Search Results (131)

Ribosome-inactivating proteins are a class of toxins that target eukaryotic ribosomes, inhibit protein synthesis, and ultimately induce cell death. Several of these toxins pose significant clinical and public health threats. Among these, ricin, derived from the castor bean plant (Ricinus communis), is a highly potent biotoxin with recognized bioterrorism potential. Other ribosome-inactivating proteins, including Shiga toxin produced by pathogenic Shigella and Escherichia coli, as well as mucoricin from Mucorales fungi, contribute to disease severity and can lead to life-threatening complications. Despite these risks, no approved therapeutics are currently available. The development of effective inhibitors depends on robust and well-defined strategies to identify and validate small molecules that disrupt toxin–ribosome interactions. Efforts to target the catalytic active site have met with limited success, largely due to its broad, shallow, and highly polar architecture, which is not conducive to high-affinity binding by drug-like molecules. In contrast, the ribosome-binding interface represents a more tractable target, as it is essential for toxin recruitment and offers more structurally defined and druggable features. Inhibitors targeting this interface can also exert allosteric effects by disrupting long-range conformational coupling between the ribosome-binding region and the active site, thereby attenuating catalytic activity without directly engaging the catalytic pocket. In this review, we compile and evaluate biophysical and biochemical assays for the discovery and characterization of small-molecule inhibitors that target toxin–ribosome interactions. We examine in vitro binding approaches, including surface plasmon resonance-based fragment screening and fluorescence anisotropy assays for ranking inhibitory activity. We further review biochemical and molecular assays that assess ribosome protection from toxin-mediated depurination, along with complementary cell-based assays that evaluate functional rescue in cellular systems. Collectively, this review consolidates current screening methodologies and highlights opportunities to refine assay strategies, thereby supporting the advancement of targeted therapeutics. Full article

Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) include small organic anions derived from the gut microbiome that interact with organic anion transporters of the SLC22 family, many of which are expressed in the kidney proximal tubule. According to the Remote Sensing and Signaling Theory (RSST), crosstalk between organs (e.g., gut–liver–kidney axis, gut–brain axis) and the gut microbiome is mediated by metabolites and signaling molecules transported by multi-specific “drug” transporters. The renal drug transporter OAT1 (SLC22A6) is also a major transporter of gut-microbiome products and uremic toxins (e.g., indoxyl sulfate); it has been shown to act as part of a regulatory feedback loop involving the gut microbiome. SCFAs, especially propionate and butyrate, have been shown to play a central role in the transcriptional regulation of OAT1 through HDAC inhibition. By fecal metagenomics analyses of Oat1 knockout mice, we now find that propionate synthesis is among the most altered pathways in the gut microbiome. In contrast, these pathways were only minimally altered in the Oat3 (Slc22a8) knockout. Metabolomics analyses indicate that serum propionate derivatives (e.g., propionyl glycine) and 3-hydroxybutyrate are dependent on OAT1 in the knockout mice and in humans treated with probenecid, an OAT1 inhibitor. The gut microbiome of the Oat1 knockout mice also exhibited greater fatty acid synthesis, which generates odd-chain-length fatty acids (e.g. heptanoate) when propionate is available. Overall, the data, especially when considered in light of in vitro experiments of others, indicates the in vivo existence of a feedback loop connecting gut-microbiome-derived SCFAs and MCFAs to kidney proximal tubule uptake via OAT1. This bidirectional feedback loop in turn regulates OAT1 expression through HDAC inhibition. The feedback loop is clearly consistent with the Remote Sensing and Signaling Theory—in particular, the centrality of multi-specific “drug” transporters in organ crosstalk and host–microbiome interactions via small molecules with “high information content.” The key role of OAT1 function in maintaining tubular secretion in CKD supports the importance of this RSST loop in renal pathophysiology. Modulating this RSST loop could have therapeutic value in chronic kidney disease and other contexts. Full article

