J Control Release. 2025 Jul 16:114041. doi: 10.1016/j.jconrel.2025.114041. Online ahead of print.

ABSTRACT

Acute kidney injury (AKI) is a prevalent and life-threatening condition, particularly in patients undergoing high-risk surgeries, where the incidence can exceed 50 %. Despite its growing impact, therapeutic options remain limited, with dialysis being the primary treatment. Drug repurposing offers a better risk-versus-reward trade-off for accelerating the development of effective therapies. Mesalamine, a clinically approved anti-inflammatory agent for ulcerative colitis, can be a promising candidate for AKI treatment due to its ability to modulate various inflammatory pathways. However, their risk of nephrotoxicity from systemic exposure underscores the need for strategies to control off-target effects. Here, we propose a mesalamine prodrug, a conjugate between mesalamine and a cathepsin B-cleavable peptide, which spontaneously forms nanoassemblies through intermolecular interactions. In a mouse AKI model, these nanoassemblies accumulate in the inflamed kidney by becoming trapped between disrupted tight junctions, subsequently releasing mesalamine precisely at the site of injured tubular cells to alleviate the disease. Meanwhile, side effects from non-specific drug release are minimized as the nanoassemblies remain inactive in healthy tubular cells and other normal organs with relatively low cathepsin B expression. This study provides valuable insights into a rational approach to facilitating drug repositioning for the effective and safer use of mesalamine in AKI.

PMID:40681020 | DOI:10.1016/j.jconrel.2025.114041

Eur J Pharmacol. 2025 Jul 16:177963. doi: 10.1016/j.ejphar.2025.177963. Online ahead of print.

ABSTRACT

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurological condition marked by social, communication, and behavioral challenges. Current treatments are limited, with few approved drugs. This study used network analysis of key driver genes from blood and brain tissues to identify potential therapeutic drugs for ASD.

METHOD: We examined Gene Expression Omnibus (GEO) data from postmortem brain (GSE28521) and blood leukocyte (GSE42133) samples to find differentially expressed genes. Key driver genes were identified using weighted key driver analysis, supported by literature, knockout mouse model databases, and enrichment analysis. Drug repositioning was performed with PharmOmics and Connectivity Map (CMap) platforms.

RESULTS: In blood samples, 204 key driver genes were discovered, associated with cell cycle regulation and stress response. In brain samples, 290 key driver genes focused on ribosomal activity and protein production. An integrated protein-protein interaction (PPI) network identified 16 shared key driver genes, demonstrating common disease signatures including RNA metabolism, protein regulation, SLIT and ROBO signaling, and antiviral pathways. Drug repositioning revealed 23 potential drugs for ASD, with sulpiride and everolimus demonstrating promise, and 19 drugs exhibiting neurological significance, including six with substantial blood-brain barrier permeability.

CONCLUSIONS: Our study reveals both tissue-specific and shared molecular signatures of ASD in blood and brain tissues through PPI network analysis. We identified 16 key driver genes and 23 potential therapeutic drugs. Additionally, we discovered twelve novel key driver genes associated with ASD, emphasizing their roles in neurological and immune functions. These findings enhance our understanding of the molecular basis of ASD and suggest new therapeutic possibilities.

PMID:40680984 | DOI:10.1016/j.ejphar.2025.177963

Int J Parasitol Drugs Drug Resist. 2025 Jul 8;28:100602. doi: 10.1016/j.ijpddr.2025.100602. Online ahead of print.

ABSTRACT

The emergence and spread of artemisinin-resistant malaria over the past 15 years has led to a recent rise in global malaria cases and represents a major public health concern. Following decades of intense research efforts, the first malaria vaccine has been approved for clinical use in October of 2021. However, its 36 % efficacy highlights the ongoing need for novel and effective drugs to combat malaria. The majority of current antimalarials are derivatives of previous efficient compounds whilst new treatments with diverse chemical scaffolds have not been implemented into clinical practice since 1996. We argue that current research efforts should focus on developing novel chemical classes of compounds to help fight drug resistant malaria. Here we provide a comprehensive review of the antimalarial treatments currently in clinical use and discuss their significant limitations due to parasite drug resistance. Further, we discuss various approaches to antimalarial drug discovery and offer new perspectives on the topic, informing on current methods, both rarely and extensively used. Collating the most recent and up-to-date drug discovery strategies will not only maximise current global research efforts but will ensure all possible drug development avenues are trialed. This review provides innovative insights to circumvent antimalarial drug resistance and diversify malaria therapeutics.

