Search Results (2,958)

New psychoactive substances (NPSs) have emerged as a significant global public health challenge due to their ability to mimic traditional drugs. Among these, mephedrone has gained attention because of its widespread use and associated toxicities. This review provides a comprehensive analysis of the structure, pharmacokinetic properties, and metabolic pathways of mephedrone, highlighting its phase I and phase II metabolites as potential biomarkers for detection and forensic applications. A comprehensive literature search was performed without date restrictions. The search employed key terms such as “mephedrone metabolites”, “pharmacokinetics of mephedrone”, “phase I metabolites of mephedrone”, and “phase II metabolites of mephedrone”. Additionally, the reference lists of selected studies were screened to ensure a thorough review of the literature. Mephedrone is a chiral compound existing in two enantiomeric forms, exhibiting different affinities for monoamine transporters and distinct pharmacological profiles. In vivo animal studies indicate rapid absorption, significant tissue distribution, and the formation of multiple phase I metabolites (e.g., normephedrone, dihydromephedrone, 4-carboxymephedrone) that influence its neurochemical effects. Phase II metabolism involves conjugation reactions leading to metabolites such as N-succinyl-normephedrone and N-glutaryl-normephedrone, further complicating its metabolic profile. These findings underscore the importance of elucidating mephedrone’s metabolic pathways to improve detection methods, enhance our understanding of its toxicological risks, and inform future therapeutic strategies. Full article

Background: Pulmonary fibrosis (PF), the end-stage manifestation of interstitial lung disease, is defined by excessive extracellular matrix deposition and alveolar destruction. Activated fibroblasts, the primary matrix producers, rely heavily on dysregulated glucose metabolism for their activation. While Salt Inducible Kinase 2 (SIK2) regulates glycolytic pathways in oncogenesis, its specific contributions to fibroblast activation and therapeutic potential in PF pathogenesis remain undefined. This study elucidates the functional role of SIK2 in PF and assesses its viability as a therapeutic target. Methods: SIK2 expression/localization in fibrosis was assessed by Western blot and immunofluorescence. Fibroblast-specific Sik2 KO mice evaluated effects on bleomycin-induced fibrosis. SIK2’s role in fibroblast activation and glucose metabolism impact (enzyme expression, metabolism assays, metabolites) were tested. SIK2 inhibitors were screened and evaluated therapeutically in fibrosis models. Results: It demonstrated significant SIK2 upregulation, specifically within activated fibroblasts of fibrotic lungs from both PF patients and murine models. Functional assays demonstrated that SIK2 is crucial for fibroblast activation, proliferation, and migration. Mechanistically, SIK2 enhances fibroblast glucose metabolism by increasing the expression of glycolysis-related enzymes. Additionally, this study demonstrated that the SIK2 inhibitor YKL06-061 effectively inhibited PF in both bleomycin and FITC-induced PF mouse models with the preliminary safety profile. Furthermore, we identified a novel therapeutic application for the clinically approved drug fostamatinib, demonstrating it inhibits fibroblast activation via SIK2 targeting and alleviates PF in mice. Conclusions: Our findings highlight SIK2 as a promising therapeutic target and provide compelling preclinical evidence for two distinct anti-fibrotic strategies with significant potential for future PF treatment. Full article

Gas chromatography with mass spectrometry (GC-MS) is a common analytical technique used for identifying and quantifying drugs of abuse, as well as their metabolites, extracted from biological samples. Depending on the properties of the analyzed compounds, particularly in the case of metabolites, derivatization is often necessary. In this article, we will address the definition, properties, sample preparation, and GC-MS analysis of the most common drugs of abuse in their native (seized) form and their metabolites in biological samples (urine, blood, hair, and tissue). Drugs that will be described are: amphetamines and their derivatives, cannabinoids, cocaine, opioids, lysergide (LSD), benzodiazepines, gamma-hydroxybutyric acid (GHB), phencyclidine (PCP), mescaline, psilocin, and psilocybin. The literature review showed that the analysis of the drugs of abuse requires a simple extraction procedure and analysis with or without derivatization. However, the analysis of the metabolites requires removing the interferences from the matrix (proteins, other compounds, water, and other species that may interfere with the analysis or contaminate the GC-MS). This review article will provide insights into the available procedures for sample preparation and analytical methods, helping authors gain the necessary information and select the desired procedure for analysis. Full article

