Pharmacological Reviews[JOURNAL]
Sun
200 papers
"Letter to the Editor: Pharmacological study of the safety, efficacy, and potential of M201-A on paroxysmal and persistent atrial fibrillation".
Aphale P, Dokania S, Shekhar H
J Pharmacol Exp Ther · 2026 Jan · PMID 41418593 · Publisher ↗
Abstract loading — click title to view on PubMed.
Special collection on novel targeted therapies for advanced prostate cancer.
Chen M, Wang QJ
J Pharmacol Exp Ther · 2026 Jan · PMID 41412092 · Publisher ↗
Abstract loading — click title to view on PubMed.
Matrix metalloproteinases and their association with preeclampsia/eclampsia with maternal age: A potential link to cardiovascular disease in later life.
Taherkhani S, Sheibani M, Ahmadi R … +4 more , Mohammadkhanizadeh A, Virag JAI, de Castro Braz LE, Azizi Y
J Pharmacol Exp Ther · 2026 Jan · PMID 41412091 · Publisher ↗
Maternal age is a well established risk factor for preeclampsia and eclampsia, with advanced maternal age (>35 years) associated with a significantly increased risk of developing these disorders. Preeclampsia and eclamps...
Maternal age is a well established risk factor for preeclampsia and eclampsia, with advanced maternal age (>35 years) associated with a significantly increased risk of developing these disorders. Preeclampsia and eclampsia are 2 of the most severe and life-threatening complications of pregnancy, affecting approximately 2%-8% of pregnancies worldwide. These disorders are characterized by high blood pressure, proteinuria, and multiorgan dysfunction, which can lead to maternal and fetal morbidity and mortality if left untreated. Despite advances in medical technology and prenatal care, the etiology of preeclampsia and eclampsia remains poorly understood, and there is a pressing need for the identification of novel biomarkers and therapeutic targets. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have a functional role in the degradation and remodeling of the extracellular matrix. MMP expression and activity changes in women with preeclampsia and eclampsia. For example, MMP-2 and MMP-9 have been shown to be elevated in the serum and placenta of women with preeclampsia, whereas MMP-1 and MMP-3 have been found to be decreased. These changes in MMP expression and activity may contribute to the development of preeclampsia and eclampsia by promoting inflammation, endothelial dysfunction, and vascular remodeling. The dysregulation of MMPs in preeclampsia/eclampsia can lead to the breakdown of the maternal-fetal interface, resulting in the release of proinflammatory cytokines and the activation of immune cells. Addressing MMP dysfunction in preeclampsia and eclampsia requires a multifaceted approach, combining pharmacological interventions, genetic insights, and a focus on oxidative stress to improve maternal and fetal health outcomes. SIGNIFICANCE STATEMENT: This study highlights the critical role of maternal age and matrix metalloproteinases (MMPs) in preeclampsia and eclampsia, severe pregnancy complications with high morbidity and mortality. Advanced maternal age increases risk, whereas dysregulated MMPs contribute to inflammation, endothelial dysfunction, and vascular remodeling, disrupting the maternal-fetal interface. Understanding MMP alterations offers potential for novel biomarkers and therapeutic targets, aiming to improve outcomes through integrated pharmacological and genetic approaches addressing immune and oxidative stress pathways.
Enhancing local glioblastoma treatment via in vitro synergistic pairing of Janus kinase/signal transducer and activator of transcription-3 inhibitor with antiepileptic drugs.
Bărăian AI, Raduly L, Zănoagă O … +3 more , Iacob BC, Berindan-Neagoe I, Bodoki E
J Pharmacol Exp Ther · 2026 Jan · PMID 41406909 · Publisher ↗
The heterogeneity and treatment resistance of glioblastoma (GBM) can be addressed through multidrug combination therapies that target multiple biological pathways simultaneously. In this study, we explored the repurposin...