The rising threat of antimicrobial resistance necessitates the search for novel bioactive molecules from natural sources. This study investigated the phytochemical composition, antibacterial potency, and molecular docking interactions of Citrus aurantium peel ethanol extract against Escherichia coli outer-membrane and topoisomerase proteins and Staphylococcus aureus toxins as drug target proteins. Qualitative and quantitative phytochemical compositions were examined using standard analytical methods, chemical compounds were evaluated and qualified using Gas Chromatography–Mass Spectrometry (GC-MS), and antibacterial effects were investigated in silico and validated in vitro. Qualitative and quantitative analyses revealed high concentrations of flavonoids (4.54 ± 0.11%), alkaloids (1.6 ± 0.03%), terpenoids (1.35 ± 0.01%), tannins (1.02 ± 0.05%), phenols (0.97 ± 0.07%), and saponins (0.80 ± 0.01%). GC–MS profiling identified several dominant compounds, including β-D-glucopyranose, neo-inositol, 8-(2,3-dihydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one, and D-allose. In silico docking studies against bacterial druggable proteins (PDB IDs: 4C56 and 3MFG, which are S. aureus toxins; 1BXW and 3FV5, which are E. coli outer-membrane and topoisomerase proteins) revealed strong binding affinities (−6.477 to −8.774 kcal/mol), comparable to standard antibiotics. ADMET predictions confirmed favorable pharmacokinetic and safety profiles, with most lead compounds displaying high intestinal absorption, low hepatotoxicity, and compliance with Lipinski’s rule of five. The extract exhibited stronger antibacterial activity, producing inhibition zones of 25.11 ± 0.017 and 23.04 ± 0.25 mm against clinical isolates of S. aureus and E. coli, respectively, at a concentration of 10 mg/mL, comparable to ciprofloxacin (30.35 ± 0.26 mm). These findings highlight C. aurantium peel phytoconstituents as promising scaffolds for antibacterial drug development and justify further in vivo validation for combating multidrug-resistant pathogens. Full article

Chitosan-based interpenetrating networks (IPNs) have become highly attractive as advanced super-adsorbent materials due to their ability to combine a high density of functional adsorption sites with enhanced structural stability under physiological conditions. While chitosan offers intrinsic advantages such as biocompatibility, biodegradability, and chemical functionality, its adsorption efficiency, mechanical strength, and long-term stability may offer limited performance in complex biomedical environments. The formation of interpenetrating networks provides an effective strategy to overcome these limitations by interlacing chitosan with other polymer networks, resulting in a synergistic enhancement of physicochemical and adsorption properties. The formation of chitosan-based IPNs offers tunable control of network structure, porosity, swelling behaviour, and adsorption kinetics, which in turn results in enhanced retention and controlled interaction of drugs, biomolecules, toxins, and other therapeutic agents. Variations in polymer composition, crosslinking density, and network interactions further facilitate the controlled tailoring of adsorption properties for targeted biomedical applications. This review presents a comprehensive and critical assessment of recent progress in the fabrication, functionalization, and structure–property relationships of chitosan-based IPNs, with a main emphasis on their super-adsorbent behaviour. Furthermore, this review highlights key biomedical applications of IPNs, including controlled drug delivery, wound healing systems, tissue engineering scaffolds, detoxification platforms, and biosensing devices. Current issues in scalability, stability, and clinical translation are discussed, as well as future perspectives that highlight the potential of chitosan-based IPNs as high-performance, sustainable super-adsorbent materials for advanced biomedical technologies. Full article

Although nanomedicine has enabled significant advances in drug delivery, the clinical translation of conventional synthetic nanocarriers is limited by immune clearance, non-specific biodistribution, and gastrointestinal instability. This poses major challenges for therapy targeting the intestines. Cell membrane-coated nanotechnology (CMCT) and membrane vesicle-based systems have emerged as biomimetic platforms integrating synthetic nanomaterials with naturally derived biological interfaces. These biohybrid systems inherit biological functions originating from cells, including immune evasion, prolonged circulation, lesion homing, and microenvironment-responsive interactions, through the direct transfer of intact membrane components. This review summarizes recent advances in CMCT and membrane vesicle-based strategies for intestinal drug delivery. It covers fabrication methodologies, programmable manufacturing approaches, and functional regulation enabled by diverse membrane sources and hybrid engineering designs. Applications in inflammatory bowel disease, colorectal cancer, and intestinal infections are highlighted, emphasizing key therapeutic mechanisms, such as targeting inflammation, neutralizing toxins, modulating the immune system, and regulating the microbiome. We also discuss the major challenges of translation, such as preserving membrane and coating integrity, ensuring oral stability, achieving batch reproducibility, and ensuring biosafety. Overall, this review establishes a conceptual and engineering framework to guide the transition of membrane-based nanocarriers from passive biomimicry to adaptive, clinically translatable intestinal delivery systems. Full article