Background/Objective: Pharmacological interventions often exert systemic effects beyond their primary targets, underscoring the need for a comprehensive evaluation of their metabolic impact. Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that alleviates pain, fever, and inflammation by inhibiting cyclooxygenase-2 (COX-2), thereby reducing prostaglandin synthesis. While its pharmacological effects are well known, the broader metabolic impact and potential mechanisms underlying improved clinical outcomes remain underexplored. Untargeted metabolomics, which profiles the metabolome without prior selection, is an emerging tool in clinical pharmacology for elucidating drug-induced metabolic changes. In this study, untargeted metabolomics was applied to investigate metabolic changes following a single oral dose of etodolac in healthy male volunteers. By analyzing serial blood samples over time, we identified endogenous metabolites whose concentrations were positively or inversely associated with the drug’s plasma levels. This approach provides a window into both therapeutic pathways and potential off-target effects, offering a promising strategy for early-stage drug evaluation and multi-target discovery using minimal human exposure. Methods: Thirty healthy participants received a 400 mg dose of Etodolac. Plasma samples were collected at five time points: pre-dose, before Cmax, at Cmax, after Cmax, and 36 h post-dose (n = 150). Samples underwent LC/MS-based untargeted metabolomics profiling and pharmacokinetic analysis. A total of 997 metabolites were significantly dysregulated between the pre-dose and Cmax time points, with 875 upregulated and 122 downregulated. Among these, 80 human endogenous metabolites were identified as being influenced by Etodolac. Results: A total of 17 metabolites exhibited time-dependent changes closely aligned with Etodolac’s pharmacokinetic profile, while 27 displayed inverse trends. Conclusions: Etodolac influences various metabolic pathways, including arachidonic acid metabolism, sphingolipid metabolism, and the biosynthesis of unsaturated fatty acids. These selective metabolic alterations complement its COX-2 inhibition and may contribute to its anti-inflammatory effects. This study provides new insights into Etodolac’s metabolic impact under healthy conditions and may inform future therapeutic strategies targeting inflammation. Full article

Concern over the presence of pharmaceutical waste in the environment has prompted research into the management of emerging organic micropollutants (EOMs). In response, sustainable technologies have been applied as alternatives to reduce the effects of these contaminants. This study investigated the capacity of filamentous fungi isolated from iron mine soil in the Amazon region to biodegrade the drug chloroquine diphosphate. An initial screening assessed the growth of four fungal strains on solid media containing chloroquine diphosphate: Trichoderma pseudoasperelloides CBMAI 2752, Penicillium rolfsii CBMAI 2753, Talaromyces verruculosus CBMAI 2754, and Penicillium sp. cf. guaibinense CBMAI 2758. Among them, Penicillium sp. cf. guaibinense CBMAI 2758 was selected for further testing in liquid media. A Box–Behnken factorial design was applied with three variables, pH (5, 7, and 9), incubation time (5, 10, and 15 days), and chloroquine diphosphate concentration (50, 75, and 100 mg·L⁻¹), totaling 15 experiments. The samples were analyzed by gas chromatography–mass spectrometry (GC-MS). The most effective conditions for chloroquine biodegradation were pH 7, 100 mg·L⁻¹ concentration, and 10 days of incubation. Four metabolites were identified: one resulting from N-deethylation M1 (N4-(7-chloroquinolin-4-yl)-N1-ethylpentane-1,4-diamine), two from carbon–carbon bond cleavage M2 (7-chloro-N-ethylquinolin-4-amine) and M3 (N1,N1-diethylpentane-1,4-diamine), and one from aromatic deamination M4 (N1-ethylbutane-1,4-diamine) by enzymatic reactions. The toxicity analysis showed that the products obtained from the biodegradation of chloroquine were less toxic than the commercial formulation of this compound. These findings highlight the biotechnological potential of Amazonian fungi for drug biodegradation and decontamination. Full article

