Bioorg Med Chem Lett. 2025 Jun 29:130320. doi: 10.1016/j.bmcl.2025.130320. Online ahead of print.

ABSTRACT

Genipin, a natural compound derived from the fruit of Gardenia jasminoides, has demonstrated anticancer effects in various malignancies, including gastric, cervical, breast, and lung cancers. In this study, a series of genipin derivatives was designed, synthesized, and evaluated for their anticancer activity against A549 non-small-cell lung cancer (NSCLC) cells to identify more potent analogs and elucidate their mechanisms of action. Several derivatives exhibited stronger antiproliferative effects than genipin, with compound 2b showing the most potent activity (IC₅₀ = 117 μM) and effectively suppressing colony formation. Further investigations revealed that 2b induced cell cycle arrest and apoptotic cell death. Mechanistically, 2b inhibited the phosphorylation of EGFR, JAK1, and STAT3, and modulated epithelial-mesenchymal transition (EMT)-related protein expression, thereby attenuating cell migration and invasion. Notably, although 2b did not inhibit ATP-dependent EGFR kinase activity in vitro, molecular docking simulations indicated its binding to the EGFR extracellular domain (domain III), suggesting an alternative, ATP-independent mechanism-likely via interference with EGF binding. Collectively, these results highlight 2b (MRC-G-001) as a promising lead-like compound for further optimization and preclinical development targeting EGFR-driven A549 cancer cells.

PMID:40592362 | DOI:10.1016/j.bmcl.2025.130320

Cytokine. 2025 Jun 30;193:156988. doi: 10.1016/j.cyto.2025.156988. Online ahead of print.

ABSTRACT

Rheumatoid arthritis (RA) and osteoarthritis (OA) are the most common joint diseases globally, posing major public health challenges. Although they are often distinguished from each other in clinical diagnoses, we hypothesize that RA and OA could have overlapping molecular pathways. Hence, this study was designed to explore the shared molecular changes and potential therapeutic targets for RA and OA. Transcriptome data were obtained from the Gene Expression Omnibus (GEO) database (GSE51588, GSE12021 and GSE55235), which included 117 synovial membrane samples (33 healthy, 50 OA, and 34 RA). Differentially expressed genes (DEGs) were identified using the "limma" package in R, and functional enrichment analyses were conducted using Gene ontology and Kyoto Encyclopedia of Genes and Genomes frameworks. Protein-protein interaction networks were constructed through STRING, and further analyzed using GeneMANIA. Immune cell infiltration in RA and OA samples was evaluated using the CIBERSORT algorithm; microRNA-messenger RNA interactions were predicted through miRanda, miRDB, miRWalk, and TargetScan databases; and lncRNAs targets were identified via the SpongeScan database. Gene-drug interactions were analyzed using DGIdb, and the results were validated in RA and OA mouse models via immunohistochemistry and western blot. In RA and OA, 38 DEGs were identified, including 23 downregulated and 15 upregulated genes (FDR < 0.05, |log2FC| > 0), associated with key pathways such as ubiquitin-mediated proteolysis, mTOR, JAK-STAT, and Wnt signaling. Hub genes, including EIF3B, KHSRP, nucleolin (NCL), PDCD1LG2, SLC25A37, demonstrated significant differential expression (p < 0.05). In addition, the receiver operating characteristic (ROC) curve analysis indicated good diagnostic potential, with areas under the curve (AUC) values ranging from 0.795 to 0.958. Furthermore, immune cell infiltration analysis revealed significant involvement of plasma cells, T cells, monocytes, and dendritic cells (p < 0.05). Several hub genes were targeted by existing drugs, such as NCL by AS1411, and PDCD1LG2 by Pembrolizumab. In vivo validation revealed that EIF3B, KHSRP, NCL, and PDCD1LG2 were downregulated in both RA and OA mouse models compared to controls (p < 0.01), with EIF3B exhibiting higher expression in RA than in OA (p < 0.01). Mitoferrin 1 expression showed no significant differences among groups. These findings suggest that RA and OA share common molecular pathways that may serve as promising diagnostic biomarkers and therapeutic targets.

