Drug Dev Res. 2025 May;86(3):e70101. doi: 10.1002/ddr.70101.

ABSTRACT

The global antibiotic resistance crisis demands innovative strategies targeting bacterial virulence rather than survival. Quorum sensing (QS), a key regulator of virulence and biofilm formation, offers a promising avenue to mitigate resistance by disarming pathogens without bactericidal pressure. This study investigates the repurposing of nitroimidazoles as anti-QS and anti-virulence agents at subminimum inhibitory concentrations (sub-MICs). In Silico analyses, including molecular docking and molecular dynamics (MD) simulations, were performed to investigate ligand-receptor interactions with structurally distinct Lux-type QS receptors and assess binding stability and conformational dynamics over time. In Vitro assays evaluated the effects of representative nitroimidazoles, metronidazole (MET) and secnidazole (SEC), on QS-controlled phenotypes, including violacein production in Chromobacterium violaceum and biofilm formation and protease activity in Pseudomonas aeruginosa, Acinetobacter baumannii, Salmonella enterica, and Proteus mirabilis. In Vivo efficacy was assessed using a murine infection model and HeLa cell invasion assays. Molecular docking revealed high-affinity binding to QS receptors, corroborating their mechanistic interference. Sub-MIC MET/SEC significantly suppressed violacein synthesis, biofilm biomass, and protease secretion in Gram-negative pathogens. Both compounds reduced bacterial invasiveness in HeLa cells and In Vivo protected mice from lethal P. aeruginosa infections. Crucially, nitroimidazoles attenuated virulence without affecting bacterial viability, preserving microbial ecology. These findings position nitroimidazoles as dual-function agents; antimicrobial at bactericidal doses and anti-virulence at sub-MICs. Their validated efficacy across In Silico, In Vitro, and In Vivo models underscores their potential as adjunctive therapies, bridging the gap between drug repurposing and next-generation anti-infective development.

PMID:40384051 | DOI:10.1002/ddr.70101

Integr Cancer Ther. 2025 Jan-Dec;24:15347354251339121. doi: 10.1177/15347354251339121. Epub 2025 May 18.

ABSTRACT

Chemotherapy-induced peripheral neuropathy (CIPN) has a markedly deleterious impact on a patient's quality of life. It manifests as pain, paresthesia, numbness, and weakness, particularly in the context of cisplatin (CDDP), a widely utilised chemotherapeutic agent renowned for its pronounced peripheral nerve toxicity. Trichosanthes kirilowii Maxim. (Cucurbitaceae, TK) and cucurbitacin D(CucD), its bioactive compound, have been demonstrated to possess anti-tumour, anti-inflammatory, and antioxidant properties. However, their potential to alleviate CIPN has not been fully exploredyet. The present study evaluated effectiveness of TK and CucD in mitigating CDDP-induced neuropathic pain using both cellular and animal models. CDDP, TK extracts (TKD and TKE), and CucD dose-dependently reduced viability and apoptosis of PC12 cells. Conversely, pre-treatment with TKD, TKE, and CucD exhibited significant protective effects against CDDP-induced cytotoxicity, preserving cell viability and morphology while enhancing neurite outgrowth. In vivo, administration of CDDP resulted in the development of mechanical allodynia and thermalhyperalgesia in rats. However, treatment with TKD and TKE led to a notable improvement in pain threshold and a reduction in hyperalgesia, while CucD demonstrated less pronounced effects. Although body weight was reduced in the CDDP-treated group, it was not significantly mitigated bytreatments. In conclusion, results of this study indicate that TKD, TKE, and CucD have the potential to alleviate CDDP-induced neuropathic pain by protecting against cell damage, promoting neuriteregeneration, and improving pain responses in animal models. Further investigation into TK and CucD as therapeutic options for managing CIPN is warranted.

PMID:40383960 | DOI:10.1177/15347354251339121

Carbohydr Polym. 2025 Jun 15;358:123478. doi: 10.1016/j.carbpol.2025.123478. Epub 2025 Mar 6.