Nudibranchs have garnered increasing interest in biomedical research due to their complex chemical defense mechanisms, many of which are derived from their diet, including sponges, cnidarians, tunicates, and algae. Their remarkable ability to sequester dietary toxins and synthesize secondary metabolites positions them as a promising source of biologically active compounds with potential therapeutic applications, particularly in oncology. This study aimed to review and summarize the available literature on the bioactive potential of nudibranch-derived compounds, focusing mainly on their antitumor properties. Although research in this area is still limited, recent studies have identified alkaloids and terpenoids isolated from species such as Dolabella auricularia, Jorunna funebris, Dendrodoris fumata, and members of the genus Phyllidia. These compounds exhibit notable cytotoxic activity against human cancer cell lines, including those from colon (HCT-116, HT-29, SW-480), lung (A549), and breast (MCF7) cancer. These findings suggest that compounds derived from nudibranchs could serve as scaffolds for the development of more effective and selective anticancer therapies. In conclusion, nudibranchs represent a valuable yet underexplored resource for antitumor drug discovery, with significant potential to contribute to the development of novel cancer treatments. Full article

Background/Objectives. This manuscript presents an overview of advances in oncological radiotherapy as an effective treatment method for cancerous tumors, focusing on mechanisms of action within metabolite–antimetabolite systems. The urgency of this topic is underscored by the fact that cancer remains one of the leading causes of death worldwide: as of 2022, approximately 20 million new cases were diagnosed globally, accounting for about 0.25% of the total population. Given prognostic models predicting a steady increase in cancer incidence to 35 million cases by 2050, there is an urgent need for the latest developments in physics, chemistry, molecular biology, pharmacy, and strict adherence to oncological vigilance. The purpose of this work is to demonstrate the relationship between the nature and mechanisms of past diagnostic and therapeutic oncology approaches, their current improvements, and future prospects. Particular emphasis is placed on isotope technologies in the production of therapeutic nuclides, focusing on the mechanisms of formation of simple and complex theranostic compounds and their classification according to target specificity. Methods. The methodology involved searching, selecting, and analyzing information from PubMed, Scopus, and Web of Science databases, as well as from available official online sources over the past 20 years. The search was structured around the structure–mechanism–effect relationship of active pharmaceutical ingredients (APIs). The manuscript, including graphic materials, was prepared using a narrative synthesis method. Results. The results present a sequential analysis of materials related to isotope technology, particularly nucleus stability and instability. An explanation of theranostic principles enabled a detailed description of the action mechanisms of radiopharmaceuticals on various receptors within the metabolite–antimetabolite system using specific drug models. Attention is also given to radioactive nanotheranostics, exemplified by the mechanisms of action of radioactive nanoparticles such as Tc-99m, AuNPs, wwAgNPs, FeNPs, and others. Conclusions. Radiotheranostics, which combines the diagnostic properties of unstable nuclei with therapeutic effects, serves as an effective adjunctive and/or independent method for treating cancer patients. Despite the emergence of resistance to both chemotherapy and radiotherapy, existing nuclide resources provide protection against subsequent tumor metastasis. However, given the unfavorable cancer incidence prognosis over the next 25 years, the development of “preventive” drugs is recommended. Progress in this area will be facilitated by modern medical knowledge and a deeper understanding of ligand–receptor interactions to trigger apoptosis in rapidly proliferating cells. Full article

Mitochondria, pivotal organelles in cellular metabolism and energy production, have emerged as critical players in the pathogenesis of cancer. This review outlines the progress in mitochondrial profiling through mass spectrometry-based metabolomics and its applications in cancer research. We provide unprecedented insights into the mitochondrial metabolic rewiring that fuels tumorigenesis, metastasis, and therapeutic resistance. The purpose of this review is to provide a comprehensive guide for the implementation of mitochondrial metabolomics, integrating advanced methodologies—including isolation, detection, and data integration—with insights into cancer-specific metabolic rewiring. We first summarize current methodologies for mitochondrial sample collection and pretreatment. Furthermore, we then discuss the recent advancements in mass spectrometry-based methodologies that facilitate the detailed profiling of mitochondrial metabolites, unveiling significant metabolic reprogramming associated with tumorigenesis. We emphasize how recent technological advancements have addressed longstanding challenges in the field and explore the role of mitochondrial metabolism-driven cancer development and progression for novel drug discovery and translational research applications in cancer. Collectively, this review delineates emerging opportunities for therapeutic discovery and aims to establish a foundation for future investigations into the therapeutic modulation of mitochondrial pathways in cancer, thereby paving the way for innovative diagnostic and therapeutic approaches targeting mitochondrial pathways. Full article