The ATP-binding cassette subfamily G member 2 (ABCG2), also known as breast cancer resistance protein (BCRP), is an efflux transporter expressed in key pharmacokinetic tissues and biological barriers. It regulates exposure to many endogenous compounds, drugs, and environmental toxins. Genetic variability in ABCG2 has been recognised as an important contributor to interindividual variability in drug response, especially in terms of efficacy and toxicity. This narrative review summarises current knowledge on the clinical relevance of ABCG2 genetic variants, with a focus on their effects on pharmacokinetics, adverse drug reactions and drug–drug–gene interactions, as well as their potential implementation in personalised therapy. A literature search was performed in PubMed, Scopus and the Clinical Pharmacogenomics Database (ClinPGx), with an emphasis on clinically relevant studies and available pharmacogenomic guidelines. The most investigated ABCG2 variant, c.421C>A (rs2231142; p.Gln141Lys), is consistently associated with reduced transporter activity and increased systemic exposure to several substrate drugs, including statins, allopurinol and anticancer agents, which may influence both treatment response and the risk of toxicity. Although growing evidence supports the clinical relevance of ABCG2 genotyping, its routine implementation remains limited. Integration of ABCG2 variability into polygenic models and clinical decision-support tools may further improve individualised treatment, particularly in patients with multimorbidity and polypharmacy. Full article

Currently, commercially available pain medications can cause adverse effects. Within this framework, researchers have been exploring new drug candidates derived from animal venoms and toxins. The objective of this study was to investigate the number of molecules with potential for pain relief derived from animal venoms and toxins, which could potentially contribute to the development of new biopharmaceuticals. We conducted a literature search in January 2025, covering the period from 1960 to 2025, in two Latin American and nine international scientific databases. The results consisted of 212 articles selected for review. From these articles, 152 toxins and venoms with analgesic potential were identified and classified into 14 different types of pharmacological targets. The peptides investigated, with masses between 500 Da and 5000 Da, are strong candidates for alternative biopharmaceuticals. Most of the toxins found interact with ion channels, representing an alternative to commercially available drugs. Full article

Toxin–antitoxin (TA) modules represent sophisticated regulatory networks that have evolved from simple plasmid maintenance factors into multifunctional genetic modules orchestrating bacterial stress responses, pathogenesis, and ecological adaptation. This review highlights a compelling correlation between the abundance of toxin–antitoxin (TA) modules and bacterial pathogenicity, as exemplified by Mycobacterium tuberculosis (M.tb), which encodes 118 TA loci—significantly more than the fewer than 10 found in closely related saprophytic species. The clinical significance of TA modules extends beyond traditional stress response roles to encompass antimicrobial persistence, where systems like VapBC and MazEF facilitate dormant subpopulations that survive antibiotic therapy while maintaining chronic infections. Recent discoveries have revealed TA modules as sophisticated bacterial defense mechanisms against bacteriophage infection, with DarTG and ToxIN systems representing novel antiviral immunity components that complement CRISPR-Cas and restriction–modification systems. The immunomodulatory capacity of TA modules demonstrates their role in host–pathogen interactions, where systems such as VapC12 in M.tb promote macrophage polarization toward permissive M2 phenotypes while inducing anti-inflammatory cytokine production. Large-scale genomic analyses reveal that TA modules function as drivers of horizontal gene transfer networks, with their signatures enabling accurate prediction of plasmid community membership and serving as determinants of microbial community structure. The biotechnological applications of TA modules have expanded to include genetic circuit stabilization, biocontainment device construction, and multi-species microbial community engineering, while therapeutic strategies focus on developing multi-target inhibitors against conserved TA protein families as promising approaches for combating drug-resistant bacterial infections. The evolutionary conservation of TA modules across diverse bacterial lineages underscores their fundamental importance as central organizing principles in bacterial adaptation strategies, where their multifunctional nature reflects complex selective pressures operating across environmental niches and host-associated ecosystems. This review provides an integrated perspective on TA modules as dynamic regulatory elements that support bacterial persistence, immune evasion, and ecological versatility, establishing them as genetic elements with truly “many faces and functions” in prokaryotic biology. Full article