PMID:40592131 | DOI:10.1016/j.cyto.2025.156988

Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul 1. doi: 10.1007/s00210-025-04289-3. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, and new treatment options are urgently needed. Drug repositioning has gained attention as a strategy to identify new therapeutic applications for CRC. This approach can expedite drug development and reduce costs by leveraging drugs already undergoing safety testing. Computational and experimental methods are used to identify potential candidates for drug repositioning in CRC. However, challenges such as a lack of comprehensive knowledge regarding the molecular mechanisms underlying the disease and resolving intellectual property and regulatory issues must be overcome. Drug repositioning has the potential to revolutionize CRC treatment by identifying new drugs for gastrointestinal tumors. For example, metformin, a biguanide antidiabetic drug, is effective for CRC by inhibiting the PI3K-Akt-mTOR pathway. COX-2 inhibitors, which block cyclooxygenase-2 to reduce inflammation and cancer progression, may also be examples of drug repositioning for CRC. Several approaches have been employed to identify potential candidates for drug repositioning in colorectal cancer, including computational methods such as data mining and network analysis and experimental techniques such as high-throughput screening and in vitro assays. Despite its potential benefits, drug repositioning in colorectal cancer faces several challenges, including the lack of comprehensive knowledge regarding the disease's molecular mechanisms. Further research is needed to overcome these challenges and identify specific drug targets for CRC treatment. With continued efforts and advancements in this field, drug repositioning has the potential to revolutionize colorectal cancer treatment. This review provides an overview of drug repositioning in the context of colorectal cancer, highlighting its advantages, challenges, and potential future directions.

PMID:40590920 | DOI:10.1007/s00210-025-04289-3

Addiction. 2025 Jul 1. doi: 10.1111/add.70117. Online ahead of print.

ABSTRACT

AIMS: To identify variation in identification of medical consumers using alternative self-reported measures and assess whether differences in these rates exist across jurisdictions with different medical policy approaches using evidence from an international study on cannabis use.

DESIGN: Secondary analysis of wave 4 (2021) of the International Cannabis Policy Study (ICPS) cross-sectional survey.

SETTING: United States, Canada and Australia.

PARTICIPANTS: 16 951 (USA 10 472; CAN 5935; AUS 544) respondents who completed the survey and reported past year cannabis use across the three jurisdictions.

MEASUREMENTS: Four different medical cannabis use measures were available, and rates of each were estimated using logistic regression methods that adjusted for age, gender, education and ethnicity. Medical cannabis use measures included potentially authorized use (i.e. involving a licensed health professional recommendation, authorization or prescription), pharmaceutical use (i.e. involving a pharmaceutical-grade product), therapeutic use (i.e. to manage physical or mental health conditions) and self-identified medical cannabis use. Country-specific differences were compared and discussed in light of measure and differing cannabis policies.

FINDINGS: In wave 4 of the ICPS, 34.0% reported any past year cannabis use, but rates of medical use differed significantly according to the specific question. Far more individuals reported therapeutic use in the past year across all countries [77.3%; 95% confidence interval (CI) = 76.4%-78.2%] than any other measure of medical use. While just over one quarter (28.2%; 95% CI = 27.3%-29.2%) self-identified as a medical user, fewer reported being potentially authorized (22.8%; 95% CI = 22.0%-23.7%) or having a pharmaceutical prescription from a medical professional (12.3%; 95% CI = 11.6%-13.0%). Australians (27.2%; 95% CI = 23.0%-31.4%) and Americans (25.9%; 95% CI = 24.6%-27.2%) were more likely to report potentially authorized use than Canadians (17.3%; 95% CI = 16.1%-18.4%), but only Australians (27.4%; 95% CI = 23.6%-31.2%) reported high levels of prior use of a pharmaceutical-grade cannabinoid.

CONCLUSIONS: In the International Cannabis Policy Study, the proportion of respondents (adjusted for demographic factors) who reported medical use varied depending on the measures used within and between countries.

PMID:40590488 | DOI:10.1111/add.70117

Int J Fertil Steril. 2025 May 14;19(3):277-283. doi: 10.22074/ijfs.2025.2009299.1516.