Methicillin-resistant Staphylococcus aureus (MRSA), a multidrug-resistant pathogen, poses a significant threat to global healthcare. This review evaluates the potential of marine algal metabolites as novel antibacterial agents against MRSA. We explore the clinical importance of S. aureus, the emergence of MRSA as a “superbug”, and its resistance mechanisms, including target modification, drug inactivation, efflux pumps, biofilm formation, and quorum sensing. The limitations of conventional antibiotics (e.g., β-lactams, vancomycin, macrolides) are discussed, alongside the promise of algal-derived compounds such as fatty acids, pigments, polysaccharides, terpenoids, and phenolic compounds. These metabolites exhibit potent anti-MRSA activity by disrupting cell division (via FtsZ inhibition), destabilizing membranes, and inhibiting protein synthesis and metabolic pathways, effectively countering multiple resistance mechanisms. Leveraging advances in algal biotechnology, this review highlights the untapped potential of marine algae to drive innovative, sustainable therapeutic strategies against antibiotic resistance. Full article

Background: Salmonella infections pose a serious threat to both animal and human health worldwide. Notably, there is an increasing trend in the resistance of Salmonella to fluoroquinolones, the first-line drugs for clinical treatment. Methods: Utilizing Salmonella Typhimurium CICC 10420 as the test strain, ciprofloxacin was used for in vitro induction to develop the drug-resistant strain H1. Changes in the minimum inhibitory concentrations (MICs) of various antimicrobial agents were determined using the broth microdilution method. Transcriptomic and metabolomic analyses were conducted to investigate alterations in gene and metabolite expression. A combined drug susceptibility test was performed to evaluate the potential of exogenous metabolites to restore antibiotic susceptibility. Results: The MICs of strain H1 for ofloxacin and enrofloxacin increased by 128- and 256-fold, respectively, and the strain also exhibited resistance to ceftriaxone, ampicillin, and tetracycline. A single-point mutation of Glu469Asp in the GyrB was detected in strain H1. Integrated multi-omics analysis showed significant differences in gene and metabolite expression across multiple pathways, including two-component systems, ABC transporters, pentose phosphate pathway, purine metabolism, glyoxylate and dicarboxylate metabolism, amino sugar and nucleotide sugar metabolism, pantothenate and coenzyme A biosynthesis, pyrimidine metabolism, arginine and proline biosynthesis, and glutathione metabolism. Notably, the addition of exogenous glutamine, in combination with tetracycline, significantly reduced the resistance of strain H1 to tetracycline. Conclusion: Ciprofloxacin-induced Salmonella resistance involves both target site mutations and extensive reprogramming of the metabolic network. Exogenous metabolite supplementation presents a promising strategy for reversing resistance and enhancing antibiotic efficacy. Full article

Resistance of various bacterial pathogens to the activity of clinically approved drugs currently leads to serious infections, rapid spread of difficult-to-treat diseases, and even death. Taking the threats for human health in mind, researchers are focused on the isolation and characterization of novel natural products, including plant secondary metabolites. These molecules serve as inspiration and a suitable structural platform in the design and development of novel semi-synthetic and synthetic derivatives. All considered compounds have to be adequately evaluated in silico, in vitro, and in vivo using relevant approaches. The current review paper briefly focuses on the chemical and metabolic properties of resveratrol (1), as well as its oligomeric structures, viniferins, and viniferin-based molecules. The core scaffolds of these compounds contain so-called privileged structures, which are also present in many clinically approved drugs, indicating that those natural, properly substituted semi-synthetic, and synthetic molecules can provide a notably broad spectrum of beneficial pharmacological activities, including very impressive antimicrobial efficiency. Except for spectral verification of their structures, these compounds suffer from the determination or prediction of other structural and physicochemical characteristics. Therefore, the structure–activity relationships for specific dihydrodimeric and dimeric viniferins, their bioisosteres, and derivatives with notable efficacy in vitro, especially against chosen Gram-positive bacterial strains, are summarized. In addition, a set of descriptors related to their structural, physicochemical, pharmacokinetic, and toxicological properties is generated using various computational tools. The obtained values are compared to those of clinically approved drugs. The particular relationships between these in silico parameters are also explored. Full article

