Search Results (3,692)

Background: Pulmonary fibrosis (PF) is a major global health issue associated with substantial morbidity across all age groups. One of the important etiological factors contributing to PF is drug-induced lung injury, which can result from both direct and indirect damage to the pulmonary parenchyma caused by various pharmacological agents, including chemotherapeutics, antirheumatic drugs, cardiovascular medications, and certain antimicrobial agents. The aim of our study was to assess the structure of antibacterials involved in drug-induced PF (DIPF) and analyze signals of DIPF, calculating the reporting odds ratio (ROR) and proportional reporting ratio (PRR) using spontaneous reports (SRs) extracted from the Russian National Pharmacovigilance database. Methods: A retrospective, descriptive pharmacoepidemiological analysis of SRs from the AIS database for the period 1 April 2019–31 March 2025 was conducted. Results: A total of 130 SRs with data on DIPF associated with antibacterial agents were identified, with patients’ mean age of 59.1 ± 14.46 years. Death was reported in 65 SRs (50%) with a mean age of 53.0 ± 13.66 years. Next, antibacterials were identified as leaders: sulfamethoxazole (used alone or in combination with trimethoprim, 20.7% (n = 50)), azithromycin (18.2%, n = 44), levofloxacin (12.4%, n = 30), doxycycline (11.6%, n = 28), and cefuroxime (10.7%, n = 26). Disproportionality analysis performed with PRR and ROR calculation revealed the strongest association with DIPF for cefuroxime (PRR = 15.11, 95% confidence interval, CI: 10.25–22.27; ROR = 15.31, 95% confidence interval, CI: 10.33–22.68). Conclusions: Cefuroxime was revealed as a drug with an unexpected but robust safety signal for DIPF, warranting heightened clinical awareness and further investigation. The observed associations between antibacterial agents and DIPF should be interpreted with caution, as they may reflect protopathic bias (antibiotics prescribed for early symptoms of unrecognized pulmonary fibrosis) or context-dependent biological effects rather than true pro-fibrotic drug properties. Our findings do not establish causality but rather generate safety signals that warrant validation through prospective studies with detailed clinical phenotyping and mechanistic investigations using human cell lines. Full article

Natural products are the fundamentals of drug discovery due to their exceptional structural diversity and biological activity’s evolutionary optimization. The review provides a critical and integrative analysis of natural products in pharmaceutical chemistry, highlighting their significance for current biomedicine and pharmacotherapy. The review is organized around a system that connects structure, function, and translation, focusing on structural analysis, scaffold design, and mechanistic understanding in major disease-relevant therapeutic areas. Investigations on representative compounds like paclitaxel, artemisinin, and curcumin are presented to explain the way molecular architecture regulates pharmacological activity, drug selectivity, and clinical performance. The review evaluates significant medicinal chemistry strategies, including semisynthetic modification, prodrug design, and scaffold optimization, and their crucial roles in enhancing potency, pharmacokinetics, and safety. We critically examine the latest advancements in drug delivery technologies, particularly those based on nanotechnology and carrier-free methods, regarding their translational potential and regulatory concern. Current challenges pertaining to pharmacokinetics and ADMET properties, as well as the standardization of analysis, are also examined, emphasizing their impact on reproducibility in research. Researchers investigate the role and limitations of emerging fields such as genome mining, synthetic biology, and network pharmacology in enhancing discovery pipelines. Thus, this review integrates chemical, pharmacological, and translational approaches and suggests an effective strategy to overcome challenges in the development of natural products as the next generation of precision medicine therapeutic agents. Full article