ABSTRACT

BACKGROUND: Endometriosis is a prevalent women's health disorder that lacks a definitive cure. Numerous studies have been conducted to identify the underlying causes of this disease and select the most effective pharmaceutical intervention. ISL LIM homeobox 2 (ISL2) plays a significant role in promoting angiogenesis. Contemporary investigations strongly suggest that inhibiting angiogenesis could lead to the modulation of endometriosis and reduce associated symptoms. This study aims to repurpose drugs to target ISL2 for endometriosis treatment.

MATERIALS AND METHODS: In this computational study, we sought to confirm that ISL2 is an appropriate target for this study by evaluating its expression in the endometrial tissues of patients diagnosed with endometriosis, as well as in tissues from a control group of healthy women. Subsequently, we used computational techniques to select the best inhibitor for ISL2 from among select food and drug administration (FDA)-approved drugs.

RESULTS: There was a significant increase ISL2 gene expression in the tissues of women with endometriosis. Therefore, we selected the ISL2 protein as a target for drug repurposing. Initial docking results revealed that, out of 2471 FDAapproved drugs, six (Dactinomycin, Paritaprevir, Ivermectin, Ergotamine, Alectinib, and Simeprevir) exhibited the most favourable binding energy (ΔG ≤-8 kcal/mol) with ISL2. Molecular dynamics (MD) simulations of these six complexes showed that Ivermectin displayed the lowest root mean square fluctuation (RMSF) and root mean square deviation (RMSD), as well as the highest count of hydrogen bonds and number of contacts, which indicated a more stable formation of this complex with ISL2.

CONCLUSION: Although these six drugs appear to be promising candidates for modulating endometriosis, Ivermectin is more likely to effectively inhibit ISL2.

PMID:40590287 | DOI:10.22074/ijfs.2025.2009299.1516

In Silico Pharmacol. 2025 Jun 28;13(2):96. doi: 10.1007/s40203-025-00373-x. eCollection 2025.

ABSTRACT

Epilepsy represents a prevalent symptom across various neurological disorders, which is characterized by the abnormal firing of neurons from diverse brain regions, resulting in impulsive frequent seizures, protracted seizures can cause cell death and neuronal damage. Ferroptosis, recently acknowledged as a regulated form of cell death, involves the excessive deposition of iron ions culminating in the build-up of harmful lipid-based reactive oxygen species. Some recent research findings have suggested that lysyl oxidase (LysOx) depicts a vital role in the development of various neurological diseases, yet the precise mechanism behind it is still not obscure. This study is done to study the mechanism of how LysOX leads to ferroptosis leading to epileptogenesis. We have screened compounds from FDA-approved libraries, and molecules with top docking scores were selected. Pharmacokinetic property, mainly its capability to permeate the blood-brain barrier is important for therapeutic compounds. In this extensive study, we executed virtual screening using an in-silico approach to identify a novel therapeutic compound, capable of targeting LysOX. We used an FDA-approved library to analyze the capability of ligands with LysOX. furthermore, ADMET was also performed (Absorption, Distribution, Metabolism, Excretion, Toxicity) profiling, and molecular dynamics simulations, to identify the most capable compounds. Our elaborate computational study uncovered a set of highly encouraging compounds. These compounds showed great results in inhibiting LysOX and preventing the ferroptotic cell death mechanism which leads to epilepsy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00373-x.

PMID:40589766 | PMC:PMC12206222 | DOI:10.1007/s40203-025-00373-x

Theranostics. 2025 Jun 9;15(14):6686-6701. doi: 10.7150/thno.111606. eCollection 2025.