Cancer presents significant challenges owing to its complex molecular pathways and resistance to therapy. Natural metabolites have significant medicinal potential by regulating the sensing and signaling pathways associated with cancer development. Recognizing their interactions within the tumor microenvironment may unveil innovative techniques for inhibiting malignant activities and improve therapy success. This article highlights studies regarding ovarian cancer metabolism, signaling mechanisms, and therapeutic natural substances. This study summarizes clinical and experimental results to emphasise the synergistic effects of alkaloids, flavonoids, and terpenoids in improving therapeutic effectiveness and alleviating drug resistance. Bioactive compounds are essential in regulating ovarian cancer metabolism and signaling pathways, affecting glycolysis, lipid metabolism, and the survival of tumor cells. This review examines metabolic programming and essential pathways, including glycolysis, TCA cycle, lipid metabolism, PI3K/AKT/mTOR, AMPK, and MAPK, emphasizing their therapeutic significance. The integration of metabolic treatments with medicines based on natural compounds has significant potential for enhancing treatment effectiveness and mitigating therapeutic resistance. Ovarian cancer needs an integrated strategy that includes metabolic reprogramming, signaling modulation, and drugs derived from natural products. Natural chemicals provide intriguing approaches to address chemotherapy resistance and improve treatment efficacy. Further research is required to enhance these methodologies and evaluate their practical applicability for improved patient outcomes. Full article

Narcotics trafficking is a fundamental part of organized crime, posing significant and evolving challenges for forensic investigations. Addressing these challenges requires rapid, precise, and scientifically validated analytical methods for reliable identification of illicit substances. Over the past five years, forensic drug testing has advanced considerably, improving detection of traditional drugs—such as tetrahydrocannabinol, cocaine, heroin, amphetamine-type stimulants, and lysergic acid diethylamide—as well as emerging new psychoactive substances (NPS), including synthetic cannabinoids (e.g., 5F-MDMB-PICA), cathinones (e.g., α-PVP), potent opioids (e.g., carfentanil), designer psychedelics (e.g., 25I-NBOMe), benzodiazepines (e.g., flualprazolam), and dissociatives (e.g., 3-HO-PCP). Current technologies include colorimetric assays, ambient ionization mass spectrometry, and chromatographic methods coupled with various detectors, all enhancing accuracy and precision. Vibrational spectroscopy techniques, like Raman and Fourier transform infrared spectroscopy, have become essential for non-destructive identification. Additionally, new sensors with disposable electrodes and miniaturized transducers allow ultrasensitive on-site detection of drugs and metabolites. Advanced chemometric algorithms extract maximum information from complex data, enabling faster and more reliable identifications. An important emerging trend is the adoption of green analytical methods—including direct analysis, solvent-free extraction, miniaturized instruments, and eco-friendly chromatographic processes—that reduce environmental impact without sacrificing performance. This review provides a comprehensive overview of innovations over the last five years in forensic drug analysis based on the ScienceDirect database and highlights technological trends shaping the future of forensic toxicology. Full article

Glutathione S-transferases (GSTs) are phase II detoxification enzymes that display several enzymatic activities, including transferase, peroxidase, reductase, and isomerase functions, as well as non-enzymatic roles (e.g., serving as binding proteins). Their complex functionality lies in the biotransformation of xenobiotics (e.g., pesticides, drugs) and certain endogenous compounds, primarily metabolites produced by phase I detoxification enzymes. Several plant-derived compounds have been shown to modulate the activity and expression levels of these enzymes. Phytochemical activators of GSTs are potentially beneficial for detoxification in cases of exposure to various toxic compounds, whereas inhibitors of GSTs could have positive effects as adjuvant treatments for cancers that express high levels of GSTs associated with drug resistance. Full article

Antimicrobial resistance (AMR) has emerged as a global health crisis, with methicillin-resistant Staphylococcus aureus (MRSA) representing one of the most clinically significant multidrug-resistant pathogens. In this study, three structurally unique anthracycline derivatives—keto-ester (1), 4-deoxy-ε-pyrromycinone (2), and misamycin (3)—were first isolated and characterized from the fermentation broth of the marine-derived Streptomyces tauricus NBUD24. These compounds exhibited notable antibacterial efficacy against MRSA, with minimum inhibitory concentrations (MICs) ranging from 16 to 32 µg/mL. Cytotoxicity assays confirmed their safety profile at therapeutic concentrations. The biofilm formation assay demonstrated that 4-deoxy-ε-pyrromycinone inhibited biofilm formation of MRSA ATCC43300, with an inhibition rate of 64.4%. Investigations of antibacterial mechanisms revealed that these compounds exert antibacterial effects primarily through disruption of bacterial cell wall integrity and destruction of DNA structure. These findings underscore the potential of marine-derived microbial metabolites as promising scaffolds for developing next-generation antimicrobial candidates to combat drug-resistant infections. Full article