The heterogeneity and treatment resistance of glioblastoma (GBM) can be addressed through multidrug combination therapies that target multiple biological pathways simultaneously. In this study, we explored the repurposing of antiepileptic drugs with potential antitumor effects, combined with the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3) inhibitor ruxolitinib (RUX), as an alternative local therapeutic approach for GBM. The cytotoxic effects of valproic acid (VPA), oxcarbazepine (OXC), and gabapentin (GBP) were evaluated on A172 and U251 GBM cells. Both VPA and OXC significantly reduced cell viability, prompting further investigation of their effects in combination with RUX. When tested in 3-dimensional multicellular tumorspheres, the combinations at their IC50 exhibited suboptimal effectiveness compared with single-agent treatment. Using a factorial experimental design based on a minimal combination approach to analyze dose-response data, followed by subsequent Bliss synergy analysis, synergistic interactions were revealed exclusively for RUX + VPA on A172 cells. Although the interaction between RUX and OXC was additive, GBM cells displayed increased sensitivity to this combination, suggesting potential therapeutic value. Ultimately, the most effective drug ratios were assessed using live/dead cell fluorescence staining in 3-dimensional multicellular tumorspheres. The variable treatment response observed among GBM cell lines underscores the need for personalized treatment strategies tailored to the specific molecular profile of individual tumors. SIGNIFICANCE STATEMENT: Given the unmet needs in glioblastoma treatment, the study explores novel combinations of Janus kinase/signal transducer and activator of transcription-3 inhibitor ruxolitinib and antiepileptics for local codelivery, aiming to overcome resistance and heterogeneity through synergistic effects and sustained release via molecularly imprinted reservoirs.
Social stress cue exposure heightens opioid preference and locus coeruleus neuroimmune activity in female rats.
Smiley CE, Childress TE, Bielicki BH … +1 more , Wood SK
J Pharmacol Exp Ther · 2026 Jan · PMID 41406908 · Publisher ↗
Stress exposure is often a precipitating factor underlying drug-seeking behavior that can lead to the establishment of comorbid posttraumatic stress disorder and substance use disorder (SUD) in clinical populations. The...
Stress exposure is often a precipitating factor underlying drug-seeking behavior that can lead to the establishment of comorbid posttraumatic stress disorder and substance use disorder (SUD) in clinical populations. The vicarious witness stress (WS) model is a potent ethologically relevant stressor that imparts many of its deleterious effects through heightened neuroimmune signaling in key stress sensitive brain regions. The present set of studies were designed to determine the impact of this psychosocial stressor on oxycodone place preference and central immune activity in female rats. In this way, we aim to better understand the neural correlates of stress-induced drug seeking in an effort to establish novel treatment targets for stress-related posttraumatic stress disorder/SUD. Female Sprague-Dawley rats were exposed to WS or nonstress control conditions prior to training for conditioned place preference with 3.0 mg/kg oxycodone. Following conditioned place preference training, rats with a history of stress were either exposed to the WS cues or left undisturbed and compared to controls for oxycodone place preference. Acute exposure to the WS cues led to the highest amount of time spent in the drug-paired compartment and this stress-induced augmentation of opioid preference was accompanied by significant increases in proinflammatory cytokines in the locus coeruleus. Taken together, these experiments established a comorbid model of stress and drug preference in female rats and have begun to identify potential brain regions that could be targeted to prevent stress-related sensitization to SUDs in females. SIGNIFICANCE STATEMENT: These studies offer insights into neuroimmune targets for the prevention of stress-induced opioid seeking with the overall goal of testing translationally relevant pharmacotherapies to prevent stress-sensitized drug-seeking responses in females.
Leading artificial intelligence-driven drug discovery platforms: 2025 landscape and global outlook.
Dharmasivam M, Kaya B, Akinware A … +2 more , Azad MG, Richardson DR
Pharmacol Rev · 2026 Jan · PMID 41389441 · Publisher ↗
Artificial intelligence (AI) has progressed from experimental curiosity to clinical utility, with AI-designed therapeutics now in human trials across diverse therapeutic areas. This review critically compares 5 leading A...
Artificial intelligence (AI) has progressed from experimental curiosity to clinical utility, with AI-designed therapeutics now in human trials across diverse therapeutic areas. This review critically compares 5 leading AI-driven discovery platforms: generative chemistry, phenomics-first systems, integrated target-to-design pipelines, knowledge-graph repurposing, and physics-plus-machine learning design. Key developments since 2024 include positive phase IIa results for Insilico Medicine's Traf2- and Nck-interacting kinase inhibitor, ISM001-055, in idiopathic pulmonary fibrosis. Another key development was the Recursion-Exscientia merger, which integrated phenomic screening with automated precision chemistry into a full end-to-end platform. In addition, advancement of the Nimbus-originated tyrosine kinase 2 inhibitor, zasocitinib (TAK-279), into phase III clinical trials exemplifies Schrödinger's physics-enabled design strategy reaching late-stage clinical testing. Emerging platforms such as Insitro, Isomorphic Labs, Atomwise, and XtalPi illustrate the field's expanding geographic and technical footprint. SIGNIFICANCE STATEMENT: Artificial intelligence (AI) is reshaping pharmacology by shortening discovery timelines, potentially reducing attrition, and expanding the design space of therapeutic candidates. Alongside technical milestones, regulatory and ethical frameworks from the US Food and Drug Administration and European Medicines Agency are beginning to address transparency, bias, accountability, intellectual property, and data privacy. Robotics tightly integrated with AI now enables self-driving laboratories that accelerate design-make-test-learn cycles and improve reproducibility. Together, these advances chart a forward-looking roadmap in which multimodal foundation models, robotics-led platforms, and hybrid physics-AI strategies are poised to accelerate translation, derisk development, and establish trustworthy AI as a cornerstone of modern drug discovery.