Peptide therapeutics have emerged as a versatile class of biomolecules bridging the gap between small-molecule drugs and large biologics. Advantages of such molecules include high target specificity, potent bioactivity and reduced off-target toxicity. Despite these, broader clinical translation remains constrained by inherent limitations like poor metabolic stability, rapid renal clearance, limited membrane permeability and scalable synthesis. This review aims to systematically integrate advances in peptide science across natural discovery, synthetic methodologies, structural engineering, and translational delivery systems, while identifying critical research gaps hindering clinical adoption. We highlight diverse natural sources of bioactive peptides, including plant- (lunasin), animal- (Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP)), microbial- (nisin and cyclosporine), marine- (dolastatins) and venom-derived (chlorotoxin and ω-conotoxin MVIIA (ziconotide)) agents. Advances in solid-phase peptide synthesis (SPPS), green chemistry, and catalytic strategies are discussed alongside emerging in silico approaches, including artificial intelligence-driven sequence design and molecular modeling. Structural modifications such as cyclization, hydrocarbon stapling, PEGylation, and lipidation are critically evaluated for their role in enhancing pharmacokinetic and pharmacodynamic properties. Furthermore, nanoformulation strategies, including self-assembling peptides and cell-penetrating systems, are examined for their potential to overcome biological barriers. Importantly, this review identifies key unresolved challenges, including the lack of predictive models for peptide delivery systems, safety concerns associated with long-term modifications, and limited in vivo validation of naturally derived peptides. Addressing these gaps through integrated computational and experimental approaches will be essential for advancing next-generation peptide therapeutics. Collectively, this work provides a comprehensive framework for the rational design and translation of peptide-based precision medicines. Full article

Ring chromosome 14 (RC14) syndrome is an ultra-rare disorder characterized by drug-resistant epilepsy, intellectual disabilities, autism, and recurrent infections, suggesting a possible underlying immune dysregulation. We analyzed immunoglobulin G (IgG) N-glycosylation profiles in six RC14 patients and compared them with age-matched healthy controls using ultra-high-performance liquid chromatography (UHPLC) coupled with fluorescence detection (FLR) and high-resolution electrospray ionization mass spectrometry (ESI-MS). Patients showed decreased galactosylation and sialylation, resembling pro-inflammatory patterns observed in autoimmune diseases. These alterations were not observed in total serum glycoproteins, indicating a selective effect on IgG. One patient treated with intravenous immunoglobulin (IVIG) showed clinical improvement, which led us to investigate causality. Full article

Background/Objectives: Breast cancer (BC) is a highly prevalent neoplasm worldwide. Despite the wide range of therapeutic options currently available, it remains the leading cause of cancer-related mortality among women. Capecitabine, a prodrug of 5-fluorouracil (5-FU), is widely used in the treatment of advanced BC. However, despite its efficacy, capecitabine exhibits considerable interindividual variability in therapeutic response. This study aimed to evaluate the effect of single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine bioactivation on progression-free survival (PFS) in patients with BC. Methods: An ambispective cohort study was conducted. Four relevant SNPs in the CES1, CDA, and TYMP genes were analyzed in 85 Caucasian patients with BC using real-time polymerase chain reaction (PCR) with TaqMan^® probes. Results: A significant association was observed between shorter PFS and the GA genotype of the CES1 rs71647871 SNP (p = 0.010; HR = 7.46; 95% CI = 1.24–122.52), as well as with the TT genotype of the CDA rs602950 SNP (p = 0.009; HR = 3.50; 95% CI = 1.36–9.03). Conclusions: These findings suggest that CES1 rs71647871 and CDA rs602950 may serve as predictive biomarkers of capecitabine effectiveness in patients with BC. Further studies involving larger cohorts are needed to validate these findings and generate additional evidence to support their potential implementation in clinical practice. Full article