ABSTRACT

Acute myeloid leukaemia (AML) accounts for 30 % of adult leukaemia cases, predominantly affecting individuals over 60. The standard "7 + 3" intensive chemotherapy regimen is unsuitable for many elderly patients, contributing to AML's poor prognosis. While progress in drug therapies has been made, breakthroughs remain limited, indication-specific, and slow to expand. Drug repurposing offers a faster route to therapy development, while nanocarrier encapsulation broadens the scope of viable drug candidates. Chlorpromazine (CPZ) is an antipsychotic which has been identified as a potential anti-leukaemic agent. Due to its ability to cross the blood-brain barrier, it is likely to cause central nervous system (CNS) effects. The drug-in-cyclodextrin-in-liposome (DCL) nanocarrier platform enables the formulation of CPZ encapsulated with cyclodextrins (CDs) such as HP-γ-CD, SBE-β-CD, and Sugammadex. The CD/CPZ formulations were equally, or more efficient than free CPZ in inducing AML cell death. Uptake of the DCL in AML cells quickly reached saturation, with minimal differences among formulations, except for SBE-β-CD. When injected intravenously in zebrafish larvae, the different DCLs did not differ in biodistribution, and no brain accumulation was observed at two days post-injection. These DCL-based CPZ formulations maintain anti-leukaemic activity, avoid CNS accumulation, and allow drug availability adjustments based on the included CD.

PMID:40383608 | DOI:10.1016/j.carbpol.2025.123478

Mol Neurobiol. 2025 May 17. doi: 10.1007/s12035-025-05047-5. Online ahead of print.

ABSTRACT

Disruption of the Wnt signaling pathway (WSP), a highly conserved pathway essential for growth and organ development, has been proven to play a role in the pathogenesis of Alzheimer's disease (AD). This study focused on repurposing the FDA-approved drug, Voglibose to target the DKK1-LRP6 site with the goal of upregulating WSP in in vitro as well as rodent model of AD. Based on our previous computational approach, Voglibose was evaluated for the DKK1 binding, neuroprotective effects were examined using SHSY5Y cells, while WSP activation was analyzed through RTPCR in the HEK293/LRP6 cell line. Rodent model of AD was developed using intracerebroventricular administration of Aβ25-35. Male Wistar rats were randomly assigned to receive oral doses of Voglibose (1 and 10 mg/kg) for 28 days, after which behavioral assessments, biochemical analyses, RT-PCR, and histopathological evaluations were conducted. Voglibose showed significant reduction in the DKK1 binding, neuroprotective property in SHSY5Y as well as activation of WSP in LRP6 overexpressed HEK293 cells. There was a significant decrease in the island latency in rats treated with lower dose (p < 0.01) and higher dose (p < 0.05) of Voglibose when compared to the disease control rats. Similarly, in the behavioral tests, Voglibose significantly improved cognition. The deposition of amyloid plaques was found to be considerably more in the disease control rats which got reduced in the treatment groups as observed in the histopathological slides stained with Congo red. Significant alterations in mRNA levels and protein expression of glycogen synthase kinase-β (GSK-3β), β-catenin (β-cat) was observed in rat brain homogenates indicating upregulation of WSP. In conclusion, Voglibose demonstrated significant neuroprotective potential in a cell line study and showed potential cognitive benefits in a rat model of AD. Furthermore, its ability to activate WSP highlights its immense potential as AD therapeutic to enhance memory and modulate key neuroprotective mechanisms.

PMID:40381169 | DOI:10.1007/s12035-025-05047-5

BMC Microbiol. 2025 May 16;25(1):299. doi: 10.1186/s12866-025-03973-x.