PMID:40680501 | DOI:10.1016/j.ijpddr.2025.100602

Daru. 2025 Jul 18;33(2):24. doi: 10.1007/s40199-025-00562-1.

ABSTRACT

Cancer leads the list of causes of death worldwide, and the search for new and rapid treatment options for this disease has accelerated. New chemotherapeutic agents that inhibit tumor growth and proliferation are being introduced to the market; however, it presents various challenges, including the lengthy effectiveness of clinical trials, difficulty transitioning to phase 3 clinical stages, and high financial costs. A drug that had previously gained popularity in the market, has recently been repositioned for a different purpose, making it an excellent target for the treatment of several diseases. This review specifically focuses on the anti-cancer effects of repositioned antipsychotic medications that were studied for cancer treatment as well as their combination studies with other chemotherapeutic agents, using a literature search. A literature review covering the last 15 years was conducted using the PubMed (MEDLINE), Google Scholar, and Web of Science databases, with the keywords 'anticancer,' 'antipsychotic drugs,' and 'drug repurposing' used in combination. Studies that yielded productive results across broad historical ranges were included in the review. Initially, the correlation between schizophrenia patients and cancer was explored. Next, antipsychotic drugs with reported anticancer activities were identified, and their in vitro and in vivo anticancer mechanisms were revealed. Finally, the potential contributions and significance of these drugs in future therapeutic approaches were highlighted. In conclusion our literature search has revealed that antipsychotic medications can be useful in treating cancer.

PMID:40679681 | DOI:10.1007/s40199-025-00562-1

J Pharm Anal. 2025 Jun;15(6):101295. doi: 10.1016/j.jpha.2025.101295. Epub 2025 Apr 9.

ABSTRACT

Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

PMID:40678478 | PMC:PMC12268079 | DOI:10.1016/j.jpha.2025.101295

J Pharm Anal. 2025 Jun;15(6):101275. doi: 10.1016/j.jpha.2025.101275. Epub 2025 Mar 21.

ABSTRACT

Drug repurposing offers a promising alternative to traditional drug development and significantly reduces costs and timelines by identifying new therapeutic uses for existing drugs. However, the current approaches often rely on limited data sources and simplistic hypotheses, which restrict their ability to capture the multi-faceted nature of biological systems. This study introduces adaptive multi-view learning (AMVL), a novel methodology that integrates chemical-induced transcriptional profiles (CTPs), knowledge graph (KG) embeddings, and large language model (LLM) representations, to enhance drug repurposing predictions. AMVL incorporates an innovative similarity matrix expansion strategy and leverages multi-view learning (MVL), matrix factorization, and ensemble optimization techniques to integrate heterogeneous multi-source data. Comprehensive evaluations on benchmark datasets (Fdataset, Cdataset, and Ydataset) and the large-scale iDrug dataset demonstrate that AMVL outperforms state-of-the-art (SOTA) methods, achieving superior accuracy in predicting drug-disease associations across multiple metrics. Literature-based validation further confirmed the model's predictive capabilities, with seven out of the top ten predictions corroborated by post-2011 evidence. To promote transparency and reproducibility, all data and codes used in this study were open-sourced, providing resources for processing CTPs, KG, and LLM-based similarity calculations, along with the complete AMVL algorithm and benchmarking procedures. By unifying diverse data modalities, AMVL offers a robust and scalable solution for accelerating drug discovery, fostering advancements in translational medicine and integrating multi-omics data. We aim to inspire further innovations in multi-source data integration and support the development of more precise and efficient strategies for advancing drug discovery and translational medicine.

PMID:40678475 | PMC:PMC12268076 | DOI:10.1016/j.jpha.2025.101275

Turk J Biol. 2025 Apr 7;49(3):233-246. doi: 10.55730/1300-0152.2741. eCollection 2025.