This translational synthesis highlights the potential role of obesity-induced low-grade chronic inflammation in modulating clinical outcomes among patients with spondyloarthritis (SpA). Obesity transforms adipose tissue into a pro-inflammatory endocrine organ, where hypertrophic adipocytes release adipokines such as leptin alongside cytokines including TNF-α and IL-6, potentially contributing to macrophage polarization toward an M1 phenotype and activating NF-κB signaling pathways. This systemic immunometabolic priming may lower activation thresholds at the enthesis—the primary pathological site in SpA—potentially amplifying IL-23/IL-17 axis activity via Th17 bias, innate-like lymphocyte responses, and stromal–immune crosstalk under mechanical stress. Clinically, patients with SpA and obesity have been reported to demonstrate heightened disease activity (BASDAI, ASDAS), impaired function (BASFI), accelerated radiographic progression (syndesmophytes, enthesophytes), and diminished biologic response rates, potentially attributable to pharmacokinetic alterations (e.g., subtherapeutic TNF inhibitor levels) and pharmacodynamic resistance. Multisystem comorbidities, including non-alcoholic fatty liver disease, cardiovascular events, metabolic syndrome, sleep disturbances, and depression, further exacerbate morbidity and diminish quality of life. Therapeutic implications emphasize obesity as a modifiable disease modifier. Weight loss interventions, including hypocaloric diets, anti-inflammatory regimens (e.g., Mediterranean diet), multicomponent exercise, GLP-1 receptor agonists, and bariatric surgery, have been associated with reductions in inflammatory biomarkers, improved remission rates (MDA, DAPSA), and prolonged drug survival by restoring adipokine balance and disrupting mechano-inflammatory loops. Future randomized controlled trials should prioritize long-term evaluations of integrated multidisciplinary strategies that combine metabolic optimization with immunomodulatory therapies, addressing adherence challenges through psychological support and patient-tailored protocols, while elucidating dose–response relationships for GLP-1RAs and exercise in diverse SpA subtypes to establish precision management paradigms that mitigate cardiometabolic burden and improve holistic outcomes. Full article

Euphorbia clavarioides Boiss. is traditionally used in wound healing and other medicinal applications. Its bioactive compounds and pharmacological potential remain underexplored. This study investigated the phytochemical composition, antioxidant, anti-inflammatory, and anticancer activities of E. clavarioides Boiss. traditionally used in wound healing. Plant extracts were characterized using phytochemical screening, Fourier-transform infrared spectroscopy (FTIR), and liquid chromatography–mass spectrometry (LC-MS). Antioxidant activity was evaluated via DPPH and nitric oxide (NO) scavenging assays, anti-inflammatory effects through nitrite inhibition in LPS-stimulated RAW 264.7 macrophages, and anticancer potential using the MTT assay against DU-145, PC-3, SKU-T, and AGS cell lines. Phytochemical screening confirmed tannins, phlobatannins, saponins, flavonoids, alkaloids, steroids, terpenoids, and cardiac glycosides. FTIR spectra of aqueous extracts revealed peaks at 2990.66 cm⁻¹ (O–H), 1738.68 cm⁻¹ (C=O), 1217.22 cm⁻¹ (C–N), and 527.37 cm⁻¹ (C–Cl). LC-MS profiling identified diverse metabolites, including phenolics (pseudolaroside B, cinnamtannin A2, (−)-medicarpin, butyrolactol A) and terpenoids (zerumbone, sclareol isomer, diterpenoid-like compounds), underpinning the plant’s bioactivity. Methanol extracts exhibited the strongest DPPH scavenging activity (IC₅₀ = 755.71 µg/mL), whereas aqueous and ethanol extracts demonstrated superior NO scavenging. Ethanol extracts showed maximal anti-inflammatory activity, while aqueous extracts induced pro-inflammatory effects. Cytotoxicity assays indicated negligible toxicity. In anticancer assays, ethanol and methanol extracts significantly inhibited the proliferation of all tested cell lines at 100 µg/mL, exceeding drug control, whereas aqueous extracts displayed lower activity. The bioactive compounds in E. clavarioides support its traditional wound-healing use and demonstrate mechanistic antioxidant, anti-inflammatory, and anticancer activities, highlighting its potential as a source of multi-target natural therapeutics. Full article

Bipolar cancellation (BPC) is an efficiency-limiting phenomenon in bipolar nanosecond pulsed electric field (nsPEF) exposures, in which the second, opposite-polarity phase reduces or partially reverses the electroporation induced by the first phase. Nisin, a cationic antibiotic peptide, has been reported to interact with lipid membranes in bacterial systems and artificial bilayer models, where it may contribute to membrane destabilization and increased permeability during pulsed electric field exposure. This study investigated whether nisin may enhance the efficacy of bleomycin electrochemotherapy (ECT) in the presence of bipolar nanosecond pulses, which are typically associated with pronounced BPC effects. Pulsed electric field (PEF) parameters and drug concentrations were selected based on preliminary viability and Yo-Pro-1 uptake experiments in CLS-354 human squamous cell carcinoma cells. To evaluate the effect of nisin, cell viability and membrane permeabilization were assessed following exposure to 300 ns pulses across a range of bipolar PEF protocols, with or without nisin, while identical unipolar pulses were used for comparison. Nisin (50 µg/mL) increased membrane permeabilization across the tested range of field amplitudes (9–15 kV/cm) and burst repetition frequencies (0.1–1.66 MHz). The presence of nisin was also associated with increased efficacy of bleomycin-based ECT under both unipolar and symmetrical bipolar PEF conditions. Under the optimized parameters tested (13 kV/cm; 150 pulses of 300 ns at 1.66 MHz), bipolar nsPEFs in combination with nisin reached levels of efficacy comparable to those observed with unipolar waveforms, suggesting a potential attenuation of bipolar cancellation effects. Full article

