Search Results (9,401)

Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists are used long term for obesity and diabetes, but their oesophageal safety is uncertain: weight loss may reduce Barrett’s oesophagus and adenocarcinoma risk, whereas delayed gastric emptying may worsen reflux. We performed a genetic assessment of target-mediated oesophageal safety. Methods: Two-sample drug-target Mendelian randomisation used cis-expression quantitative trait loci for both receptors (31,684 participants). Outcomes were European genome-wide association studies of gastro-oesophageal reflux disease and the Barrett’s oesophagus/oesophageal adenocarcinoma axis, with a trans-ancestry squamous cell carcinoma comparator. A prespecified gated workflow required positive-control validation, and target specificity required genetic colocalisation (posterior probability of a shared causal variant ≥ 0.70). Candidate metabolic mediators were examined in two-step analyses, and findings were replicated in an independent Finnish population (FinnGen R12). Results: Genetically proxied GLP-1 receptor expression was not associated with reflux disease (odds ratio 0.97, 95% confidence interval 0.85–1.11), arguing against a substantial target-mediated reflux liability; the GIP receptor estimate was not estimable. For the Barrett’s oesophagus/adenocarcinoma endpoint, estimates were near the null for both receptors (GLP-1R 0.96, 0.47–1.96; GIPR 1.00, 0.42–2.37); colocalisation was uninformative because the outcome loci carried no detectable association signal, and wide intervals did not exclude moderate effects. The null reflux findings were reproduced in FinnGen. Adiposity showed the most consistent pathway association, whereas glycaemic traits did not, including when HbA1c was instrumented from a population-based genome-wide association study providing an order of magnitude more variants. Conclusions: GLP-1 receptor perturbation was not associated with reflux disease, providing cautious genetic reassurance. For the Barrett’s oesophagus/adenocarcinoma axis, no target-specific association was demonstrated, but colocalisation was uninformative because the outcome loci carried no detectable signal, and imprecision precludes firm safety conclusions; larger adenocarcinoma-specific studies are warranted. Full article

Background/Objectives: Glia-mediated inflammation contributes to a wide range of central nervous system (CNS) disorders, including epilepsy. Pregabalin (PGB) and cannabidiol (CBD) are CNS-acting drugs prescribed for various neuropsychiatric conditions, especially seizures. This study investigated the effects of PGB and CBD on glial properties in an astrocyte–microglia co-culture model of inflammation. Methods: Physiological (M5, containing 5–10% microglia) and pathological inflammatory astrocyte–microglia co-cultures (M30, containing 30–40% microglia) were collected from the postnatal brain hemispheres of Wistar rats (P0-P2) according to an established protocol and treated with different concentrations of PGB (3, 10, 30 and 60 µg/mL) for 24 h or CBD (50, 500 and 1000 ng/mL) for 1 h or 24 h. Metabolic activity was assessed by the MTT assay. Microglial phenotypes and astroglial connexin (Cx)43 expression were detected by immunocytochemistry. Results: In M5 co-cultures, short-term incubation (1 h) with high concentrations (1000 ng/mL) of CBD significantly reduced glial viability (p < 0.05), while no significant changes were observed in M30 co-cultures. After 24 h of incubation, M5 cultures exhibited a significant increase in metabolic activity at 50 ng/mL (p < 0.0001) and 500 ng/mL (p < 0.05), and a reduction at 1000 ng/mL (p < 0.05), suggesting impaired viability at high concentrations under physiological conditions. The distribution of microglial phenotypes in physiological M5 co-cultures incubated with CBD remained unchanged. In M30 co-cultures, CBD incubation for 1 and 24 h significantly reduced microglial activation and promoted a shift from reactive, phagocytic to homeostatic, ramified microglial phenotype (p < 0.05, p < 0.01, p < 0.0001). In contrast, PGB did not affect glial cell viability, microglial phenotypes or Cx43 expression in physiological and inflammatory co-cultures, indicating that the mechanisms of action of PGB probably do not include modulation of glial cells in vitro. Conclusions: The inhibition of microglial reactivity by CBD suggests potential positive effects on the neuroinflammatory component involved in the pathogenesis of CNS disorders such as epilepsy. Full article