ABSTRACT

BACKGROUND: The urgent need for new antibacterial drugs has driven interest in repurposing therapies to combat Gram-positive biofilms and persisters. Fingolimod, an Food and Drug Administration (FDA)-approved drug for multiple sclerosis, shows bactericidal activity, particularly against Methicillin-resistant Staphylococcus aureus (MRSA) and biofilm-related infections. With a well-documented safety profile and strong translational potential, it aligns with World Health Organization's goals for antimicrobial repurposing. However, the action mode and mechanism of Fingolimod against gram-positive bacteria remain elusive.

METHODS: This study utilized clinical Staphylococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis), Streptococcus agalactiae (S. agalactiae). And their susceptibility to Fingolimod and other antibiotics was tested via Minimum Inhibitory Concentration (MIC) assays. Biofilm inhibition and hemolytic activity were evaluated using crystal violet staining, Confocal Laser Scanning Microscopy (CLSM), and hemolysis assays, respectively, while the effect of phospholipids on Fingolimod efficacy was assessed with checkerboard assays. Membrane permeability and integrity were measured using SYTOX green staining and transmission electron microscopy. Whole-genome sequencing was performed on Fingolimod-resistant S. aureus isolates to identify Single Nucleotide Polymorphisms (SNPs) linked to resistance.

RESULTS: Our data indicated that Fingolimod exerted bactericidal activity against a wide spectrum of gram-positive bacteria, including S. aureus, E. faecalis, S. agalactiae. Moreover, Fingolimod could significantly eliminate the persisters, inhibit biofilm formation and eradicate in-vitro mature biofilms of S. aureus. The mechanism by which Fingolimod rapidly eradicated S. aureus involved a pH-dependent disruption of bacterial cell permeability and envelope integrity. Concomitantly, exogenous supplementation of phospholipids in the culture medium resulted in a dose-dependent increase in the MIC of Fingolimod. Specifically, the addition of 64 μg/mL of cardiolipin (CL) and phosphatidylethanolamine (PE) completely nullified the bactericidal activity of Fingolimod at a concentration of 4 times the MIC. After four months of Fingolimod exposure, the MIC values of S. aureus showed a slight increase, indicating that it is not prone to developing drug resistance.

CONCLUSION: Fingolimod exhibits bactericidal activity against diverse gram-positive bacteria, with remarkable effects on S. aureus (including MRSA), disrupting bacterial cell structural integrity in a pH-dependent way and eradicating biofilms and persisters of S. aureus.

PMID:40380090 | DOI:10.1186/s12866-025-03973-x

Int J Biol Macromol. 2025 May 14:144230. doi: 10.1016/j.ijbiomac.2025.144230. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD), the most common neurodegenerative disease in humans, has been a major medical challenge. Lactoferrin (Ltf) in salivary glands might be identified as a potential detectable biomarker in AD and a therapeutic target for AD. Pharmaceutical studies directly addressing this biomarker, though, are scarce. Using a computational strategy for drug repurposing, we explored the proximal neighborhood of Ltf by exploring its interactome and regulatory constellations. We aimed to focus on the discovery of potential therapeutic agents for AD. Based on extensive analytical evaluation comprising structural congruence scales, profiling disease clusters, pathway enrichment analyses as well as molecular docking, SPR, in vivo studies, and immunofluorescence assays, our research identified three candidate repurposed drugs: Lovastatin, SU-11652, and SB-239063. Taken together, these results highlight strong binding affinities of the drug candidates to Ltf. In vitro studies showed that such compounds decrease β-amyloid (Aβ) production by increasing the fluorescence signal emitted by Ltf in N2a-sw cells, and that they act by modulating the expression of amyloidogenic pathway-associated enzymes (BACE1 and APH1α). In addition, in vivo studies showed a concomitant reduction in the expression levels of amyloidogenic pathway-related enzymes (BACE1 or APH1α). Thus, computational studies have focused on Ltf interactions that may recommend drug repurposing strategies and options for AD.

PMID:40379164 | DOI:10.1016/j.ijbiomac.2025.144230

J Chem Inf Model. 2025 May 16. doi: 10.1021/acs.jcim.5c00435. Online ahead of print.