Background and Objectives: Neuroblastoma represents the most common extracranial solid tumor in childhood and is associated with a poor prognosis in high-risk cases. Amygdalin, a naturally occurring cyanogenic glycoside, has been reported to exhibit anti-tumor properties in various cancer models; however, its effects on neuroblastoma cells remain insufficiently characterized. The present study was conducted with the objective of investigating the effects of amygdalin on cell proliferation, apoptosis, and invasion in SH-SY5Y neuroblastoma cells in vitro. Materials and Methods: The SH-SY5Y neuroblastoma cells were cultivated under the optimal conditions for their growth. The cytotoxic effect of amygdalin was determined using the CCK8 assay, which is dose- and time-dependent. Total RNA isolation was performed using Trizol. Subsequently, a process of cDNA synthesis was initiated. The real-time PCR method was utilized to ascertain alterations in the expression levels of mRNA molecules associated with apoptosis, namely Bax, Bcl2, caspase-3, caspase-7, caspase-8, caspase-9, caspase-10, NFkB, and invasion-related genes MMP2, MMP9, TIMP1, and TIMP3. Furthermore, alterations in NFkB levels were examined through the utilization of the ELISA method. Results: The IC50 value of amygdalin in SH-SY5Y cells was determined to be 112.7 µM at 24 h. Amygdalin demonstrated a dose-dependent cytotoxic effect on neuroblastoma cells. Furthermore, the study revealed that the drug induced apoptosis through the upregulation of BAX and BID, and the downregulation of BCL-2 and NF-κB. This process led to a reduction in cell proliferation. Furthermore, the study demonstrated an anti-invasive effect through the downregulation of MMP9 and the upregulation of TIMP1 and TIMP3. In addition, a substantial decrease in NF-κB protein concentration was observed. Conclusions: These findings demonstrate that amygdalin exerts anti-proliferative, pro-apoptotic, and anti-invasive effects in SH-SY5Y neuroblastoma cells in vitro. Amygdalin may represent a promising natural compound for further investigation as a potential therapeutic agent in neuroblastoma. Full article

Background: Neuroinflammation is increasingly recognized as a central mechanism in the pathogenesis of epilepsy, particularly drug-resistant epilepsy (DRE), where conventional anti-seizure medications fail to achieve adequate control. Microglia, the resident immune cells of the central nervous system, play a critical role in mediating inflammatory responses that contribute to seizure initiation, propagation, and pharmacoresistance. Persistent microglial activation promotes the release of pro-inflammatory mediators, exacerbating neuronal hyperexcitability and epileptogenesis. Objectives: This scoping review aimed to systematically map the existing evidence on microglial activation in DRE and to identify emerging therapeutic strategies targeting microglia-mediated neuroinflammation. Methods: The review was conducted in accordance with Joanna Briggs Institute (JBI) methodology and reported following PRISMA-ScR guidelines. A comprehensive search of PubMed, PubMed Central, Scopus, Google Scholar, Embase, and Web of Science was performed without date restrictions. Eligible studies included preclinical, clinical, and review articles investigating microglial activation, neuroinflammatory pathways, or microglia-targeted therapies in epilepsy. Data were charted and synthesized using a narrative approach. Results: A total of 521 records were identified, of which 53 studies met the inclusion criteria after screening and full-text review. The included studies, published between 1998 and 2021, demonstrated a growing research interest in microglia-related mechanisms in epilepsy. Evidence consistently highlighted the role of microglial activation in promoting neuroinflammation and seizure persistence. Emerging therapeutic strategies included anti-inflammatory pharmacotherapies, microglial modulators, cannabinoid-based interventions, gene therapy, and stem cell-based approaches. Conclusions: Targeting microglial activation represents a promising and evolving therapeutic strategy for DRE. While preclinical and early clinical evidence is encouraging, challenges related to specificity, timing, and translational applicability remain. Future research should focus on precision-based interventions to optimize clinical outcomes and enable disease modification beyond seizure control. Full article