ABSTRACT

Rationale: Coronary collateral circulation (CCC) is essential for myocardial recovery after infarction, yet effective strategies to enhance CCC formation are scarce. In this study, we aimed to identify potential FDA-approved drugs that can promote CCC after MI injury. Methods: Candidate drugs were screened through multiple analyses using cMap and public CCC-related databases. Male C57BL/6J mice underwent myocardial infarction (MI) surgery, and 3D micro-CT imaging and immunostaining for smooth muscle actin (SMA) in the watershed region of the heart were employed to evaluate CCC formation. Cardiac function was assessed through Masson's trichrome staining and cardiac ultrasonography. Macrophage polarization was analyzed using flow cytometry, qRT‒PCR, and immunostaining. Additionally, a macrophage and THP-1 cell coculture system was established to simulate the in vivo microenvironment, and mitochondrial morphology was assessed using electron microscopy. Results: Our screen revealed that methimazole (MMI) efficiently promotes CCC formation by driving the polarization of macrophages from the proinflammatory M1-like phenotype to the proangiogenic M2-like phenotype. In vitro, MMI enhanced the differentiation of THP-1 cells into M2-like macrophages and increased VEGFA secretion. Mechanistically, molecular docking studies confirmed a direct interaction between MMI and MAPK1, leading to the suppression of the MAPK1/ROS axis and inhibition of ferroptosis, which facilitated M2 polarization. Furthermore, in vivo, honokiol (HK), a MAPK activator, reversed the effects of MMI on CCC, confirming the pivotal role of the MAPK1 pathway. Conclusions: This study reveals a novel therapeutic role for MMI in promoting CCC formation following MI through the modulation of macrophage polarization via the MAPK1/ROS axis-mediated inhibition of ferroptosis. These findings highlight the potential of MMI as a strategy for enhancing cardiac repair and advancing collateral circulation therapies for ischemic heart disease.

PMID:40585971 | PMC:PMC12203669 | DOI:10.7150/thno.111606

Cureus. 2025 May 29;17(5):e85033. doi: 10.7759/cureus.85033. eCollection 2025 May.

ABSTRACT

The COVID-19 pandemic spurred an unprecedented wave of drug repurposing as scientists and clinicians raced to find immediate treatment options for a novel disease. This narrative review examines how those crisis-driven repurposing efforts fared. It highlights key successes and failures in translating research into practice and assessing their pharmacoeconomic implications in high-income health systems. It also distills lessons to guide future pandemic preparedness and improve equitable global access to effective treatments. We performed a broad literature search across major databases (2020-2025) to identify studies and reports on repurposed COVID-19 therapies and health economic outcomes. While repurposing accelerated the delivery of treatments, results were mixed: a handful of existing drugs, such as the widely available steroid dexamethasone, that reduced mortality, emerged as life-saving interventions, but many other initially promising drugs ultimately showed limited or no efficacy. Agile translational research frameworks like large adaptive trials proved critical, separating truly effective therapies from many speculative candidates. From a pharmacoeconomic perspective, repurposed therapies yielded cost-effective breakthroughs and costly disappointments. High-income countries invested substantial resources in repurposed drugs. In some cases, this approach provided rapid access to evidence-based care but also led to significant spending on unproven interventions, underscoring the importance of timely evidence generation and prudent resource allocation. Disparities in access to effective therapies between wealthy and low-resource settings highlight a persistent global equity challenge. The collective experience of pandemic drug repurposing provides a pragmatic blueprint for balancing urgency with scientific rigor, economic prudence, and equity. This will ultimately guide how we might better pivot from crisis to cure in future global health emergencies.

PMID:40585709 | PMC:PMC12205848 | DOI:10.7759/cureus.85033

Res Sq [Preprint]. 2025 Jun 16:rs.3.rs-6728958. doi: 10.21203/rs.3.rs-6728958/v1.

ABSTRACT

Drug repurposing offers a time-efficient and cost-effective approach for therapeutic development by finding new uses for existing drugs. Additionally, achieving explainability in drug repurposing remains a challenge due to the lack of transparency in decision-making processes, hindering researchers' understanding and trust in the generated insights. To address these issues, we present DrugReX, a system integrating a literature-based knowledge graph, embedding, scoring system, and explanation modules using large language models (LLMs). We validated DrugReX on 15 established drug repurposing cases, achieving significantly high scores. As a real-world use case, we applied DrugReX to identify candidate drugs for Alzheimer's disease and related dementias (ADRD) and thoroughly evaluated the pipeline. The system identified 25 promising candidates, with nine clustering with FDA-approved ADRD drugs and 10 linked to ongoing clinical trials. For explainability, an LLM was employed to generate explanations supported by evidence from the literature-based knowledge graph. Domain expert evaluation revealed that DrugReX-produced explanations were superior in quality and clarity than using an LLM alone, enhancing the explainability of repurposing predictions. This study represents the first integration of LLMs to provide explainable insights into drug repurposing, bridging computation precision with explainability, and thus, ultimately enabling more transparent and reliable decision-making in therapeutic development.