ABSTRACT

Drug repositioning, which identifies novel therapeutic applications for existing drugs, offers a cost-effective alternative to traditional drug development. However, effectively capturing the complex relationships between drugs and diseases remains challenging. We present HGCL-DR, a novel heterogeneous graph contrastive learning framework for drug repositioning that effectively integrates global and local feature representations through three key components. First, we introduce an improved heterogeneous graph contrastive learning approach to model drug-disease relationships. Second, for local feature extraction, we employ a bidirectional graph convolutional network with a subgraph generation strategy in the bipartite drug-disease association graph, while utilizing a graph diffusion process to capture long-range dependencies in drug-drug and disease-disease relation graphs. Third, for global feature extraction, we leverage contrastive learning in the heterogeneous graph to enhance embedding consistency across different feature spaces. Extensive experiments on four benchmark data sets using 10-fold cross-validation demonstrate that HGCL-DR consistently outperforms state-of-the-art baselines in both AUPR, AUROC, and F1-score metrics. Ablation studies confirm the significance of each proposed component, while case studies on Alzheimer's disease and breast neoplasms validate HGCL-DR's practical utility in identifying novel drug candidates. These results establish HGCL-DR as an effective approach for computational drug repositioning.

PMID:40377926 | DOI:10.1021/acs.jcim.5c00435

Tissue Barriers. 2025 May 16:2503523. doi: 10.1080/21688370.2025.2503523. Online ahead of print.

ABSTRACT

Vascular endothelial barrier disruption is a critical determinant of morbidity and mortality in sepsis. Whole blood represents a key source of paracrine signaling molecules inducing vascular endothelial barrier disruption in sepsis. This study analyzes whole-genome transcriptome data from sepsis patients' whole blood available in the NCBI GEO database to identify paracrine mediators of vascular endothelial barrier dysfunction, uncovering novel insights that may guide drug repositioning strategies. This study identifies the regulated expression of paracrine signaling molecules TFPI, MMP9, PROS1, JAG1, S1PR1, and S1PR5 which either disrupt or protect vascular endothelial barrier function in sepsis and could serve as potential targets for repositioning existing drugs. Specifically, TFPI (barrier protective), MMP9 (barrier destructive), PROS1 (barrier protective), and JAG1 (barrier destructive) are upregulated, while S1PR1 (barrier protective) and S1PR5 (barrier protective) are downregulated. Our observations highlight the importance of considering both protective and disruptive mediators in the development of therapeutic strategies to restore endothelial barrier integrity in septic patients. Identifying TFPI, MMP9, PROS1, JAG1, S1PR1, and S1PR5 as druggable paracrine regulators of vascular endothelial barrier function in sepsis could pave the way for precision medicine approaches, enabling personalized treatments that target specific mediators of endothelial barrier disruption to improve patient outcomes in sepsis.

PMID:40376886 | DOI:10.1080/21688370.2025.2503523

Trends Cancer. 2025 May 15:S2405-8033(25)00106-2. doi: 10.1016/j.trecan.2025.04.010. Online ahead of print.

ABSTRACT

The acknowledged relationship between metabolism and cancer retains important potential as a novel target in therapy. Reallocating glucose-lowering drugs (GLDs) in cancer treatment offers valuable perspectives for the ability of these molecules to regulate metabolism at cellular and systemic level. This comprehensive review addresses the therapeutic potential of the main antidiabetic classes of glucose-lowering drugs with emerging anticancer effects, such as metformin, rosiglitazone, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium/glucose cotransporter-2 inhibitors. The multifaceted actions of these drugs are explored, from in vitro evidence to clinical evidence as monotherapy or as a sparing agent with chemotherapy and immunotherapy. For each molecule, unconventional mechanisms, benefits, and limitations are dissected and possible concerns addressed, supporting evidence for the potential use of the drug in cancer.