Background: Oral colon-targeted delivery for inflammatory bowel disease (IBD) faces significant challenges, including limited gastrointestinal stability, premature drug release, and insufficient mucosal retention. Methods: To address these limitations, a mucoadhesive polysaccharide-based composite hydrogel incorporating prednisolone-loaded polymeric micelles was developed to enhance colonic delivery and promote mucosal repair. Amphiphilic oxidized dextran–oleylamine (ODEX-OA) copolymers were synthesized to self-assemble into prednisolone-loaded micelles. These micelles were subsequently embedded within a thiolated chitosan (CSSH) hydrogel through a Schiff base reaction, yielding the ODEX-OA-Pred-CSSH composite. The resulting system was comprehensively characterized for particle size, mucoadhesion, degradation, and pH/ROS dual-responsive drug release. Its colon-targeting capability and therapeutic efficacy were subsequently assessed in a dextran sulfate sodium (DSS)-induced colitis mouse model. Results: In vitro, the composite hydrogel demonstrated nanoscale micellar size, enhanced drug release kinetics under simulated inflammatory colonic conditions, and prolonged colonic retention for up to 24 h following oral administration. In vivo, studies confirmed that ODEX-OA-Pred-CSSH significantly alleviated colitis, evidenced by a reduced disease activity index, diminished pro-inflammatory cytokine levels, restored colon length, decreased spleen index, and improved histological mucosal repair. Conclusions: These findings collectively suggest that this mucoadhesive micelle–hydrogel composite represents a promising and effective oral colon-targeted platform for the treatment of IBD. Full article

Background: Dragon’s blood (dried resin of Dracaena cochinchinensis (Lour.) S.C.Chen) is a classic traditional medicine for treating ischemic stroke, yet its bioactive components capable of penetrating the blood–brain barrier (BBB) remain ill-defined. This study aims to elucidate its material basis and the synergistic mechanism of Borneol as a “guide drug.” Methods: A systematic strategy integrating UHPLC-Q-TOF-MS/MS and metabolomics was employed to map the chemical profile of dragon’s blood and identify its migrating constituents in rats. Results: A total of 96 compounds were characterized in vitro. In vivo analysis of the cerebrospinal fluid (CSF) revealed a brain-penetrating profile that was significantly enriched by Borneol, with the number of detected constituents increasing from 11 in the DB group to 16 in the DB + B group. The results demonstrated that demethylation, glycoside hydrolysis, and oxidation are primary metabolic pathways, validating a “pro-drug” mechanism where aglycones and hydroxylated derivatives act as the central effectors. Notably, Borneol not only enhanced the BBB permeability of lipophilic flavonoids but also facilitated unique metabolic transformations, such as the cyclization of berberrubine to coptisine. Conclusions: This study elucidates the brain-penetrating material basis of dragon’s blood and reveals the dual synergistic mechanism of Borneol involving both physical permeation enhancement and metabolic modulation, offering scientific evidence for its clinical application in central nervous system diseases. Full article