Synergistic combinations of antimicrobial peptides and conventional antibiotics: A strategy to delay resistance emergence in World Health Organization priority bacteria.
Roque-Borda CA, Zhang Q, Nguyen TPT … +10 more , Nguyen TTH, Medhi H, Rodrigues HLS, Canales Carnero CS, Sutherland D, Helmy NM, Araveti PB, de la Torre BG, Albericio F, Pavan FR
Pharmacol Rev · 2026 Jan · PMID 41389440 · Publisher ↗
Antimicrobial resistance represents one of the most pressing global health challenges of the 21st century, significantly compromising the efficacy of conventional antibiotics. In response to this crisis, the World Health...
Antimicrobial resistance represents one of the most pressing global health challenges of the 21st century, significantly compromising the efficacy of conventional antibiotics. In response to this crisis, the World Health Organization has updated its 2024 list of priority bacterial pathogens-classified into critical-, high-, and medium-risk groups-based on their resistance mechanisms, clinical impact, and global dissemination. This comprehensive review explores the emerging therapeutic potential of antimicrobial peptides (AMPs) when used in synergistic combinations with conventional antibiotics. By dissecting the mechanistic interplay-ranging from membrane disruption and efflux pump inhibition to biofilm penetration and intracellular antibiotic delivery-we provide a structured analysis of how these dual strategies overcome specific resistance barriers. Special emphasis is given to the World Health Organization-designated pathogens such as Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-resistant/vancomycin-resistant), Enterococcus faecium, Salmonella spp., Shigella spp., and Mycobacterium tuberculosis. Supported by extensive in vitro and in vivo data, this review catalogs dozens of successful AMP-antibiotic pairings, highlighting their fractional inhibitory concentration indices, clinical relevance, and implications for translational development. The evidence presented demonstrates that AMPs not only potentiate antibiotic action but also extend the useful lifespan of existing drugs while reducing toxicity. These findings support the advancement of AMP-based combination therapies as a next-generation strategy to contain resistance and restore the effectiveness of the antimicrobial arsenal. SIGNIFICANCE STATEMENT: Antimicrobial resistance remains a global health emergency, especially among World Health Organization 2024 priority pathogens. This review highlights the therapeutic promise of synergistic combinations between antimicrobial peptides and conventional antibiotics, offering a rational strategy to restore efficacy, overcome resistance mechanisms, and extend the clinical utility of existing drugs. By bridging microbiology, pharmacology, and translational medicine, this work provides timely insights for researchers and policymakers seeking innovative solutions to combat multidrug-resistant infections.
Metformin-mechanisms of its glycemia-reducing effect.
Drewe J, Foretz M, Krähenbühl S
Pharmacol Rev · 2026 Jan · PMID 41389439 · Publisher ↗
Metformin currently serves as the basis of oral treatment for patients with type 2 diabetes. While metformin's effect on glycemia is well established, its mode of action remains unclear. In clinical studies, long-term me...