PMID:40374399 | DOI:10.1016/j.trecan.2025.04.010

J Mol Graph Model. 2025 May 10;139:109076. doi: 10.1016/j.jmgm.2025.109076. Online ahead of print.

ABSTRACT

The hallmark of Alzheimer's disease (AD), a progressive neurodegenerative condition, is the buildup of amyloid-beta (Aβ) plaque, which is mainly caused by β-secretase 1 (BACE-1) activity. BACE-1 inhibition is a potentially effective treatment strategy to lower the progression of AD. In order to find possible BACE-1 inhibitors using a drug repurposing technique, this study uses an integrated computational approach that includes pharmacophore modelling, virtual screening, molecular docking, MM-GBSA, molecular dynamics (MD) simulations, in-silico ADMET profiling, and PBPK modelling. A pharmacophore model, was created with known BACE-1 inhibitors to enable virtual screening of both novel and FDA-approved chemical libraries. Top candidates with good free energy scores and strong binding affinities were found using molecular docking and MM-GBSA calculations. The stability of shortlisted Hits inside the BACE-1 active site was further validated using MD simulations, which showed that some of the important interactions were maintained across a period of 50ns. ADMET and PBPK studies predicted favorable pharmacokinetic and safety profiles for the shortlisted hits, particularly for B2 and B9. These findings identify potential candidates for future experimental validation, offering an inexpensive approach for identification of compounds as potential BACE-1 inhibitors.

PMID:40373679 | DOI:10.1016/j.jmgm.2025.109076

Protein Sci. 2025 Jun;34(6):e70156. doi: 10.1002/pro.70156.

ABSTRACT

Since the emergence of SARS-CoV-2 at the end of 2019, the virus has caused significant global health and economic disruptions. Despite the rapid development of antiviral vaccines and some approved treatments such as remdesivir and paxlovid, effective antiviral pharmacological treatments for COVID-19 patients remain limited. This study explores Nsp15, a 3'-uridylate-specific RNA endonuclease, which has a critical role in immune system evasion and hence in escaping the innate immune sensors. We conducted a comprehensive drug repurposing screen and identified 44 compounds that showed more than 55% inhibition of Nsp15 activity in a real-time fluorescence assay. A validation pipeline was employed to exclude unspecific interactions, and dose-response assays confirmed 29 compounds with an IC50 below 10 μM. Structural studies, including molecular docking and x-ray crystallography, revealed key interactions of identified inhibitors, such as TAS-103 and YM-155, with the Nsp15 active site and other critical regions. Our findings show that the identified compounds, particularly those retaining potency under different assay conditions, could serve as promising hits for developing Nsp15 inhibitors. Additionally, the study emphasizes the potential of combination therapies targeting multiple viral processes to enhance treatment efficacy and reduce the risk of drug resistance. This research contributes to the ongoing efforts to develop effective antiviral therapies for SARS-CoV-2 and possibly other coronaviruses.

PMID:40371758 | DOI:10.1002/pro.70156

Brief Bioinform. 2025 May 1;26(3):bbaf215. doi: 10.1093/bib/bbaf215.