PMID:40585221 | PMC:PMC12204371 | DOI:10.21203/rs.3.rs-6728958/v1

medRxiv [Preprint]. 2025 Jun 10:2025.01.02.25319880. doi: 10.1101/2025.01.02.25319880.

ABSTRACT

Alzheimer's disease (AD), the leading cause of dementia, imposes a significant societal and economic burden; however, its complex molecular mechanisms remain unclear. This study integrates multi-omics data with advanced artificial intelligence (AI) methods to uncover the molecular basis underlying AD phenotype regulation and explore personalized drug repositioning strategies based on individual genetic backgrounds. First, we applied the PrediXcan method to identify candidate genes closely associated with AD cognitive diagnosis, selecting from 61 brain-related traits. We validated these findings through individual-level analysis using gene expression and genotype data from 553 dorsolateral prefrontal cortex samples in the ROSMAP database. Simultaneously, we constructed a deep, multi-layer information fusion model (AD-MIF) by integrating genotype and gene expression data and employing autoencoders as well as graph autoencoders for multi-modal feature extraction. The results revealed a 10-20% improvement in the Area Under the Curve (AUC) for predicting AD-related phenotypes. Both approaches showed high consistency across cellular structures, brain regions, and neurobiological pathways, demonstrating their complementary advantages. Gene enrichment analysis indicated that APOE and its interacting gene APOC1 play a central role in cholesterol metabolism, lipid transport, and immune regulation, while genes such as SCIMP and KAT8 are involved in immune signaling, epigenetic regulation, and neuroprotection. After incorporating attention mechanisms, AD-MIF highlighted the importance of key genes, such as POLR2C and TRAPPC4, in regulating neuronal function. Based on predictive results and enrichment analysis, we further identified candidate drugs, including sirolimus, dasatinib, and MGCD-265. In vivo experiments confirmed that MGCD-265, also known as Glesatinib, and dasatinib significantly improve cognitive deficits in the SAMP8 AD model mice by inhibiting neuroinflammation, pathological tau phosphorylation, and Aβ deposition. This study demonstrates the complementary advantages of bioinformatics pipelines and AI-based multi-modal fusion methods in elucidating the complex pathological mechanisms of AD and enhancing phenotype prediction accuracy. It also provides new theoretical support for personalized drug interventions based on individual genetic characteristics, laying a solid foundation for optimizing early screening, prediction, and personalized treatment strategies.

PMID:40585083 | PMC:PMC12204425 | DOI:10.1101/2025.01.02.25319880

medRxiv [Preprint]. 2025 Jun 9:2025.01.04.25319995. doi: 10.1101/2025.01.04.25319995.

ABSTRACT

Multi-organ research investigates interconnections among multiple human organ systems, enhancing our understanding of human aging and disease mechanisms. Here, we used multi-organ imaging ( N =105,433), individual- and summary-level genetics, and proteomics ( N =53,940) from the UK Biobank, Baltimore Longitudinal Study of Aging, FinnGen, and Psychiatric Genomics Consortium to delineate a brain-heart-eye axis via 2003 brain patterns of structural covariance 1 (PSC), 82 heart imaging-derived phenotypes 2 (IDP) and 84 eye IDPs 3-5 . Cross-organ phenotypic associations highlight the central autonomic network between the brain and heart and the central visual pathway between the brain and eye. Proteome-wide associations of the PSCs and IDPs show both within-organ specificity and cross-organ interconnections, verified by the RNA and protein expression profiles of the 2923 plasma proteins. Pleiotropic effects of common genetic variants are observed across multiple organs, and key genetic parameters, such as SNP-based heritability, polygenicity, and selection signatures, are comparatively evaluated among the three organs. A gene-drug-disease network shows the potential of drug repurposing for cross-organ diseases. Colocalization and causal analyses reveal cross-organ causal relationships between PSC/IDP and chronic diseases, such as Alzheimer's disease, heart failure, and glaucoma. Finally, integrating multi-organ/omics features improves prediction for systemic disease categories and cognition compared to single-organ/omics features. This study depicts a detailed brain-heart-eye axis and highlights future avenues for modeling human aging and disease across multiple scales. All results are publicly available at https://labs-laboratory.com/medicine/ .