ABSTRACT

BACKGROUND/AIM: The COVID-19 pandemic caused by SARS-CoV-2 necessitated rapid development of effective therapeutics, prompting this study to identify potential inhibitors targeting key viral and host proteins: RNA-dependent RNA polymerase (RdRp), main protease (Mpro), transmembrane serine protease 2 (TMPRSS2), and angiotensin-converting enzyme 2 (ACE2).

METHODS: We used covalent docking and molecular dynamics (MD) simulations to screen FDA-approved compounds against these targets using diverse covalent reaction mechanisms. Top-ranking compounds underwent further evaluation through MD simulations to assess binding stability and conformational dynamics.

RESULTS: Several promising drug repurposing candidates were identified: bremelanotide, lanreotide, histrelin, and leuprolide as potential RdRp inhibitors; azlocillin, cefiderocol, and sultamicillin for Mpro inhibition; tenapanor, isavuconazonium, and ivosidenib targeting TMPRSS2; and cefiderocol, cefoperazone, and ceftolozane as potential ACE2 inhibitors.

CONCLUSION: This study provides valuable insights into repurposing existing drugs as potential COVID-19 therapeutics by targeting crucial viral proteins. However, further experimental validation and preclinical studies are necessary to confirm the efficacy and safety of these compounds before consideration for clinical application.

PMID:40678415 | PMC:PMC12266346 | DOI:10.55730/1300-0152.2741

Scientifica (Cairo). 2025 Jul 9;2025:2105236. doi: 10.1155/sci5/2105236. eCollection 2025.

ABSTRACT

This study aimed to investigate the potential of natural products (NPs) as inhibitors of decaprenylphosphoryl-D-ribose 2'-epimerase (DprE1), an enzyme crucial in Mycobacterium tuberculosis cell wall synthesis. Over 100 NPs were screened for anti-TB properties. Subsequently, the binding mechanism of the most potent inhibitor to DprE1 was investigated using computational methods, including molecular docking and simulations. Three compounds (CNP0123918, CNP0041612, and CNP0281145) were identified with promising binding interactions within DprE1's active site. CNP0123918 emerged as the top candidate, exhibiting good interaction with key residues in DprE1. This study suggests that computer-aided drug repurposing holds potential as a successful strategy for identifying novel anti-TB drugs. These findings contribute to the development of novel DprE1 inhibitors. Future research will focus on in vitro assays and in vivo and toxicology assessment of CNP0123908 to establish its potential as an effective DprE1 inhibitor.

PMID:40678077 | PMC:PMC12267967 | DOI:10.1155/sci5/2105236

Curr Top Med Chem. 2025 Jul 16. doi: 10.2174/0115680266360882250702093727. Online ahead of print.

ABSTRACT

Triple-negative breast cancer (TNBC) is the most lethal kind of illness, causing the cancer to spread to other regions of the body and eventually resulting in death. The lack of licensed, targeted drugs that can completely eliminate TNBC is a challenge to the present level of therapeutic options. Developing novel uses for already-approved drugs expedites the lengthy and expensive process of creating new ones. Drug repositioning has been made possible by developments in cheminformatics, genomics, and systems biology. Here we provide what is presumably the first thorough taxonomy of approaches to in silico drug repurposing, classifying them into four categories: structure-based, data-mining-based, transcription signature-based, and physiological networksbased. The most relevant studies from preclinical and clinical contexts are highlighted in this review, which focusses on molecular processes and signalling pathways such as adrenergic receptor, androgen receptor, STAT3, nitric oxide (NO) synthase, or AXL. Its main objective is to repurpose existing medications for the treatment of TNBC. We also focus on repurposing and modifying medications that particularly target this cell type in order to combat metastases and recurrence linked to TNBC. The reason for this is that CSCs are very important and may play a major role in tumour aggressiveness and unfavourable clinical outcomes.

PMID:40676789 | DOI:10.2174/0115680266360882250702093727

Leukemia. 2025 Jul 17. doi: 10.1038/s41375-025-02693-5. Online ahead of print.

NO ABSTRACT

PMID:40676205 | DOI:10.1038/s41375-025-02693-5

Sci Rep. 2025 Jul 17;15(1):25912. doi: 10.1038/s41598-025-10452-w.