Cannabis-derived compounds are increasingly used as adjuncts in cancer therapy due to their reported antiproliferative and pro-apoptotic effects. However, potential drug–herb interactions with standard anticancer agents—namely sorafenib—remain unclear. This study investigated the interaction between cannabis and sorafenib, together with transcriptomic alterations in human hepatoma HepG2 cells. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the Combenefit program. RNA sequencing was performed to characterize gene expression changes across treatment groups. Combination analysis demonstrated concentration-dependent synergistic effects at intermediate doses. Transcriptomic profiling revealed that the combination treatment induced a broader and more distinct set of differentially expressed genes compared with single treatments. Integrated enrichment analyses showed consistent activation of stress- and inflammation-related pathways, including tumor necrosis factor-α via nuclear factor-kappaB (TNF/NF-κB), mitogen-activated protein kinase (MAPK), janus kinase/signal transducers and activators of transcription (JAK–STAT), oxidative stress, and p53-mediated apoptosis, alongside suppression of metabolic and proliferative processes. While several pathways were shared across treatments, the combination group exhibited a more coordinated transcriptional response, including enrichment of integrated stress response, cytokine signaling, endoplasmic reticulum stress, and epigenetic regulation. These findings were supported by increased reactive oxygen species production and apoptosis, particularly in the combination group. Overall, cannabis may potentiate sorafenib activity through enhanced cellular stress and anti-proliferative signaling. Full article

Chagas disease and trichomoniasis are two neglected parasitic infections (NPIs) in need for new therapies that address both the toxicity and limited bioavailability impacting on the effectiveness of benznidazole (BZ) and nifurtimox, the only drugs available for treating the infection caused by Trypanosoma cruzi, as well as the resistance that Trichomonas vaginalis has developed to 5-nitroimidazoles. Herein, we report the outcomes of the primary screening of a series of eighteen quinoxaline-1,4-di-N-oxides (QdNOs) carried out against both protozoan parasites. Computational approaches revealed that these derivatives have adequate oral bioavailability and do not pose toxicity risks associated with their chemical structures. Meanwhile, biological studies disclosed that compounds 4b and 4m exhibit considerable activity against T. cruzi at the highest concentration tested, showing 4m a trypanocidal profile (IC₅₀ = 23.66 µM) similar to that of BZ (IC₅₀ = 21.66 µM), and a selectivity index (SI) > 5.32. Regarding the activity on T. vaginalis, derivative 4n stands out with an IC₅₀ value of 9.85 µM, showing no cytotoxicity towards mammalian cells. However, their potency decreases when tested over resistant parasites. Alterations in either the hydrogenosomal membrane potential or the production of reactive oxygen species (ROS) were also explored. The findings suggest that the trichomonacidal activity of compound 4n is not mediated by a direct disruption of hydrogenosomal bioenergetics or a pro-oxidant effect. Altogether, these preliminary results support that the QdNO scaffold could be introduced as a proper template for developing novel trypanocidal and trichomonacidal agents. Full article

Background: Nitrous oxide (N₂O) is increasingly used as a recreational drug, leading to neurological and systemic toxicities. However, due to the rapid elimination and minimal alteration of nitrogen oxides, the short direct detection window complicates the assessment of N₂O exposure. Method: In this study, we investigated the effects of chronic N₂O exposure on plasma metabolites using an untargeted metabolomics approach in a mouse model. C57BL/6 mice were exposed to 90,000 ppm N₂O (1 h, twice daily for 28 days) or room air. Plasma samples were analyzed via UHPLC -Triple TOF -MS. Orthogonal partial least squares discriminant analysis (OPLS-DA) and receiver operating characteristic (ROC) curves were used to identify differential metabolites. Result: A total of 35 differential metabolites were identified. Eight metabolites with an area under the curve (AUC) > 0.90 were selected as candidate biomarkers, including up-regulated SOPC and PC(16:0/16:0) (suggesting disrupted phospholipid remodeling and membrane integrity), and down-regulated DL-tryptophan, creatine, ectoine, indole, His-Ser, and Ile-Pro. Pathway enrichment analysis revealed significant alterations in glycine, serine and threonine metabolism; phenylalanine, tyrosine and tryptophan biosynthesis; protein digestion and absorption; and tryptophan metabolism. Conclusions: Our data indicate that chronic N₂O exposure disrupts multiple amino acid-related metabolic pathways (e.g., tryptophan-kynurenine pathway) and phospholipid homeostasis. The identified metabolite changes, along with vitamin B₁₂, homocysteine, and methylmalonic acid, may constitute a specific metabolic fingerprint for N₂O exposure. These findings help reveal the intrinsic mechanistic links underlying metabolic disorders induced by N₂O exposure. Full article