Obesity is a multifactorial disorder with increasing global prevalence, highlighting the importance of identifying early-life factors that may influence long-term metabolic outcomes. While metformin is widely used to improve metabolic dysfunction in adulthood, whether neonatal exposure to this drug modifies adult responses to subsequent dietary challenges remains poorly understood. This exploratory study evaluated whether intraperitoneal metformin administration during the neonatal period alters adult metabolic responses to hyperlipidic diet (HL) exposure in Wistar rats. Following weaning and sex determination, male offspring (n = 80) were included in the study and distributed among four experimental groups, i.e., saline–normolipidic (SAL-NL), saline–high-fat (SAL-HL), metformin–normolipidic (MET-NL), and metformin–high-fat (MET-HL), with 20 animals per group. From postnatal days 1 to 12, animals received daily intraperitoneal saline or metformin (100 mg/kg/day). From days 60 to 90, animals were fed normolipidic or hyperlipidic diets. Body mass, food intake, glucose tolerance (GTT), and insulin tolerance (ITT) were assessed. Neonatal metformin exposure was associated with reduced body mass gain in MET-HL animals compared to SAL-HL, while food intake differed according to dietary condition. Metformin-treated animals also exhibited improved insulin sensitivity, reflected by higher kITT values, while no significant differences were observed in glucose tolerance. These preliminary findings suggest that neonatal metformin administration may influence adult metabolic responses to dietary challenge. Further studies are required to elucidate the mechanisms and long-term implications of this early-life intervention. Full article

Background/Objectives: Adverse drug reactions (ADRs) caused by drug–drug interactions (DDIs) represent an important problem in pharmacotherapy, especially in patients receiving multiple medications. Most computational approaches to DDI-associated ADR prediction formulate the task as a binary classification, but they do not explicitly consider the severity of adverse reactions. Our study aims to develop structure-based models that predict the severity of ADRs associated with specific drug pairs. Methods: Datasets were generated using DrugMAP as the source of drug pair–ADR associations with annotated severity categories, and TwoSides was used as an additional source to generate conditionally negative examples. The drug pairs were represented using PoSMNA descriptors, which encode pair-specific structural features derived from the molecular structures of both compounds. Predictive models were built using PASS DDI software. Model performance was evaluated using a modified cross-validation procedure that excluded compound-level overlap between the training and test sets, thereby reducing information leakage caused by the repeated occurrence of the same drugs in different pairs. Results: Models were developed for 14 clinically relevant ADR types, including cardiovascular, hepatotoxic, nephrotoxic, hemorrhagic, metabolic, and neurological effects. The unweighted class-level macro-average AUC values ranged from 0.830 for the Major category to 0.911 for the Minor category, while balanced accuracy ranged from 0.776 to 0.857. Predictive performance varied significantly between ADR types and severity categories. Higher accuracy was observed for some ADR types that were better captured by the structure-based descriptors used in this study, whereas complex multifactorial reactions, such as hepatotoxicity, were less accurately predicted. Case-based assessment using clinically documented drug combinations showed that the predicted severity profiles were generally consistent with the expected clinical risk patterns. Conclusions: The proposed approach demonstrates that the PoSMNA descriptors of drug pairs can be used for preliminary prediction of DDI-associated ADR severity. The developed models can help to filter out potentially dangerous drug combinations at an early stage and are implemented in the AdverDDIPred web-application. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive inflammatory and fibrotic subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), and its treatment landscape is rapidly moving from nonspecific liver fat reduction towards mechanism-based drug positioning. Since 2024, resmetirom and semaglutide have received U.S. Food and Drug Administration accelerated approval for non-cirrhotic MASH with moderate-to-advanced fibrosis, while tirzepatide, survodutide, and fibroblast growth factor 21 analogues have shown biopsy-based phase 2 or 2b efficacy signals. This narrative review organises approved and emerging pharmacotherapies within a pathogenesis-informed three-axis framework: the weight-insulin resistance-substrate load axis, the intrahepatic lipid reprogramming axis, and the inflammation-fibrosis transition and multi-axis integration axis. We further grade evidence maturity from regulatory or phase 3 histological evidence to phase 2 biopsy-based evidence and earlier imaging- or biomarker-based signals. This framework is intended to support phenotype-sensitive treatment positioning rather than a fixed therapeutic sequence. In particular, weight-centred treatment should not be assumed to apply to all patients, including normal-weight or lean MASH. Overall, future MASH therapy will likely depend on matching drug mechanisms, fibrosis stage, cardiometabolic phenotype, and treatment goals. Full article