Metformin currently serves as the basis of oral treatment for patients with type 2 diabetes. While metformin's effect on glycemia is well established, its mode of action remains unclear. In clinical studies, long-term metformin treatment improved glucose disposal and reduced hepatic gluconeogenesis. The effects on gluconeogenesis have been confirmed in experimental animals and cell preparations, but mostly at higher doses than those used in humans. Proposed hepatic mechanisms can be grouped into those with and without AMP-activated protein kinase (AMPK) activation; the latter include inhibition of mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase. Experimental studies on the effects of metformin on skeletal muscles suggest that AMPK activation and anti-inflammatory activities are possible mechanisms for increasing glucose disposal. Inhibition of renal gluconeogenesis may contribute to the extraintestinal glycemia-lowering effects of metformin. Following the observation that short-term intravenous metformin lacks glycemia-lowering effects in humans, intestinal mechanisms have been investigated. Suggested mechanisms include inhibition of intestinal glucose absorption owing to increased glycolysis driven by complex I inhibition in the mitochondria of enterocytes, stimulation of glucose transport into the colon, and stimulation of glucagon-like peptide-1 (GLP-1) secretion. Intestinal GLP-1 activates the gut-brain-liver axis, which impairs hepatic gluconeogenesis through vagal stimulation. Metformin can enhance intestinal GLP-1 secretion by L-cells directly through AMPK activation via complex I inhibition or indirectly by increasing the availability of glucose, bile acids, and/or metabolites produced by intestinal bacteria. Thus, metformin improves muscle glucose disposal, reduces gluconeogenesis, and has several intestinal effects that impact glycemia. Inhibition of mitochondrial complex I in different organs appears to be an important mechanism of metformin's glucose-lowering effect. SIGNIFICANCE STATEMENT: Most previous studies on the mechanism of metformin's glycemia-reducing effect focused on inhibition of hepatic gluconeogenesis. However, clinical studies show that increased glucose transport into skeletal muscle is at least as important. Furthermore, recent studies suggest that intestinal effects, including inhibition of glucose absorption, stimulation of the gut-liver and gut-brain-liver axes, and changes in the intestinal microbiota, contribute to metformin's glycemia-lowering effect. Thus, metformin's glycemia-reducing effect is multifactorial, affecting glucose metabolism in the gut, liver, and skeletal muscle.
Computational drug design in the artificial intelligence era: A systematic review of molecular representations, generative architectures, and performance assessment.
Abbasi K, Razzaghi P, Gharizadeh A … +4 more , Ghareyazi A, Dehnad A, Rabiee HR, Mofrad MRK
Pharmacol Rev · 2026 Jan · PMID 41389438 · Publisher ↗
Generative drug design has emerged as a transformative approach in pharmaceutical research, leveraging deep learning models to create novel molecules with targeted properties. This systematic review analyzes the current...
Generative drug design has emerged as a transformative approach in pharmaceutical research, leveraging deep learning models to create novel molecules with targeted properties. This systematic review analyzes the current landscape of computational approaches across 3 critical dimensions: molecular representation strategies (1-dimensional, 2-dimensional, and 3-dimensional), generative architectural frameworks (including variational autoencoders, generative adversarial networks, reinforcement learning systems, and diffusion models), and evaluation methodologies. We provide a comprehensive categorization of these approaches, critically assessing their relative advantages and limitations. Additionally, we examine the datasets driving development in this field and the metrics employed to evaluate model performance. Through structured analysis of these interconnected components, we identify significant research gaps and propose promising future directions for advancing artificial intelligence-driven drug discovery. This review offers researchers a unified framework for understanding the complex interplay between representation choices, generative mechanisms, and evaluation paradigms in computational drug design. SIGNIFICANCE STATEMENT: This review provides a unique framework for generative drug design by categorizing methods first by drug representation and then by generative model type. This novel taxonomy clarifies which models are best suited for specific molecular data types, offering practical guidance for researchers. We also critically discuss the advantages, disadvantages, key datasets, and evaluation metrics, delivering a comprehensive and actionable resource for the field.
Genetic therapies for neurological diseases.
Rahim AA, Kurian MA, Zhou H … +5 more , Ferguson R, Tabrizi SJ, Lignani G, Aquilina K, Waddington SN
Pharmacol Rev · 2026 Jan · PMID 41389437 · Full text
Often, gene therapy reviews concentrate upon specific therapeutic modalities-particularly either viral vector-mediated or a nonviral approach. Here, we draw together a comprehensive array of knowledge across the field of...
Often, gene therapy reviews concentrate upon specific therapeutic modalities-particularly either viral vector-mediated or a nonviral approach. Here, we draw together a comprehensive array of knowledge across the field of genetic therapy for genetic neurological disease. The sections on preclinical and clinical application of viral vectors are followed by sections on RNA-based therapies and then by antisense oligonucleotide approaches also in preclinical and clinical settings. We present a separate section on gene editing strategies and conclude with a section elaborating on the neurosurgical techniques and the expertise required for clinical application of many of these technologies. SIGNIFICANCE STATEMENT: Genetic therapies have significant potential to treat life-limiting neurological diseases. This review examines the different approaches, clinical successes, and considerations on how to deploy them.
Investigating the effectiveness and adverse events of medicinal cannabis for patients with muscle spasticity or spasms.
Nastatos XL, Schubert EA, Wheate NJ
J Pharmacol Exp Ther · 2026 Jan · PMID 41386046 · Publisher ↗
Appropriate treatment of muscle spasticity and spasms is important as these conditions may significantly impair patients' quality of life. Conventional pharmacological treatments for these conditions have poor effectiven...