Antibiotic resistance, especially among Gram-negative bacterial strains, places a massive burden on global healthcare systems as resistance development has outpaced antibiotic discovery. Protein–protein interactions, successful in other therapeutic contexts, are emerging as promising, yet underexplored, targets for the development of novel classes of antibacterials. Pathogen-specific protein–protein interactions are attractive targets because they are often structurally and functionally distinct from host proteins and are less likely to elicit rapid resistance. This review summarizes recent developments in targeting protein–protein interactions in Gram-negative bacteria, focusing on the modulation of five critical cellular processes: membrane regulation, replication, transcription, translation, and toxin-antitoxin systems. We highlight the design and discovery of both small-molecule and peptide-based inhibitors. While many identified modulators exhibit potent in vitro activity against their respective targets, achieving effective penetration of the complex Gram-negative cell envelope remains a major challenge. Nevertheless, the diverse and essential nature of these bacteria-specific protein–protein interactions represents an attractive strategy for developing next-generation antimicrobials to combat drug-resistant pathogens. Full article

The intestine is a complex organ whose main functions are food digestion and nutrient absorption. It is therefore of great interest for pharmaceutical research as a preferred route for drug delivery. In vitro intestinal models are valuable tools for the preclinical evaluation of absorption, distribution, metabolism, and excretion of new therapeutic formulations; consequently, several attempts have been made to recreate the human intestine barrier in vitro. The models so far set up were aimed at mimicking specific intestinal features related to the molecules or processes under investigation. Artificial membranes are suitable to study passive absorption; systems based on 2D/3D cell cultures reproduce the transcellular pathway; organs-on-a-chip mimic the in vivo cellular and mechanical complexity, allowing the identification of the multiple factors involved in molecular interactions with the intestinal barrier; and intestine explants replicate in full the native organ under controlled conditions, thus providing the most comprehensive in vitro model. All these models have advantages and disadvantages but all have given important contribution to advance the knowledge on the interaction of drugs, toxins, and xenobiotic with the intestinal barrier. Full article

Animal toxins contain various bioactive peptides and proteins which have evolved to interact in specific ways. As such, they are a good starting point for developing new drugs and vaccines. This paper examines three natural neurotoxins derived from the black mamba (Dendroaspis polylepis), which show significant pharmacological potential: mambalgins, fasciculins and dendrotoxins. All three may be of value in the treatment of pain, cancer and neurodegenerative disease. Mambalgins provide similar pain relief to opioids but without the risk of addiction; they act by selectively blocking acid-sensitive ion channels (ASICs), especially ASIC1a. Thanks to this inhibitory activity they also demonstrate selective activity against glioblastoma, melanoma and leukemia cells as innovative anticancer drugs. Fasciculins are very strong inhibitors of acetylcholinesterase (AChE) and hence offer promise in multi-target drugs and as treatments for treating Alzheimer’s disease. Dendrotoxins such as DTX-K and DTX-I are able to modulate neuronal excitability and synaptic transmission by blocking voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.6); both have been shown to be effective against cancer cells, and to influence the cardiovascular, immune, and digestive systems. Recent advances in recombinant biotechnology and protein engineering have allowed their safe production with increased therapeutic value. The review examines the translational potential of D. polylepis venom proteins and highlights the need for additional preclinical research on bioactive molecules of toxin origin. Full article

Scorpion venoms contain a wide range of toxins that interact with a variety of target molecules (ion channels, receptors and enzymes) associated with synaptic transmission, action potential propagation, cardiac function, hemostasis and other physiological systems. Scorpion toxins are also active towards bacteria, viruses, fungi and parasites. Such interactions make scorpion toxins useful lead molecules for developing compounds with biotechnological and therapeutic applications, and as tools for cell biology. In addition, scorpion toxins act as insectotoxins, with promising applications as insecticides. This review describes the range of scorpion toxins and discusses their usefulness for the development of insecticides and therapeutic drugs. Full article