PMID:40585072 | PMC:PMC12204406 | DOI:10.1101/2025.01.04.25319995

JHEP Rep. 2025 Apr 22;7(7):101426. doi: 10.1016/j.jhepr.2025.101426. eCollection 2025 Jul.

ABSTRACT

BACKGROUND & AIMS: Patient-derived tumor organoids (PDTOs) are a reliable model for preclinical and translational studies. Despite positive retrospective correlations with patient response, challenges such as culture success, cost, standardization, and time constraints hinder their clinical utility in precision medicine. Here, we optimize PDTO establishment using growth factor-reduced media (GF-) to mitigate these challenges and (1) identify somatic variant indicators that can improve the therapeutic index of existing FDA-approved drugs against hepatocellular carcinoma (HCC), (2) elucidate synthetic lethal candidates against undruggable HCC driver mutations, and (3) assess the feasibility of PDTOs in personalized therapy.

METHODS: We successfully established a panel of 23 PDTOs from patients with HCC undergoing curative hepatectomy using a protocol primarily based on growth factor-reduced medium. PDTOs were subjected to comprehensive analyses, including the identification of hallmark mutations, assessment of genomic heterogeneity, transcriptomic profiling, and histological characterization. A 100-drug repurposing screen was conducted on the PDTOs and organoids derived from adjacent non-tumoral and normal livers to explore tumor-specific drug responses. Pharmacogenomic analysis using elastic net was performed (cut-off p <0.05) and synthetic lethality links were subject to experimental validation. The clinical relevance of PDTOs in personalized therapy were investigated through two case studies.

RESULTS: Our results reveal that GF-derived PDTOs mimic histology and genetic heterogeneity of HCC. Pharmacogenomic analysis showed that the majority of tested FDA-approved drugs were not associated with HCC driver mutations (<5%). In addition, non-canonical signaling from CTNNB1 mutations were associated with ceritinib sensitivity (p <0.0001) via polypharmacological targeting of RPS6KA3. The PDTO case study showed clear benefit to patient survival by aiding clinical management.

CONCLUSIONS: Our findings underscore the utility of PDTOs established from minimal GF media in many facets of precision oncology advancements.

IMPACT AND IMPLICATIONS: Patient-derived tumor organoids are a reliable model for preclinical and translational studies. Despite positive retrospective correlations with patient response data, challenges such as culture success, cost, standardization, and time constraints hinder their clinical utility in guiding precision medicine. This study underscores the utility of patient-derived organoids established from growth factor-reduced media in many facets of precision oncology, showing for the first time in hepatocellular carcinoma, clear benefit to patient survival in a proof-of-concept case study.

PMID:40584266 | PMC:PMC12205652 | DOI:10.1016/j.jhepr.2025.101426

Clin Pharmacol Ther. 2025 Jun 29. doi: 10.1002/cpt.3755. Online ahead of print.

NO ABSTRACT

PMID:40583355 | DOI:10.1002/cpt.3755

Inflamm Res. 2025 Jun 30;74(1):97. doi: 10.1007/s00011-025-02054-z.

ABSTRACT

Achieving better clinical outcomes in cancer research requires a deeper understanding of tumoral biology and the application of this knowledge within a clinic setting. The aim of this review is to briefly summarize the current knowledge on H3R molecular pharmacology, the clinical use of H3R antagonists, and the most recent findings reporting H3R role in cancer biology. We will discuss in detail the current landscape and clinical perspectives of the modulation of this H3R on cancer progression and treatment. We propose H3R as a promising molecular target for cancer drug repurposing and development.

PMID:40583099 | DOI:10.1007/s00011-025-02054-z

Phytomedicine. 2025 Jun 23;145:156999. doi: 10.1016/j.phymed.2025.156999. Online ahead of print.