ABSTRACT

Monkeypox (Mpox) is a major global human health threat after COVID-19. Its treatment becomes complicated with type-2 diabetes (T2D). It may happen due to the influence of both disease-causing common host key genes (cHKGs). Therefore, it is necessary to explore both disease-causing cHKGs to reveal their shared pathogenetic mechanisms and candidate drugs as their common treatments without adverse side effect. This study aimed to address these issues. At first, 3 transcriptomics datasets for each of Mpox and 6 T2D datasets were analyzed and found 52 common host differentially expressed genes (cHDEGs) that can separate both T2D and Mpox patients from the control samples. Then top-ranked six cHDEGs (HSP90AA1, B2M, IGF1R, ALD1HA1, ASS1, and HADHA) were detected as the T2D-causing cHKGs that are associated with the complexity of Mpox through the protein-protein interaction network analysis. Then common pathogenetic processes between T2D and Mpox were disclosed by cHKG-set enrichment analysis with biological processes, molecular functions, cellular components and Kyoto Encyclopedia of Genes and Genomes pathways, and regulatory network analysis with transcription factors and microRNAs. Finally, cHKG-guided top-ranked three drug molecules (tecovirimat, vindoline, and brincidofovir) were recommended as the repurposable common therapeutic agents for both Mpox and T2D by molecular docking. The absorption, distribution, metabolism, excretion, and toxicity and drug-likeness analysis of these drug molecules indicated their good pharmacokinetics properties. The 100-ns molecular dynamics simulation results (root mean square deviation, root mean square fluctuation, and molecular mechanics generalized born surface area) with the top-ranked three complexes ASS1-tecovirimat, ALDH1A1-vindoline, and B2M-brincidofovir exhibited good pharmacodynamics properties. Therefore, the results provided in this article might be important resources for diagnosis and therapies of Mpox patients who are also suffering from T2D.

PMID:40370100 | DOI:10.1093/bib/bbaf215

Indian J Microbiol. 2025 Mar;65(1):347-358. doi: 10.1007/s12088-024-01280-z. Epub 2024 Apr 18.

ABSTRACT

Antibiotic resistance in urinary tract infections (UTIs) is a growing concern due to extensive antibiotic use. The study explores a drug repurposing approach to find non-antibiotic drugs with antibacterial activity. In the present study, 8 strains of Pseudomonas spp. were used that were clinically isolated from UTI-infected patients. Amlodipine, a cardiovascular drug used in this study, has shown potential antimicrobial effect in reducing the various virulence factors, including swimming and twitching motility, biofilm, rhamnolipid, pyocyanin, and oxidative stress resistance against all the strains. Amlodipine exhibited the most potent antimicrobial activity with MIC in the range of 6.25 to 25 µg/ml. Significant inhibition in biofilm production was seen in the range of 45.75 to 76.70%. A maximum decrease of 54.66% and 59.45% in swimming and twitching motility was observed, respectively. Maximum inhibition of 65.87% of pyocyanin pigment was observed with the effect of amlodipine. Moreover, a significant decrease in rhamnolipids production observed after amlodipine treatment was between 16.5 and 0.001 mg/ml as compared to the control. All bacterial strains exhibited leakage of proteins and nucleic acids from their cell membranes when exposed to amlodipine which suggests the damage of the structural integrity. In conclusion, amlodipine exhibited good antimicrobial activity and can be used as a potential candidate to be repurposed for the treatment of urinary tract infections.

PMID:40371041 | PMC:PMC12069773 | DOI:10.1007/s12088-024-01280-z

ACS Pharmacol Transl Sci. 2025 Apr 3;8(5):1292-1312. doi: 10.1021/acsptsci.4c00680. eCollection 2025 May 9.

ABSTRACT

Despite the widespread use of selective serotonin reuptake inhibitors like sertraline, the intricate molecular mechanisms underlying major depression and the therapeutic efficacy of these treatments remain not fully elucidated. Building on our preliminary findings, this study investigates the antidepressant effects of fasudil, a Rho-associated protein kinase (ROCK) inhibitor typically utilized as a vasodilator and antispasmodic, and compares its effects with those of sertraline using a chronic restraint stress model in rats. Specifically, we examined the effects of chronic administration on dendritic spine density, key molecular survival pathways, and miRNA levels in the hippocampus. Adult male Sprague-Dawley rats were administered sertraline, fasudil (10 mg/kg/day), or saline over 14 days, with a subset experiencing daily restraint stress. Our findings demonstrate that both sertraline and fasudil effectively prevented stress-induced reductions in dendritic spine density and miR-138 levels in the rat hippocampus. Additionally, by employing a network pharmacology approach, we explored the converging molecular pathways influenced by both drugs, facilitating the identification of novel molecular targets and pathways implicated in the pathophysiology of depression and its treatment. Pharmacoinformatic analysis revealed common signaling cascades and critical proteins that may potentially underlie the observed pharmacological effects, contributing to a paradigm shift in understanding depression by integrating drug repurposing and network pharmacology, offering valuable insights into the underlying mechanisms of depression and the antidepressant effect from a new network-based paradigm rather than focusing solely on a single protein target.