Appropriate treatment of muscle spasticity and spasms is important as these conditions may significantly impair patients' quality of life. Conventional pharmacological treatments for these conditions have poor effectiveness and/or tolerability. Cannabis is being explored as a treatment. This was a longitudinal study of patient use of different cannabis products. Data was collected from patient surveys, clinic records, and changes in Patient Reported Outcome Measures Information System 29-Item scores over time. Patient-reported responses on health-related quality of life adverse events (n = 150) and outcomes (n = 78) from treatment for spasticity or spasms were analyzed. No improvements in physical functioning were observed for either group of patients across all product types. However, patients with spasticity who were using cannabidiol-only products experienced an improvement in sleep disturbance, fatigue, pain interference, and pain intensity. Patients with spasms who were using balanced, cannabidiol-dominant, or tetrahydrocannabinol-dominant products also experienced improvements in these 4 outcomes. Commonly reported adverse events were dry mouth, drowsiness, fatigue, dizziness, and nausea. Despite no observation of improvement in physical functioning, the results suggest that cannabis may help relieve some of the secondary complications associated with these conditions, such as poor sleep and pain. SIGNIFICANCE STATEMENT: This longitudinal study highlights differential benefits across cannabis product types, with cannabidiol-only formulations aiding spasticity-related symptoms and tetrahydrocannabinol- or cannabidiol-dominant products benefiting those with spasms. These findings support the potential of cannabis as a potential therapy to improve health-related quality of life in patients with limited options from conventional pharmacological treatments.
Targeting of Brahma-related gene-1 (BRG1) overcomes paclitaxel-induced multidrug resistance caused by overexpression of the subset of ATP-binding cassette (ABC) transporters.
Gronkowska K, Michlewska S, Płoszaj T … +5 more , Strachowska M, Stępień A, Borowiec M, Bednarek A, Robaszkiewicz A
J Pharmacol Exp Ther · 2025 Dec · PMID 41371092 · Publisher ↗
Multidrug resistance of cancer cells is attributed to drug-induced alteration of numerous intracellular processes. Using clinically relevant models of triple-negative breast and non-small lung cancer cells we previously...
Multidrug resistance of cancer cells is attributed to drug-induced alteration of numerous intracellular processes. Using clinically relevant models of triple-negative breast and non-small lung cancer cells we previously showed that these cells respond to repeated paclitaxel exposure by inter alia lysosome enrichment in ABCC3, ABCC5, and ABCC10, which contribute to drug sequestration in these organelles and reduced drug cytotoxicity. In this study, we provide experimental evidence that transcription of the above-mentioned ABCC genes is enabled by BRG1-based SWI/SNF chromatin remodeling complex. Pharmacological inhibition of SWI/SNF with PFI3 or ACBI1, the PROTAC degrader of SMARCA2/4, substantially reduced transcription of ABCC3, ABCC5, and ABCC10. A similar effect was caused by transient silencing of SMARCA4 (BRG1), but not SMARCA2 (BRM). The deficiency of BRG1 led to extralysosomal distribution of anticancer drugs, their deeper penetration of spheroids, and substantial increase in drug cytotoxicity. Interestingly, in BRG1-deficient cell line paclitaxel triggered mutations, which reverted BRG1 truncating deletion in SMARCA4, thereby restoring SWI/SNF ATPase expression in paclitaxel-resistant cells and increasing transcription of ABCC. Acquisition of drug resistance was associated with BRG1 redistribution in the genome, de novo occurrence at the promoters of genes functionally linked to endolysosomal system, and stronger co-occurrence with EP300. Our study indicates possible target--SWI/SNF complex for anticancer combinatorial interventions in paclitaxel-induced multidrug resistant phenotypes. SIGNIFICANCE STATEMENT: This study provides evidence that BRG1 inhibition with PFI3 and degradation of SMARCA4 mRNA substantially declines lysosomal drug sequestration and potentiate drug toxicity. Therefore, BRG1 targeting can be considered as candidate for combinatorial anticancer therapy with some standard chemotherapy drugs.
Investigation into ligand selectivity and bias at the formyl peptide receptor family.
Jack CE, Thomson CM, Dall'Angelo S … +2 more , Thompson D, Hislop JN
J Pharmacol Exp Ther · 2026 Jan · PMID 41371001 · Full text
Formyl peptide receptors (FPRs) mediate both proinflammatory and resolution phases of the inflammatory response involved in many disease states. Harnessing their potential for pharmaceutical development requires an accur...