ABSTRACT

BACKGROUND: Psoriasis and ulcerative colitis (UC) are immune-mediated chronic inflammatory diseases that affect barrier organs and share significant overlap in both pathogenesis and treatment strategies. Although the advent of biologics has transformed therapeutic options, their high cost often limits long-term accessibility, underscoring the need for alternative approaches.

PURPOSE: Natural compounds and traditional medicine represent valuable sources for novel drug discovery and repurposing, but systematic strategies for repurposing traditional medicines remain underdeveloped.

METHODS: Here, we present a computational framework for drug repurposing based on drug-target affinity and structural rationality, focused on the traditional herbs and prescriptions of JAK family and chemokine receptors.

RESULTS: We identified 204 natural compounds, among which 9-hydroxycamptothecin showed the most promising therapeutic potential for both psoriasis and UC. Notably, WU MEI PILL, a classical prescription in East Asian traditional medicine, also emerged as a promising multi-target therapy for both diseases. In vivo experiments confirmed that 9-hydroxycamptothecin and WU MEI PILL significantly alleviated disease symptoms, improved intestinal mucosal and epidermal pathologies, and upregulated intestinal Claudin-1 and MUC-2 expression. These effects were mediated through suppression of JAK1/STAT3 phosphorylation.

CONCLUSION: This study introduces a tailored approach for traditional medicine-based drug repurposing, offering a scalable and efficient strategy for identifying natural therapeutics and guiding clinical decision-making, modernization, and standardization of traditional medicine.

PMID:40582205 | DOI:10.1016/j.phymed.2025.156999

Proteomics. 2025 Jun;25(11-12):e00087. doi: 10.1002/pmic.202500087.

ABSTRACT

As space exploration becomes increasingly accessible, understanding the molecular and pathophysiological consequences of spaceflight on the human body becomes crucial. Space-induced modifications could disrupt multiple signaling pathways, with significant implications for the functional integrity of cardiovascular, nervous, and musculoskeletal systems, among others. In a recent study, Bourdakou et al. have focused on alterations in gene expression profiles linked to cardiovascular disease (CVD), using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) undergoing spaceflight and subsequent postflight conditions. Genes with known associations with CVD and nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress regulatory network have been identified to present consistent directional expression changes in both spaceflight and postflight. A computational drug repurposing analysis identified ten candidate agents with the potential to reverse observed transcriptomic modifications in spaceflight-exposed cardiomyocytes. These findings highlight the importance of molecular studies and emphasize the need for integrative, multi-omic research efforts to protect human health during and beyond spaceflight.

PMID:40579866 | DOI:10.1002/pmic.202500087

Drug Discov Today. 2025 Jun 26:104419. doi: 10.1016/j.drudis.2025.104419. Online ahead of print.

ABSTRACT

Nitroxoline, a legacy antimicrobial agent, is gaining attention for its potential repurposing in infectious diseases and oncology. Its broad-spectrum activity, including biofilm disruption and metal-chelating properties, supports diverse therapeutic applications. However, its systemic use is limited by rapid urinary excretion, short plasma half-life, and limited tissue distribution. In this review, we summarize recent advances in understanding the mechanisms of action, cross-kingdom activity, and anticancer effects of nitroxoline. Despite encouraging preclinical data, clinical translation is constrained by pharmacokinetic (PK) and regulatory challenges. As interest in repurposing established drugs grows, nitroxoline presents a compelling candidate for integration into modern therapeutic strategies across infectious and neoplastic disease domains.

PMID:40581150 | DOI:10.1016/j.drudis.2025.104419

In Vivo. 2025 Jul-Aug;39(4):2101-2108. doi: 10.21873/invivo.14005.

ABSTRACT

BACKGROUND/AIM: Lopinavir (LPV) combined with ritonavir (LPV/r) was initially developed to treat human immunodeficiency virus (HIV) infection and was subsequently repurposed to treat coronavirus disease 2019 (COVID-19) during the COVID-19 pandemic. As the efficacy of LPV/r in COVID-19 treatment has not been confirmed in clinical trials, LPV/r is not included in the Japanese COVID-19 treatment guidelines. Furthermore, previous clinical studies have not demonstrated the benefit of LPV/r against COVID-19 when used at the same dose as that used to treat HIV infection. Therefore, the aim of this study was to determine the optimal LPV/r dose combination for COVID-19 treatment.