Background/Objectives: Drug resistance is a major challenge in cancer therapy, and mitochondria contribute to this process by controlling both metabolic adaptability and cell survival signaling. Mitophagy, the selective lysosomal removal of dysfunctional mitochondria, has been implicated in therapy resistance, yet its role in sunitinib-resistant renal cancer remains poorly defined. Methods: In this study, acquired sunitinib resistance was established in ACHN renal cancer cells through eight months of stepwise dose escalation. Initial selection conditions were determined using CCK-8 viability and crystal violet colony assays in parental ACHN cells, whereas sustained proliferation under continuous sunitinib exposure was used as the operational criterion for the resistant phenotype. Resistant and parental sensitive cells were treated with 25 µM and 50 µM succinic acid, alone or in combination with sunitinib. Gene expression of BNIP3, NIX, FUNDC1, LC3, PINK1, Parkin, PGAM5, SRC, LONP1, and ATP5F1A was measured by RT-qPCR, and BNIP3 and NIX protein levels were assessed by ELISA. Results: Resistant cells showed significant upregulation of receptor-mediated mitophagy components BNIP3, NIX and FUNDC1 (p < 0.05), with no significant change in LC3, alongside suppression of PINK1, Parkin, and mitochondrial homeostasis-associated genes LONP1, PGAM5, and ATP5F1A (p < 0.05). Succinic acid predominantly reduced BNIP3 and NIX protein levels in both cell lines and suppressed BNIP3, NIX, and LC3 mRNA expression in resistant cells. In contrast, the sunitinib + 50 µM succinic acid combination selectively increased PARKIN, PGAM5, LONP1, and ATP5F1A expression in resistant cells (2.49- to 5.98-fold; p < 0.005), a pattern not observed in parental cells. Conclusions: These findings indicate that sunitinib resistance in ACHN cells is associated with upregulated transcription of receptor-mediated mitophagy components and downregulated transcription of PINK1/Parkin pathway genes, and that exogenous succinic acid selectively upregulates PARKIN and other mitochondrial homeostasis-related gene expression in resistant, but not parental, cells. Full article

The pathogenesis and progression of liver diseases are characterized by marked zonal heterogeneity, yet conventional research paradigms have long overlooked this intrinsic spatial logic. Ferroptosis and cuproptosis have been widely implicated in liver disease; however, their precise intralobular distribution and zonal susceptibility patterns remain poorly defined. We present a narrative synthesis of the literature on the spatial zonation of hepatic metabolism, redox homeostasis, and metal handling, and assess their potential roles as determinants of region-specific cell death vulnerability. We propose the novel “spatial redox–metalloptosis axis” hypothesis. The pericentral zone (Zone 3), characterized by hypoxia, high cytochrome P450 activity, and a redox environment that may favor lipid peroxidation under specific pathological conditions, is hypothesized to form a ferroptosis-susceptible niche under metabolic stress. Conversely, the periportal zone (Zone 1), characterized by active copper handling and oxidative phosphorylation-dependent metabolism, is hypothesized to be preferentially vulnerable to cuproptosis (proposed hypothesis; direct zone-resolved evidence of cuproptosis execution in Zone 1 is currently absent). Ceruloplasmin is proposed as a candidate molecular link between copper and iron metabolism. We further identify shared molecular hubs and a hypothesized spatial redox–metalloptosis axis linking these two regulated cell death modalities, while direct biological crosstalk remains to be demonstrated. We also highlight critical technological, mechanistic, and translational gaps. This review aims to shift liver disease research from viewing the liver as a homogeneous organ to a functionally compartmentalized zoned ecosystem, providing a testable theoretical framework for deciphering region-specific liver injury and developing spatially informed therapeutic strategies. Full article