ABSTRACT

Adrenocortical carcinoma (ACC), with poor prognosis, is one of the most aggressive endocrine cancers. Surgery is the mainstay of treatment; nevertheless, chemotherapy is usually needed. Mitotane, the medication licenced for ACC, has had mixed results. Drug repositioning based on gene coexpression networks has proven to be an effective method of discovering potential cancer treatments. A total of 139 human specimens were examined, comprising 106 metastatic ACCs, 14 benign adrenocortical adenomas (ACAs), and 19 normal adrenal cortex tissues. Hub genes were identified using weighted correlation network analysis (WGCNA), and their differential expression was confirmed by microarrays and RNA sequencing. Hub genes were analyzed in more depth for enrichment, coexpression, and protein-protein interaction. Two phases of survival analysis were conducted considering sex. Hub gene expression was associated with TP53 mutations and cancer stage. Hub genes were evaluated using regression analysis. Hub genes were associated with immune cell infiltration. Network analysis identified transcription factors that regulate hub genes. Drug-gene interaction network analyses were performed to reposition existing drugs. WGCNA-PPI analysis revealed 31 hub genes, 11 of which were overexpressed by more than fourfold, as well as HMMR and UBE2T, which were novel genes. All hubs showed significant correlations with survival, tumor staging, and TP53 mutation status in ACC tissues. Women overexpressing CDK1, UBE2C, PCLAF, and CCNB1 were more likely to suffer catastrophic deaths than men. In terms of ACC diagnostic capacity, all hub genes had AUCs greater than 0.90, with TOP2A, CDK1, and CCNB1 having the highest values. All hub genes, except for THYMS and RACGAP1, were negatively correlated with M2 macrophages and CD8 + T cells infiltration. Hub genes were co-expressed and regulated by 21 DE-TFs expressed differently between ACC and normal tissues. Novel pharmaceuticals are represented by fifteen out of thirty-four medications directed at hub genes and DE-TFs. Paclitaxel and cisplatin were the central nodes within the drug-gene network. Multiple drugs target TYMS and TOP2A, making them both promising targets for ACC. Fluorouracil and epirubicin target HMMR novel hub gene. HMMR as a novel ACC hub gene targets by fluorouracil and epirubicin, but fluorouracil has advantageous. The reason for this is that M2 macrophages promote fluorouracil resistance, whereas tumors overexpressing the HMMR gene demonstrate a negative infiltration of macrophages. Hub genes, associated with ACC development and progression, have negative impacts on survival rates, particularly in women. Network analysis shows fluorouracil and epirubicin target the ACC novel hub gene, HMMR. Fluorouracil was more effective due to its impact on M2 macrophage infiltration.

PMID:40676104 | DOI:10.1038/s41598-025-10452-w

Comput Biol Med. 2025 Jul 16;196(Pt B):110769. doi: 10.1016/j.compbiomed.2025.110769. Online ahead of print.

ABSTRACT

Post-translational modifications fine-tune protein function and regulate key signalling pathways in eukaryotic cells. ADP-ribosylation, which is catalyzed by the poly(ADP‒ribose) polymerase (PARP) family of enzymes, governs processes such as transcription, DNA repair, and inflammation. PARP14, a mono-ADP-ribosyltransferase, has emerged as a key player in cancer, with its overexpression linked to aggressive B-cell lymphomas and metastatic prostate cancer, positioning it as a promising therapeutic target. This study aimed to identify novel PARP14 inhibitors by repurposing existing compounds for anticancer applications via a ligand-based computational strategy. Using advanced techniques for 3D quantitative structure-activity relationship and pharmacophore modeling, we created a reliable pharmacophore model (Hypo1) via a varied dataset of 60 confirmed PARP14 inhibitors for accuracy. The evaluation of more than 71,540 compounds from the DrugBank and IBScreen libraries through virtual screening, followed by molecular docking studies, resulted in the assessment of these compounds against Veber's and Lipinski's drug-like criteria and optimal ADMET properties. This process identified four promising candidates: Furosemide, Vilazodone, STOCK1N-42868, and STOCK1N-92908. Molecular dynamics simulations and MM-PBSA analysis provided additional evidence of the stability and positive interactions of these ligands with PARP14. Furosemide and Vilazodone exhibited significant binding affinity and anticancer properties, whereas STOCK1N-42868 emerged as a novel candidate with promising in silico results. These findings suggest that Furosemide and Vilazodone could be effectively repurposed as PARP14 inhibitors, offering a strategic approach to enhance the efficacy of cancer treatment, whereas STOCK1N-42868 represents an exciting avenue for further research. This study emphasizes the possible applications of computational methods for finding new drugs and stresses the importance of pre-clinical research to examine how these inhibitors work in cancer treatment.