PATIENTS AND METHODS: Based on data from healthy volunteers and patients with HIV infection, maximum-effect models were used to estimate the relationship between LPV clearance and ritonavir plasma concentration. Pharmacokinetic simulations were performed using a range of assumptions based on previously reported modeling equations.

RESULTS: The standard LPV/r dose combination of 400 mg/100 mg twice daily did not yield optimal blood concentrations. Based on the pharmacokinetic booster effect of ritonavir, the estimated optimal dose combination was 400 mg LPV boosted with 1,200 mg ritonavir.

CONCLUSION: These findings provide a basis to quantify the booster effect of ritonavir on LPV in COVID-19 treatment and calculate the optimal LPV and ritonavir dose combination.

PMID:40579031 | DOI:10.21873/invivo.14005

PLoS One. 2025 Jun 27;20(6):e0323931. doi: 10.1371/journal.pone.0323931. eCollection 2025.

ABSTRACT

Rabies is a fatal zoonosis caused by the rabies virus (RABV) that has afflicted humans for thousands of years. RABV infection leads to neurological symptoms and death; however, its pathogenesis in the brain is unclear, which complicates patient care. Given that no treatment exists for symptomatic cases, there is an urgent need for effective antiviral drugs. In this study, we aimed to investigate the pathogenic mechanism of RABV in the brain and screen for potential anti-RABV drugs. Protein samples were extracted from the brains of RABV-positive and RABV-negative dogs, and proteomic and phosphoproteomic analyses were conducted. The results showed that the synaptic vesicle cycle is critical to RABV pathogenesis. The kinases involved in the phosphorylation of proteins in the synaptic vesicle cycle were identified and examined as potential drug targets. Casein kinase 2 and protein kinase C were found to be key kinases for RABV replication, and five inhibitors of these enzymes were tested for their anti-RABV properties. Pretreating cells with the kinase inhibitor sunitinib significantly reduced the viral yield after RABV infection. Our findings suggest that RABV interferes with synaptic communication, which leads to rabies, and that inhibiting a vital kinase can reduce viral production. Hence, our findings have implications for the development of rabies treatment regimes.

PMID:40577348 | DOI:10.1371/journal.pone.0323931

Proc Natl Acad Sci U S A. 2025 Jul;122(26):e2425537122. doi: 10.1073/pnas.2425537122. Epub 2025 Jun 27.

ABSTRACT

Multiple sclerosis (MS) is an immune-mediated disease with no current cure. Drug discovery and repurposing are essential to enhance treatment efficacy and safety. We utilized summary statistics for protein quantitative trait loci (pQTL) of 2,004 plasma and 1,443 brain proteins, a genome-wide association study of MS susceptibility with 14,802 cases and 26,703 controls, both bulk and cell-type specific transcriptome data, and external pQTL data in blood and brain. Our integrative analysis included a proteome-wide association study to identify MS-associated proteins, followed by summary-data-based Mendelian randomization to determine potential causal associations. We used the HEIDI test and Bayesian colocalization analysis to distinguish pleiotropy from linkage. Proteins passing all analyses were prioritized as potential drug targets. We further conducted pathway annotations and protein-protein interaction network analysis (PPI) and verified our findings at mRNA and protein levels. We tested hundreds of MS-associated proteins and confirmed 18 potential causal proteins (nine in plasma and nine in brain). Among these, we found 78 annotated pathways and 16 existing non-MS drugs targeting six proteins. We also identified intricateAQ PPIs among seven potential drug targets and 19 existing MS drug targets, as well as PPIs of four targets across plasma and brain. We identified two targets using bulk mRNA expression data and four targets expressed in MS-related cell types. We finally verified 10 targets using external pQTL data. We prioritized 18 potential drug targets in plasma and brain, elucidating the underlying pathology and providing evidence for potential drug discovery and repurposing in MS.

PMID:40577117 | DOI:10.1073/pnas.2425537122