Acute and chronic inflammation underlies the pathogenesis of numerous diseases, including autoimmune disorders, atherosclerosis, infections, and cancer. Although non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are widely used to control inflammation, their clinical utility is limited by adverse effects such as gastrointestinal toxicity and immunosuppression. Specialized pro-resolving mediators (SPMs), a family of endogenous lipid mediators derived from omega-3 fatty acids, have emerged as promising therapeutics because they actively promote the resolution of inflammation without suppressing host immunity. However, their clinical translation is hindered by poor chemical stability, rapid metabolic degradation, and short circulation half-lives. To overcome these limitations, a variety of delivery platforms—including liposomes, extracellular vesicles, PLGA nanoparticles, and hydrogels—have been developed to improve SPM stability, pharmacokinetics, and therapeutic efficacy. This review summarizes the cellular targets of SPMs, current delivery challenges, and emerging strategies for cell- and tissue-specific SPM delivery. We also discuss future opportunities for targeted SPM therapies in the treatment of inflammatory diseases and cancer. Full article

Peptide therapeutics occupy a unique position between small organic compounds and large protein biomolecules, combining high specificity, strong pharmacological efficacy, and favourable safety profiles. Consequently, they have emerged as important therapeutic agents for a wide range of diseases, including metabolic and oncological disorders. However, oral administration of peptide drugs remains a major challenge due to extensive enzymatic degradation, low intestinal permeability, mucus entrapment, and presystemic metabolism within the gastrointestinal tract. This review provides a comprehensive overview of contemporary strategies for improving oral peptide delivery, with special emphasis on emerging pharmaceutical formulation technologies, bioinspired delivery systems and ingestible device-assisted approaches. A qualitative literature search was conducted using major scientific databases and included relevant publications available up to May 2026. The analysis identified the main barriers responsible for low oral bioavailability of peptide drugs, as well as promising approaches to overcoming these obstacles, including peptide modification, enzyme inhibition, permeation enhancement, mucolytic strategies, and advanced carrier systems. Special attention is given to multifunctional carrier systems, ingestible medical devices and bile acid-inspired technologies as emerging directions in oral peptide delivery. The convergence of pharmaceutical sciences, bioinspired formulation strategies and biomedical engineering is expected to accelerate the clinical translation of oral peptide formulations and enable their therapeutic potential to be fully exploited. Full article

As the core transcriptional co-activators of the Hippo signaling pathway, YAP and TAZ play essential roles in maintaining tissue homeostasis and in tumorigenesis. Their aberrant activation is frequently observed in human malignancies, and accumulating evidence has identified them as crucial drivers of tumor initiation and progression. YAP/TAZ have been recently recognized as key regulators of cellular metabolic reprogramming, a hallmark of cancer that fuels tumor cell proliferation by rewiring glucose, lipid, amino acid, and nucleotide metabolism. Conversely, the activity of YAP/TAZ is modulated by metabolites such as glucose and lipids, establishing a complex bidirectional regulatory circuit. Therefore, deciphering this intricate crosstalk is of great importance for cancer therapy and drug discovery. In this review, we systematically clarify the interplay between YAP/TAZ and metabolic reprogramming in cancer, delineate the core molecular networks through which YAP/TAZ govern each metabolic pathway, and summarize the current pharmacological inhibitors targeting YAP/TAZ-regulated metabolic networks. Collectively, these findings pave the way for therapeutic approaches targeting YAP/TAZ-driven metabolic vulnerabilities in cancer. Full article

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a progressive condition predisposing to cirrhosis and hepatocellular carcinoma, with prevalence rising globally. Yet effective therapies remain limited. Wuzhi Dripping Pills (WZDP), derived from Schisandra sphenanthera, possess hepatoprotective and anti-inflammatory properties, though their efficacy against MASLD remains unexplored. Methods: Network pharmacology predicted active ingredients and targets, followed by KEGG enrichment analysis. A high-fat diet MASLD rat model was established to evaluate WZDP effects on weight, liver index, and serum markers. Serum metabolomic profiling via UPLC-MS/MS, combined with multivariate statistics and KEGG annotation, identified perturbed pathways. Results: Twelve bioactive compounds and 434 WZDP targets were retrieved, of which 74 intersected with 838 MASLD-associated genes. Enrichment implicated AGE-RAGE, insulin resistance, and HIF-1 signaling. In vivo, WZDP significantly improved anthropometric and biochemical parameters. Metabolomic analysis distinctly separated WZDP-treated from model groups, highlighting phospholipase D signaling as a key differential pathway. Conclusions: This integrative approach confirms that WZDP confers therapeutic benefits in MASLD through coordinated regulation of neuroactive ligand–receptor interaction, bile acid biosynthesis, phospholipase D signaling, and arginine–proline metabolism. Our findings furnish a molecular and metabolic rationale for further mechanistic studies and drug discovery efforts. Full article