PMID:40370991 | PMC:PMC12070322 | DOI:10.1021/acsptsci.4c00680

Acta Pharm Sin B. 2025 Mar;15(3):1680-1695. doi: 10.1016/j.apsb.2025.01.022. Epub 2025 Feb 12.

ABSTRACT

Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity, expanding antibacterial spectra, and reducing required dosages. Previously, compound 15 was identified as a potential adjuvant for Polymyxin B (PB) against multidrug-resistant (MDR) Pseudomonas aeruginosa DK2; however, its clinical utility was hindered by high cytotoxicity, uncertain in vivo efficacy, and an unclear synergetic mechanism. To address these challenges, we synthesized and evaluated a series of novel benzamide derivatives, with A22 emerging as a particularly promising candidate. A22 demonstrated potent synergistic activity to PB, minimal cytotoxicity, improved water solubility, and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains. In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22. Moreover, A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2. Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production, reducing ATP levels, increasing NOX activity, and inhibiting biofilm formation, leading to bacterial death. These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants, offering a robust approach to combating MDR Gram-negative bacterial infections.

PMID:40370545 | PMC:PMC12069892 | DOI:10.1016/j.apsb.2025.01.022

J Cereb Blood Flow Metab. 2025 May 15:271678X251340234. doi: 10.1177/0271678X251340234. Online ahead of print.

ABSTRACT

Neuroprotection after ischemic stroke has been focused on targeting one pathway of the ischemic cascade. In this study, we have hypothesized that combination therapy with alpha-1 antitrypsin (A1AT) and a blocker of tumor necrosis factor (TNFα) could be beneficial in the acute phases after ischemia. Following a detailed safety assessment of the co-administration of both drugs, we tested their neuroprotective effect in a transient mouse model of proximal middle cerebral artery occlusion (MCAo) by evaluating infarct extension and functional outcomes. Anti-TNFα (20 mg/kg) and A1AT were administered at different doses (ranging from 60 mg/kg to 700 mg/kg), as a single therapy during occlusion or at different time-points following reperfusion. Results showed that the administration of A1AT (60 mg/kg) in combination with anti-TNFα (20 mg/kg) was safe and effective when given during occlusion by reducing infarct volume at 24 h by 27% compared with the vehicle group (p = 0.0001). In conclusion, the synergy of the anti-apoptotic and anti-inflammatory properties of both drugs can reduce infarct volume in a stroke mouse model when given in the hyperacute phase. This approach shows promise as an early intervention strategy for stroke patients and underscores the potential of drug repurposing to develop new stroke treatments.

PMID:40370316 | DOI:10.1177/0271678X251340234

J Transl Med. 2025 May 14;23(1):543. doi: 10.1186/s12967-025-06491-6.

ABSTRACT

BACKGROUND: Genome-wide association studies (GWAS) and subsequent functional interpretation have been used to identify susceptible genes and potential drug-repositioning candidates. This study aimed to identify genes associated with colorectal cancer (CRC) and potential drug-repositioning candidates.

METHODS: Patients with CRC at Seoul National University Hospital (SNUH, discovery study) and Chonnam National University Hospital (CNUH, replication study) were included as case groups. The Korean Genome and Epidemiology Study (KoGES) participants were included as a control group. Single-nucleotide polymorphisms (SNPs) were extracted from blood-derived DNA (N = 409,063). A SNP-based logistic regression model was applied. Furthermore, post-GWAS analysis was conducted. Drug-repositioning candidates were identified using a pre-trained deep neural network and the druggability assessment tool.