Formyl peptide receptors (FPRs) mediate both proinflammatory and resolution phases of the inflammatory response involved in many disease states. Harnessing their potential for pharmaceutical development requires an accurate picture of their signaling and regulation to the many test compounds developed. This study compares distinct responses of mouse and human FPR subtypes to several ligands in an attempt to clarify the dual nature of FPR signaling. Here, we expressed human and mouse variants of FPR1 and FPR2 in HEK293 cells and assessed competition binding, bioluminescence resonance energy transfer assays to measure the interaction between receptors and either Arrestin 3 or mini-Gsi, internalization, and extracellular signal-regulated kinase 1/2 phosphorylation. Concentration-response curves for 11 distinct ligands at each subtype were generated, then analyzed to determine EC50s, Emax values, and ligand bias. All compounds were less potent than WKYMVm across receptor subtypes, with the strength of signaling correlating with affinity estimates. The rank order of potency was maintained across the signaling pathways. Notably, MMK1 was specific for human FPR2, and BMS-986235 was selective for FPR2 over FPR1 in both species. Little evidence of pathway bias was detectable, with the notable exception of the recently described pepducin F2Pal10. The majority of tested ligands exhibit efficacy at each subtype, meaning conclusions of physiological receptor function based on these compounds should be treated circumspectly. It is not possible to determine distinct signaling profiles that would explain proresolution versus inflammatory physiology, and the most likely explanation for these data would be a combination of FPR1 and FPR2 responses. SIGNIFICANCE STATEMENT: No evidence of ligand bias between G-protein activation, arrestin recruitment, or internalization was found at formyl peptide receptors for 11 distinct agonists. Differences in physiological outcome are more likely to reflect efficacy at both subtypes rather than inherent signaling bias.
A 5'-(R)-CH-substituted 5-fluoro-2'-deoxyuridine monophosphate reduces off-target toxicities while maintaining efficacy in a colorectal cancer model.
Monaco CM, Pribut N, Musonda CC … +5 more , Sun CQ, Petros JA, Liu KH, Miller EJ, Liotta DC
J Pharmacol Exp Ther · 2026 Jan · PMID 41352320 · Publisher ↗
Since its approval in the early 1960s, 5-fluorouracil (5-FU) has remained an important therapeutic for the treatment of late-stage and metastatic colorectal cancer (CRC). It acts through intracellular conversion to 5-flu...
Since its approval in the early 1960s, 5-fluorouracil (5-FU) has remained an important therapeutic for the treatment of late-stage and metastatic colorectal cancer (CRC). It acts through intracellular conversion to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) to inhibit thymidylate synthase (TYMS), leading to nucleotide pool imbalance, DNA damage, and disruption of tumor cell proliferation. However, 5-FU is limited by rapid clearance and off-target toxicities, which affects a large proportion of patients with CRC. To address these issues, we developed 5'-(R)-CH-FdUMP (Me-FdUMP), a 5'-(R)-CH-substituted analog of FdUMP that retains inhibitory activity against purified TYMS. Here, we show that Me-FdUMP is resistant to metabolism by phosphatases and kinases, reduces 5-FU formation, and enhances TYMS inhibition in a human CRC cell line. In mice, Me-FdUMP treatment led to markedly lower 5-FU exposure in the heart and bone marrow, 2 key sites of clinical toxicity. Furthermore, in a mouse xenograft model of human CRC, Me-FdUMP maintained antitumor efficacy comparable to FdUMP. Taken together, these results suggest 5'-(R)-CH-substituted FdUMP could be a promising new approach for improving the safety of fluoropyrimidine-based therapeutics. SIGNIFICANCE STATEMENT: Current fluoropyrimidine-based therapeutics for colorectal cancer suffer from metabolic liabilities that can often lead to severe and dose-limiting side-effects. Results reported here highlight a new fluoropyrimidine derivative with enhanced on-target activity in vitro, maintenance of antitumor efficacy in vivo, and impaired metabolism that can reduce exposure of toxic metabolites. This work represents a new strategy to address the shortcomings of current fluoropyrimidine-based therapeutics with the potential to improve patient outcomes.
The nicotine paradox: Weak primary reinforcer, strong enhancer.
Bevins RA, Barrett ST, McNealy KR … +1 more , Wakabayashi KT
J Pharmacol Exp Ther · 2026 Jan · PMID 41352319 · Publisher ↗
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Targeting X-box-binding protein-1 by Decoy oligodeoxynucleotide modulates fibrogenic features of activated hepatic stellate cells.