The global emergence of multidrug-resistant fungal pathogens, including Candida auris, Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Pneumocystis jirovecii, poses a growing threat to public health, particularly among immunocompromised individuals. The limited number of available antifungal drug classes and the rapid evolution of resistance mechanisms, including target-site mutations, efflux pump activation, biofilm formation, metabolic adaptation, and stress-response signaling, have substantially reduced treatment efficacy. This review provides a comprehensive overview of current antifungal therapies, their limitations, and emerging molecular targets for next-generation antifungal drug discovery. We highlight promising targets involved in fungal cell wall biosynthesis, membrane integrity, mitochondrial metabolism, virulence regulation, and host–pathogen interactions, emphasizing their interconnected roles within adaptive resistance networks. Attention is given to small-molecule isothiazolone-based inhibitors, including phosphoglucomutase-targeting compounds, as novel candidates capable of disrupting multiple fungal survival pathways. We further discuss advances in combination therapies, anti-virulence approaches, nanotechnology-based delivery systems, and artificial intelligence-driven drug discovery pipelines that integrate multi-omics data, structural modeling, molecular docking, and virtual screening to accelerate therapeutic development. These advances support a transition from conventional single-target strategies toward systems-level, precision-guided antifungal therapies, providing a framework for overcoming multidrug resistance and improving clinical outcomes in invasive fungal infections. Full article

Background: Drug repurposing represents an accelerated and cost-effective approach to discovering novel oncologic therapeutics. Here, we investigated the anticancer potential and underlying mechanisms of marbofloxacin (MBF), a veterinary fluoroquinolone (FQ), against breast cancer (BC) cells. Methods: The cellular impacts of MBF on cell viability, anchorage-dependent growth, tumorigenicity, migration, apoptosis, proliferation, senescence, and mitochondrial function were thoroughly characterized. To further elucidate its mechanistic activity, real-time qRT-PCR, untargeted LC-MS/MS-based metabolomics, network pharmacology, and molecular docking analysis were integrated. Results: MBF suppressed BC cell growth by inhibiting cellular proliferation and migration, disrupting mitochondrial membrane potential, and inducing ROS-mediated apoptosis and irreversible cellular senescence. These phenotypic impacts were accompanied by upregulation of tumor suppressors such as CDKN1A and PUMA and downregulation of oncogenes including MKI67, BIRC5, and BCL-2. Metabolomic analysis revealed broad suppression of biosynthesis-related metabolic pathways, characterized by the depletion of critical polyamines and nucleotide pathways. Network pharmacology and molecular docking analyses identified EGFR and HSP90AA1 as putative hub proteins potentially associated with the observed anticancer phenotype. Conclusions: These results provide initial evidence that MBF induces metabolic and molecular rewiring in BC, highlighting its promise as a repositionable therapeutic candidate. Full article

Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic liver diseases worldwide, involving multiple pathological mechanisms such as lipid metabolism disorders, oxidative stress, chronic inflammation, insulin resistance, and dysregulation of the gut–liver axis. Currently, there remains a lack of effective and long-term safe therapeutic strategies for MASLD, necessitating the development of novel interventions. Plant-derived exosome-like nanovesicles (PELNs) represent naturally secreted nanoscale vesicles derived from plant cells. Their advantages, including extensive availability, high biocompatibility, low immune activation, remarkable stability, and convenient oral administration, make them attractive platforms for therapeutic delivery. PELNs can not only encapsulate natural bioactive compounds such as polyphenols, alkaloids, terpenoids, and polysaccharides but also serve as drug delivery vehicles to achieve liver-targeted transport and synergistic therapy. Current evidence for PELNs in MASLD is predominantly preclinical. In vitro studies have provided mechanistic insights into their effects on lipid metabolism, oxidative stress, inflammatory signaling, and hepatocellular injury, whereas animal studies have demonstrated improvements in hepatic steatosis and related metabolic abnormalities for selected PELNs. A smaller number of studies have investigated tissue distribution, oral uptake, or preliminary biosafety. However, systematic pharmacokinetic, long-term toxicological, and target-species clinical evidence remains insufficient. Accordingly, the therapeutic effects discussed in this review should be interpreted primarily as preclinical findings, and the applicability of PELNs in veterinary practice remains to be established. Full article