PMID:40675094 | DOI:10.1016/j.compbiomed.2025.110769

Artif Intell Med. 2025 Jul 10;168:103218. doi: 10.1016/j.artmed.2025.103218. Online ahead of print.

ABSTRACT

Neurodegenerative diseases like Alzheimer's, Parkinson's, and HIV-associated neurocognitive disorder severely impact patients and healthcare systems. While effective treatments remain limited, researchers are actively developing ways to slow progression and improve patient outcomes, requiring innovative approaches to handle huge volumes of new scientific data. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20,889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. We focused on repurposing drugs for dementia by identifying dementia-associated genes highly ranked in other disease classes. The method was developed for detection of genes that shared across multiple conditions and classified them based on their roles in biological pathways. This led to the selection of six primary drugs for further study.

PMID:40674898 | DOI:10.1016/j.artmed.2025.103218

ACS Infect Dis. 2025 Jul 17. doi: 10.1021/acsinfecdis.4c01044. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory infections ranging from mild to severe, posing significant public health risks. The emergence of new variants highlights the need for inhibitors targeting conserved nonstructural proteins like nsp14, a key N7-methyltransferase (MTase) critical for viral RNA capping, immune evasion, and replication. Here, we screened 131 compounds using a drug repurposing approach and identified five candidates that inhibit MTase activity. Bobcat339 showed significant inhibition (IC50 = 21.6 μM) and binding affinity (ΔTm = +3.9 °C). It also reduced the replication of HCoV-229E and SARS-CoV-2 in infected Huh7 cells (EC50 = 29.8 and 28.4 μM, respectively). Molecular docking suggested Bobcat339 binds the SAM-binding pocket of nsp14 MTase. These results identify Bobcat339 as a promising lead for developing selective, non-nucleoside nsp14 inhibitors, supporting further structural optimization and preclinical evaluation.

PMID:40674601 | DOI:10.1021/acsinfecdis.4c01044

Front Cell Infect Microbiol. 2025 Jul 2;15:1506687. doi: 10.3389/fcimb.2025.1506687. eCollection 2025.

ABSTRACT

BACKGROUND: Monkeypox (MPOX) is a zoonotic disease caused by the MPOX virus (MPXV). MPOX resurfaced globally in May 2022, spreading throughout six WHO regions, resulting in nearly 87,000 cases and 112 deaths. Clinical symptoms include swollen lymph nodes, fever, joint pain and several neurological complications such as headache, encephalitis, myalgia, fatigue, photophobia and seizures. Despite these manifestations, the precise mechanisms of MPXV's neurotropism remain elusive. This study aimed to explore the genetic underpinnings of MPOX-related neurological manifestations, including headache, myalgia, fatigue, and photophobia, using advanced bioinformatics tools.

METHODS: Data were sourced from the GeneCards database, which is an integrated database of human genes. Genes linked to MPOX and its neurological manifestations were identified and cross-referenced to uncover shared genes between these conditions. Network visualization was created using STRING, followed by topological analysis in Cytoscape to identify key genes based on degree and betweenness centrality. Functional enrichment analysis through ToppGene provided insights into molecular functions, biological processes, and cellular components associated with these target genes. Pathway analysis was performed using WikiPathways, and cell-type-specific enrichment was conducted using Enrichr. Additionally, we predicted functional microRNAs using mirTarbase and identified potential drug candidates via the Stitch database.

