, which was zero in EETP-801 and lower than 1 in CCN51. Acetic acid was absent in CCN51 but significant (c.a. 5.5.%) in EETP801 and the commercial samples. The cultivar EETP801 is a viable option for a more ecologically conscious sector of the cocoa beverages consumer group. Full article

Clay minerals are promising candidates for caffeine removal due to their environmental friendliness and natural abundance. In this study, a commercially available bentonite was modified by Na⁺ exchange and characterized using Fourier transform infrared spectroscopy, X-ray diffractometry, scanning electron microscopy, zeta potential measurements, and specific surface area analysis. Caffeine adsorption was rapid, reaching equilibrium within 15 min. Adsorption isotherms for caffeine and its metabolites (theobromine, paraxanthine, and theophylline) in pure water were analyzed at 25.0 ± 0.5 °C using Langmuir and Freundlich models, both individually and in mixtures. Only caffeine exhibited favorable adsorption behavior, fitting the Langmuir equation, which allowed for the determination of a maximum adsorption capacity of 20 ± 3 mg/g, regardless of metabolite presence. The removal exceeded 85% of the caffeine from a 5.0 mg/L solution. The adsorption affinity of the studied compounds toward Na⁺-exchanged bentonite followed the order: caffeine >>> theobromine > paraxanthine ~ theophylline. The modified bentonite was then tested for caffeine removal from beverages and synthetic urine, achieving removal efficiencies exceeding 87%. To our knowledge, this is the first study investigating the effect of major caffeine metabolites on adsorption rates across different sample matrices, such as artificial urine, cola soda, soluble coffee, energy drinks, green tea, and yerba mate. Full article

Background/Objectives: Peritoneal dialysis (PD) is a renal replacement therapy for patients with kidney failure. Managing PD patients often involves addressing a complex interplay of comorbidities and complications, necessitating the use of multiple medications. This study aimed to systematically characterize commonly co-prescribed drugs in PD and to identify novel drug combinations that may target dysregulated molecular mechanisms associated with PD’s pathophysiology. Methods: We analyzed clinical records from 702 PD patients spanning 30 years, encompassing over 5500 prescription points. Using network-based modeling techniques, we assessed drug co-prescription patterns, clinical outcomes, and longitudinal treatment trends. To explore potential drug repurposing opportunities, we constructed a molecular network model of PD based on a consolidated transcriptomics dataset and integrated this with drug–target interaction information. Results: We found commonly prescribed drugs such as furosemide, sucroferric oxyhydroxide, calcitriol, darbepoetin alfa, and aluminum hydroxide to be integral components of PD patient management, prescribed in over 30% of PD patients. The molecular-network-based approach found combinations of drugs like theophylline, fluoxetine, celecoxib, and amitriptyline to possibly have synergistic effects and to target dysregulated molecules of PD-related pathomechanisms. Two further distinct categories of drugs emerged as particularly interesting in our study: selective serotonin reuptake inhibitors (SSRIs), which were found to modulate molecules implicated in peritoneal fibrosis, and vascular endothelial growth factor (VEGF) inhibitors, which exhibit anti-fibrotic properties that are potentially useful for PD. Conclusions: This comprehensive exploration of drug co-prescriptions in the context of PD-related pathomechanisms provides valuable insights for opening future therapeutic strategies and identifying new targets for drug repurposing. Full article

Indomethacin, ibuprofen, and acetylsalicylic acid (ASA) are non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin (PG) synthesis. Previous studies in airway smooth muscle demonstrated that chronic exposure to testosterone (TES, 40 nM) enhances the relaxation induced by salbutamol and theophylline due to K⁺ channel increment, without modifying cyclooxygenase expression. This study examines how indomethacin, ibuprofen, and ASA affect K⁺ currents and the relaxation response to these bronchodilators. In organ baths, tracheas from young male guinea pigs chronically (48 h) treated with 40 nM TES showed increased relaxation to salbutamol and theophylline, which was completely abolished by indomethacin. Patch-clamp recordings revealed that TES increased salbutamol- and theophylline-induced K⁺ currents, and only indomethacin fully inhibited this potentiation; ibuprofen and ASA had partial effects. The involved currents included voltage-dependent K⁺ (K_V) and high-conductance Ca²⁺-activated K⁺ (BK_Ca) channels. Our results demonstrate that indomethacin exerts a dual action, inhibiting K⁺ channel activity and PG synthesis, unlike ibuprofen and ASA. This dual mechanism explains its stronger inhibitory effect on TES-enhanced ASM relaxation. These findings suggest that indomethacin may counteract the protective effects of TES, which promotes anti-inflammatory and smooth muscle-relaxing states. Therefore, it is advisable to exercise caution when prescribing indomethacin to young males with asthma, as the protective role of TES may diminish, potentially resulting in an exacerbation of asthma symptoms. Full article

Background/Objectives: In the past, many drug release models have been presented which attempt to describe the interaction of drugs and excipients in a formulation. Nevertheless, modeling the intrinsic dissolution behavior is essential for understanding the fundamental dissolution mechanisms of drugs and for enhancing the quality of computational approaches in the long term. Methods: In this study, the intrinsic dissolution of various pharmaceutical model substances (benzocaine, carbamazepine, griseofulvin, ibuprofen, naproxen, phenytoin, theophylline monohydrate, and trimethoprim) was investigated in dissolution experiments, taking into account the flow conditions in a dissolution channel apparatus. A practicable and generally valid representation was identified to describe the diffusion properties of the drugs in terms of the boundary layer thickness without considering the particle size distribution, physical state, or viscoelastic properties. This representation was supported by numerical simulations using a high-resolution mesh. The influence of the topography on the modeling was also examined. Results: Besides the prediction of the influence of a surface reaction limitation or the solubility of a diffusion controlled drug, the boundary layer thickness at the tablet surface is modellable in terms of a freely selectable length and as a function of the diffusion coefficient, drug solubility, and the flow velocity of the dissolution medium. Conclusions: Using different methods and a large dataset, this study presents a modeling approach that can contribute to a deeper understanding of intrinsic dissolution behavior. Full article