Oral tongue squamous cell carcinoma (OTSCC) is a common type of oral cancer influenced by genetic, epigenetic, and environmental factors like exposure to environmental toxins. These environmental toxins can decrease the effectiveness of established chemotherapy drugs, such as Irinotecan, used in OTSCC treatment. Bioinformatics, drug discovery, and machine learning techniques were employed to investigate the impact of Irinotecan on OTSCC patients by identifying targets and signaling pathways, including those that positively influence protein phosphorylation, protein tyrosine kinase activity, the PI3K-Akt (Phosphatidylinositol 3-kinase- Protein Kinase B) signaling system, cancer pathways, focal adhesion, and the HIF-1 (Hypoxia-Inducible Factor 1) signaling pathway. Later, the protein–protein interactions (PPIs) network, along with twelve cytoHubba approaches to finding the most interacting molecule, was employed to find the important proteins BCL2 and EGFR. Drugs related to BCL2 and EGFR were extracted from the DGIdb database for further molecular docking. Molecular docking revealed that Docetaxel, Paclitaxel, Imatinib, Ponatinib, Ibrutinib, Sorafenib, and Etoposide showed more binding affinity than Irinotecan (i.e., −9.8, −9.6). Of these, Paclitaxel (−10.3, −11.4) and Imatinib (−9.9, −10.4) are common in targeting BCL2 and EGFR. Using these identified candidate genes and pathways, we may be able to uncover new therapeutic targets for the treatment of OTSCC. Furthermore, molecular dynamics (MD) simulations were performed for selected ligand–receptor complexes, revealing stable binding interactions and favorable energetic profiles that supported the docking results and strengthened the reliability of the proposed drug repurposing strategy. Full article

Chronic kidney disease (CKD) is associated with the systemic accumulation of uremic toxins (UTs) due to impaired renal elimination. Among these, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are particularly challenging because of their high protein binding and limited removal by dialysis. In addition to renal excretion, the transport of IS and PCS, and their microbiota-derived precursors, indole and p-cresol, across key physiological barriers—the intestinal barrier, blood–brain barrier, and renal proximal tubule—critically influences their distribution and elimination. This review provides an overview of transporter-mediated mechanisms involved in the disposition of IS, PCS, and their microbial precursors, indole and p-cresol. It also examines how these UTs may interact with commonly prescribed drugs in CKD, particularly those that share transporter pathways as substrates or inhibitors. These drug–toxin interactions may influence the pharmacokinetics and toxicity of IS and PCS, but remain poorly characterized and largely overlooked in clinical settings. A better understanding of these processes may guide future efforts to optimize pharmacotherapy and support more informed management of CKD patients, particularly in the context of polypharmacy. Full article

Bacterial pathogens have evolved diverse strategies to infect hosts, evade immune responses, and establish successful infections. While the role of transcription factors in bacterial virulence is well documented, emerging evidence highlights the significant contribution of small regulatory RNAs (sRNAs) in bacterial pathogenesis. These sRNAs function as posttranscriptional regulators that fine-tune gene expression, enabling bacteria to adapt rapidly to challenging environments. This review explores the multifaceted roles of bacterial sRNAs in host–pathogen interactions. Firstly, it examines how sRNAs regulate pathogenicity by modulating the expression of key virulence factors, including fimbriae, toxins, and secretion systems, followed by discussing the role of sRNAs in bacterial stress response mechanisms that counteract host immune defenses, such as oxidative and envelope stress. Additionally, this review investigates the involvement of sRNAs in antibiotic resistance by regulating efflux pumps, biofilm formation, and membrane modifications, which contribute to multi-drug resistance phenotypes. Lastly, this review highlights how sRNAs contribute to intra- and interspecies communication through quorum sensing, thereby coordinating bacterial behavior in response to environmental cues. Understanding these regulatory networks governed by sRNAs is essential for the development of innovative antimicrobial strategies. This review highlights the growing significance of sRNAs in bacterial pathogenicity and explores their potential as therapeutic targets for the treatment of bacterial infections. Full article