RESULTS: We identified 32 MPOX-associated genes and a large set of neurological manifestation-related genes. Ten hub genes, including CD55, CXCL1, NFKB1, CXCL8, CD4, IL6, MX1, CFH, KLRK1, and CD46 were shared between MPOX and its neurological manifestations. Five novel genes, including CFHR3, C5AR1, C3AR1, IFNA2, and CXCL3 were predicted to be associated with MPOX and its neurological complications. Gene ontology analysis highlighted biological processes such as immune regulation, viral life cycle, and lymphocyte activation, while pathway enrichment identified critical signaling mechanisms like prostaglandin signaling, toll-like receptor 4 (TLR4) signaling, complement activation, and neuroinflammation. Moreover, cell types such as T-helper cells, natural killer cells, and microglia were found to be significantly impacted by MPOX and its frequent neurological complications. We identified 11 key microRNAs associated with MPOX-neurological manifestations and repurposed eight potential drugs, offering promising therapeutic strategies.

CONCLUSION: This study emphasizes the central role of the complement system, immunological responses, and inflammatory pathways in the neurological manifestations of MPOX. The identification of novel genes and predicted therapeutic targets paves the way for future research and therapeutic interventions. Experimental validation is required to confirm these findings and determine the effectiveness of the proposed treatments.

PMID:40673003 | PMC:PMC12263605 | DOI:10.3389/fcimb.2025.1506687

J Inflamm (Lond). 2025 Jul 16;22(1):28. doi: 10.1186/s12950-025-00455-9.

ABSTRACT

BACKGROUND: Gout arthritis (GA) is an inflammatory disorder characterized by the deposition of monosodium urate (MSU) crystals within synovial joints due to increased urate concentrations in the body. The NLRP3 inflammasome drives a majority of the inflammatory response to MSU crystals; therefore, we hypothesize pharmaceutical agents that attenuate NLRP3 inflammasome activation could be used to treat GA flares.

RESULTS: We screened a drug library containing 875 FDA-approved drugs and identified five drugs that reduced NLRP3 inflammasome activation without causing cytotoxic effects in bone marrow-derived macrophages (BMDM). The best performing and therefore leading candidate, verteporfin, used to treat macular degeneration and other eye disorders, reduced Nlrp3- and Caspase-1-dependent IL-1β and IL-18 secretion by BMDM. Additionally, verteporfin-treated mice showed a marked reduction in paw swelling and pro-inflammatory cytokine/chemokine induction, including inflammasome markers (IL-1β and IL-18), in a MSU-induced mouse model of GA flares.

CONCLUSION: Collectively, these data suggest verteporfin is a NLRP3 inflammasome inhibitor that could be repurposed as a treatment for GA.

PMID:40671118 | DOI:10.1186/s12950-025-00455-9

J Antibiot (Tokyo). 2025 Jul 16. doi: 10.1038/s41429-025-00848-1. Online ahead of print.

ABSTRACT

The assignment of new therapeutic purposes to drugs, known as drug repositioning, has been an important ally in the search for new antifungal drugs. Statin compounds, which are used systemically as cholesterol-lowering, may also exert direct antifungal effects, since the statins are drugs that act to prevent sterol synthesis in both humans and fungi and for this reason they are drug promising to combat mycoses. We evaluate the in vivo efficacy of an atorvastatin-loaded topic emulgel (0.75%, 1.5%, or 3.0% m/m) in an in vivo experimental model Tinea pedis. The results showed that the cutaneous delivery-atorvastatin showed total score reduction after seven days of treatment. We concluded that atorvastatin may be a promising drug for the treatment of superficial and cutaneous mycosis.

PMID:40670739 | DOI:10.1038/s41429-025-00848-1

Am J Cancer Res. 2025 Jun 15;15(6):2701-2718. doi: 10.62347/MXZH5646. eCollection 2025.