RESULTS: In the discovery study, we conducted a 1:3 age- and sex-matched case-control study that included 500 CRC cases (mean age 63.0 ± 7.15 years) and 1,500 healthy controls (mean age 62.9 ± 7.07 years), each group comprising 50% males and 50% females. The replication study enrolled 4,860 patients with CRC and 46,384 healthy controls. The two-stage GWAS revealed statistically significant associations among MKLN1 (rs75170436, 7q32.3, beta (log odds ratio) = - 0.90, Pmeta = 5.90 × 10-13), MMP14 (rs3751489, 14q11.2, beta (log odds ratio) = - 1.91, Pmeta = 2.31 × 10-12). Post-GWAS functional analysis revealed strong associations on two genes highlighting deleterious effects and increased gene expression. Drug-repositioning analysis identified GW0742 (PPARβ/δ agonist) with the highest binding score and druggability score for MMP14 with a reference allele (12.06, 0.85).

CONCLUSIONS: Using GWAS, MKLN1 and MMP14 were found to be associated with CRC development and we identified GW0742 (PPARβ/δ agonist) as a potential drug-repositioning candidate for CRC based on MKLN1 and MMP14. These findings improve the understanding of CRC development and provide insights into novel therapeutic targets and candidates for CRC treatment.

PMID:40369569 | DOI:10.1186/s12967-025-06491-6

Hematol Oncol Clin North Am. 2025 May 13:S0889-8588(25)00046-2. doi: 10.1016/j.hoc.2025.04.008. Online ahead of print.

ABSTRACT

Ultra-rare sarcomas are sarcomas with an incidence of 1 case per million inhabitants per year, in which rarity poses a barrier to conducting histotype-specific randomized studies. This manuscript provides practical information and reference for clinicians and researchers looking to develop an understanding of the complexity, worldwide discrepancies in treatment options, and management choices for these patients. We provide definitions, diagnostic challenges, and therapeutic approaches to ultra-rare sarcomas. We highlight existing discriminations faced by patients with ultra-rare sarcoma, differences in approval status for innovative agents, and future perspectives for sarcoma experts who aim at working for a change in the field.

PMID:40368740 | DOI:10.1016/j.hoc.2025.04.008

PLoS One. 2025 May 14;20(5):e0323597. doi: 10.1371/journal.pone.0323597. eCollection 2025.

ABSTRACT

Kawasaki disease (KD) is an acute vasculitis that primarily affects children under five and is a leading cause of acquired heart disease in this age group. Despite the standard treatment with intravenous immunoglobulin (IVIG), approximately 10-20% of patients exhibit IVIG resistance, leading to persistent inflammation and an increased risk of coronary artery aneurysms（CAA）. The underlying molecular mechanisms driving KD, particularly the role of pyroptosis, remain incompletely understood. In this study, we employed integrative bioinformatics approaches to investigate the mechanistic role of pyroptosis in KD. By analyzing transcriptomic datasets, we identified differentially expressed genes (DEGs) associated with pyroptosis and immune dysregulation. Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to uncover key co-expressed gene modules, followed by functional enrichment analyses to explore the biological significance of these genes. Through machine learning-based biomarker discovery, we identified MYD88 and S100A12 as critical pyroptosis-related genes in KD. Their diagnostic potential was validated using external datasets, and their involvement in immune cell infiltration was assessed through computational deconvolution techniques. Furthermore, drug repurposing analysis and molecular docking simulations suggested that Atogepant, Ubrogepant, and Zanubrutinib could serve as potential therapeutic candidates targeting S100A12 and MYD88. These findings provide novel insights into the molecular pathogenesis of KD and highlight potential biomarkers and therapeutic targets for improving KD diagnosis and treatment strategies.

PMID:40367231 | DOI:10.1371/journal.pone.0323597

JAMA Psychiatry. 2025 May 14. doi: 10.1001/jamapsychiatry.2025.0900. Online ahead of print.

NO ABSTRACT

PMID:40366672 | DOI:10.1001/jamapsychiatry.2025.0900