Solhi R, Lotfinia M, Abdi Z … +4 more , Sahebghadam Lotfi A, Nüssler AK, Zarrabi A, Vosough M
J Pharmacol Exp Ther · 2026 Jan · PMID 41352318 · Publisher ↗
Because of their pivotal role in liver fibrosis, activated hepatic stellate cells (aHSCs) may serve as a promising target for innovative medical treatments. Endoplasmic reticulum stress activation through inositol-requir...
Because of their pivotal role in liver fibrosis, activated hepatic stellate cells (aHSCs) may serve as a promising target for innovative medical treatments. Endoplasmic reticulum stress activation through inositol-requiring enzyme1 (IRE1)-X-box-binding protein-1 (XBP1) is a significant event associated with hepatic stellate cells (HSC) activation. We evaluated the potential impact of treatment with XBP1-specific decoy oligodeoxynucleotide (ODN) on modulation of aHSC. To activate HSCs, LX-2 cells were treated with transforming growth factor β (5 ng/mL). Meanwhile, the sequence of XBP1-specific decoy ODN was designed using the JASPAR (open-access transcription factor binding profile data base) and CLC Main Workbench (Qiagen) software. The outcome of treatment with ODN on aHSC was analyzed using quantitative reverse transcription polymerase chain reaction, immunoblotting, scratch assay, and ELISA. Transfection of activated LX-2 cells with 1 μg XBP1 decoy ODN downregulated the expression level of lysyl oxidase, tissue inhibitor of matrix metalloproteinase, α-smooth muscle actin, and fibronectin genes. In addition, the immunoblotting analysis and ELISA assay showed that XBP1 decoy ODN significantly reduced protein expression of α-smooth muscle actin and collagen secretion, respectively, compared to control cells. Our research may lead to innovative treatments for liver fibrosis, providing hope for better outcomes for patients with this chronic condition. SIGNIFICANCE STATEMENT: This study applied a novel decoy oligodeoxynucleotide targeting X-box-binding protein-1 to suppress the activation of hepatic stellate cells, a key driver of liver fibrosis. By modulating endoplasmic reticulum stress and fibrogenic gene expression, this strategy offers a promising therapeutic avenue for chronic liver diseases.
Artificial intelligence-assisted drug discovery in 2025: Faster, but is it better? The robots are coming, look out!
Dharmasivam M, Azad MG, Richardson V … +2 more , Kaya B, Richardson DR
Pharmacol Rev · 2026 Jan · PMID 41337871 · Publisher ↗
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Erythropoietin as a multifaceted antiaging agent: Mechanisms and clinical potential.
Wang T, Tang Y, Xiao Y
J Pharmacol Exp Ther · 2025 Dec · PMID 41317607 · Publisher ↗
Human aging is driven by several interconnected hallmarks, including genomic instability, mitochondrial dysfunction, and cellular senescence, which collectively underlie pathologies such as neurodegeneration and metaboli...
Human aging is driven by several interconnected hallmarks, including genomic instability, mitochondrial dysfunction, and cellular senescence, which collectively underlie pathologies such as neurodegeneration and metabolic decline. Despite advances in identifying senescence-associated biomarkers and pathways, conventional antiaging compounds such as resveratrol and fisetin, lack regulatory approval owing to insufficient evidence from large-scale trials. Drug repurposing provides a cost-efficient strategy to target aging pathways by leveraging existing pharmacologic safety profiles. Erythropoietin (EPO) exemplifies this approach, demonstrating pleiotropic antiaging effects through modulation of cell survival pathways and tissue-protective mechanisms. Recent advancements in nonhematopoietic EPO derivatives, such as carbamylated EPO, further unlock its development potential by decoupling therapeutic benefits from erythropoietic activity. This review analyzes EPO molecular antiaging mechanisms and clinical applications in age-related diseases (2015-2025), focusing on multiorgan systemic effects and derivative development beyond anemia. SIGNIFICANCE STATEMENT: This review highlights erythropoietin (EPO) as a promising repurposed drug for combating aging, targeting hallmarks such as oxidative stress and cellular senescence. Crucially, nonhematopoietic EPO derivatives circumvent traditional safety risks while retaining multipathway protective effects in brain, cardiovascular, and metabolic tissues. By leveraging established pharmacology, EPO offers a cost-efficient strategy to advance aging interventions, addressing age-related pathologies beyond anemia.
Discovering the role of sulfur against atopic dermatitis via the AC010336.1/miR-3929/GPI axis with a machine-learning power.
Zheng A, Saimaiti W, Aireken W … +1 more , Han C
J Pharmacol Exp Ther · 2025 Dec · PMID 41314062 · Publisher ↗
Sulfur is clinically used for treating scabies and pruritus and shows potential in treating atopic dermatitis (AD), though its mechanism remains unclear. The potential targets of sulfur and the differentially expressed g...