ABSTRACT

H3K27-altered diffuse midline glioma (DMG) is a universally fatal disease with no available therapeutic strategies apart from palliative radiotherapy. Repurposing marketed non-cancer drugs in oncology is emerging as a fast-tracking approach to speed up the development of new treatment options, urgently needed for DMG. Repurposed anthelmintic mebendazole (MBZ) is in the spotlight against brain tumors, because it joins promising anticancer properties with high neuropenetrance, favorable pharmacokinetic and safety profile. Although MBZ is undergoing Phase I/II trials against brain tumors, including DMG, MBZ anticancer properties and the underlying mechanisms of actions have poorly been characterized in DMG preclinical models. We found that MBZ robustly reduced cell viability in six out of seven DMG cell lines with either K27M-mutated or wild-type H3. All IC50 values (range 102 to 958 nM) fell in a clinically attainable range. The antiproliferative MBZ properties were mediated by an arrest of DMG cells in the G2/M phase with a concomitant upregulation of the key cell cycle regulators p21 and p27, whereas p53 upregulation and activation were cell context-dependent. At the same growth-inhibitory concentrations, MBZ triggered apoptotic cell death, as evidenced by higher levels of the apoptotic markers caspase-3 and PARP cleavage. Consistently, Annexin V-Propidium iodide (PI) double staining showed MBZ dose-dependent increase in both stages of apoptosis. Of interest, the combination of MBZ with the first-in-class imipridone ONC201 sinergistically increased the antiproliferative effects in two DMG cell lines as assessed by combination scores with different algorithms, showing additive effects in two others cell lines. Mechanistically, the combination potentiated the proapoptotic activity of either MBZ or ONC201, while not changing the cytokinetic perturbations induced by the single drugs. Finally, one pair of ONC201-sensitive and ONC201-resistant DMG cell lines with acquired resistance showed same responsiveness to MBZ with similar values of IC50 and Emax. In conclusion, MBZ demonstrates high growth-inhibitory/proapoptotic activity, chemosensitization property to ONC201 and the ability to overcome ONC201 resistance in DMG cell cultures, proposing as a new low-toxicity therapeutic for DMG, with a potential to be used in second-line treatment and/or in combination protocols.

PMID:40667566 | PMC:PMC12256405 | DOI:10.62347/MXZH5646

bioRxiv [Preprint]. 2025 Jun 28:2025.06.25.661596. doi: 10.1101/2025.06.25.661596.

ABSTRACT

OBJECTIVE: Alzheimer disease (AD) is a neurodegenerative disorder leading to cognitive decline. Despite growing recognition of sex differences in epidemiology, symptomatology, and clinical outcomes of AD, the molecular mechanisms underlying these variations remain poorly defined. We performed transcriptome association studies of AD aiming to identify sex-specific and sex-dependent transcriptomic profiles that could provide insights into the molecular mechanisms underlying sex differences in AD pathogenesis.

METHODS: We conducted a meta-analysis of bulk-RNAseq data derived from human postmortem brain studies. Specifically, we analyzed gene expression differences between individuals diagnosed with AD and non-cognitively impaired (NCI) individuals across two key brain regions: the prefrontal cortex and the temporal lobe. We performed stratified differential expression analyses separately in males and females, alongside combined analyses across sexes. Additionally, we assessed the data in relation to known AD genes, proteomic studies, and drug repurposing opportunities.

RESULTS: Beyond the genes commonly dysregulated across both sexes, our meta-analyses identified multiple differentially expressed genes (DEGs) between AD and NCI that are either altered in only one sex or show different effects between sexes. Some genes are known AD genes from genetic studies, but others are novel. Correlation with proteomic data suggests that these transcriptional differences have functional significance, potentially contributing to the biological mechanisms underlying sex differences observed in AD. Finally, we identify drug compounds that are potential candidates for treatment.

INTERPRETATION: Our findings enhance our understanding of sex-related differences in disease etiology and progression, and underscore the importance of incorporating sex as a critical variable in transcriptomic studies of AD. These insights help pave the way for more precise, personalized medicine approaches that account for sex-specific molecular mechanisms.

PMID:40667349 | PMC:PMC12262414 | DOI:10.1101/2025.06.25.661596

bioRxiv [Preprint]. 2025 Jun 26:2025.06.23.660251. doi: 10.1101/2025.06.23.660251.

ABSTRACT

Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A). These mutations disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR) - the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2 -deficient cells. These results demonstrate the potential for pharmacologic HRI activation as a viable strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.

PMID:40666974 | PMC:PMC12262622 | DOI:10.1101/2025.06.23.660251