Sulfur is clinically used for treating scabies and pruritus and shows potential in treating atopic dermatitis (AD), though its mechanism remains unclear. The potential targets of sulfur and the differentially expressed genes of AD in the GSE237920 and GSE121212 datasets from the Gene Expression Omnibus database were identified. The intersecting genes were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. A protein-protein interaction network was established using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Through Least Absolute Shrinkage and Selection Operator, Random Forest, and Support Vector Machine-Recursive Feature Elimination algorithms, we screened the core targets. The core genes were validated using receiver operating characteristic analysis, gene set enrichment analysis, and immune cell infiltration analysis. Long noncoding RNA (lncRNA)-microRNA (miRNA)-mRNA bioinformatics networks were predicted using databases. The core lncRNA-miRNA-mRNA axis was identified by intersecting bioinformatics networks with GSE168694. Subsequently, the expression of each node in the axis was verified through animal experiments. Using machine learning and bioinformatics analysis, glucose-6-phosphate isomerase (GPI) was identified as a core target. We then predicted 5 miRNAs and 141 lncRNAs. By validating the results using the GSE168694 dataset, the AC010336.1/miR-3929/GPI axis was identified as the key competing endogenous RNA regulatory axis. Animal experiments demonstrated that sulfur exerted therapeutic effects against AD by restoring epidermal barrier function, reducing immune cell infiltration, and mitigating pruritus. Additionally, animal experiments confirmed that sulfur alleviated AD by modulating the AC010336.1/miR-3929/GPI axis. These novel findings provide valuable insights and guidance for future investigations on the competing endogenous RNA mechanism of traditional Chinese medicine in AD therapy. SIGNIFICANCE STATEMENT: This study investigates the therapeutic mechanisms of sulfur, a traditional Chinese medicine, in the treatment of atopic dermatitis, with elucidate extending to the single-gene regulatory level.
The effects of buprenorphine on fentanyl-induced respiratory depression in rats.
Baehr CA, Gebo A, Vigliaturo J … +1 more , Raleigh MD
J Pharmacol Exp Ther · 2025 Dec · PMID 41308414 · Publisher ↗
The opioid antagonists, naloxone and nalmefene, are used clinically to rapidly reverse opioid overdose, but often precipitate withdrawal symptoms in opioid-dependent individuals. This study compared 2 medications used fo...
The opioid antagonists, naloxone and nalmefene, are used clinically to rapidly reverse opioid overdose, but often precipitate withdrawal symptoms in opioid-dependent individuals. This study compared 2 medications used for opioid use disorder, buprenorphine and methadone, to naloxone for reversing fentanyl-induced effects in rats. Buprenorphine alone did not produce significant respiratory depression at 0.5-5.0 mg/kg. Rats were challenged with 0.1 mg/kg fentanyl, which resulted in a significant reduction in oxygen saturation (SpO), and naloxone 0.1 mg/kg, buprenorphine 3.0 mg/kg, methadone 2.25 mg/kg, or saline control was given to reverse fentanyl effects. Antinociception and SpO were restored to baseline by 15 minutes after administration of naloxone and buprenorphine. The saline group showed a slow return to baseline SpO within 30 minutes, whereas methadone extended the duration of, but did not enhance, the effects of fentanyl. To determine whether buprenorphine could rapidly (within minutes) reverse fentanyl-induced respiratory depression, rats were given a dose of fentanyl 0.1 mg/kg s.c., followed by saline, naloxone 0.1 mg/kg, or buprenorphine 3.0 mg/kg, and SpO was monitored continuously for 10 minutes. Both naloxone and buprenorphine reversed fentanyl effects within 3.5 minutes, whereas the saline group did not return to baseline levels during the monitoring period. Buprenorphine at 0.3 and 1.0 mg/kg also reversed fentanyl effects, with a slower onset of reversal. In a follow-up study, rats received fentanyl followed by saline, buprenorphine, or methadone for reversal, and blood and brain levels were measured. Fentanyl concentration in the brain was not significantly affected by methadone and buprenorphine treatment, suggesting that differences in SpO were not attributable to pharmacokinetic interactions. These data support repurposing buprenorphine for the treatment of opioid overdose. SIGNIFICANCE STATEMENT: Opioid overdoses cause ∼80,000 annual deaths in the United States. Buprenorphine is an opioid partial agonist used for opioid use disorder. This study used a rat model to compare buprenorphine to naloxone for efficacy in reversing fentanyl-induced respiratory depression.
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