Front Pharmacol. 2025 Mar 28;16:1564911. doi: 10.3389/fphar.2025.1564911. eCollection 2025.

ABSTRACT

Cancer is a leading cause of mortality worldwide, with most conventional treatments lacking efficacy and having significant challenges like drug resistance. Finding new molecules is quite challenging in terms of cost, time and setbacks. Hence, drug repurposing is considered sensible for skipping the long process of drug development. Dibenzazepine carboxamides, as traditional anticonvulsants, primarily function by blocking voltage-gated sodium channels, which not only mitigate seizures but also influence mood disorders through modulation of serotonin and dopamine. Recent studies have uncovered their anticancer properties, demonstrated by both in vitro and in vivo experiments. This review comprehensively examines dibenzazepine's pharmacodynamics, pharmacokinetics, and clinical applications, focusing on their emerging role in oncology. By highlighting the anticancer mechanisms of action-including apoptosis induction, inhibition of HDAC, Wnt/β-Catenin signaling, and Voltage-gated sodium channels, we suggest further research to fully elucidate their therapeutic potential and application in cancer treatment.

PMID:40223925 | PMC:PMC11985771 | DOI:10.3389/fphar.2025.1564911

Proteomics. 2025 Apr 14:e202400241. doi: 10.1002/pmic.202400241. Online ahead of print.

ABSTRACT

Spaceflight poses unique challenges to human health due to exposure to increased levels of cosmic radiation, microgravity, and associated oxidative stress. These environmental factors can lead to cellular damage, inflammation, and a range of health complications, including cardiovascular problems, immune system impairment, and an increased risk of cancer. Nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor that regulates the body's defense mechanisms against oxidative stress by promoting the expression of antioxidant enzymes. Recent research has shed more light on the critical role of NRF2 in addressing space-related health challenges. In this study, we developed a computational methodology to explore the plasticity of the gene expression profile in flight and postflight conditions, highlighting the genes and corresponding mechanisms that do not return to ground levels and correlate with gene signatures associated with cardiovascular disease (CVD). RNA sequencing (RNA-seq) data from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been used to investigate the cellular effects of microgravity on cardiac function. Gene expression monotonicity studies were performed and linked to genome-wide association studies (GWAS) to highlight the monotonically expressed genes associated with CVD. The selected monotonically expressed genes were also mapped onto the NRF2 network to investigate the impact of spaceflight on human cardiomyocyte function in the context of redox signaling pathways. Based on this knowledge, we used computational drug repurposing methods to suggest a short list of repurposed drug candidates that can be further tested in astronauts for the prevention of CVD. This study provides insights into the molecular and redox signaling alterations in cardiomyocytes induced by spaceflight, laying the foundation for future research aimed at mitigating cardiovascular risks in astronauts and advancing clinical applications on Earth.

PMID:40223711 | DOI:10.1002/pmic.202400241

Expert Opin Drug Discov. 2025 Apr 14:1-10. doi: 10.1080/17460441.2025.2490251. Online ahead of print.

ABSTRACT

INTRODUCTION: The journey from initial drug discovery to approval for respiratory diseases typically spans approximately 10.4 years and cost over $2.8 billion. This intricate process involves five stages: target identification, therapeutic molecule discovery, preclinical testing, clinical trials, and regulatory approval.

AREAS COVERED: This review examines novel drug discovery strategies for chronic obstructive pulmonary disease (COPD), focusing on advanced in vitro models that replicate human lung conditions for accurate drug testing according to the following search string: discovery AND strategy AND COPD. It explores targeted molecular therapies, structure-based drug design, and drug repurposing approaches facilitated by computational analysis. The significance of personalized medicine in tailoring treatments for diverse COPDs is emphasized, highlighting the complexity of the disease and the necessity of these innovative methodologies to improve therapeutic outcomes.

EXPERT OPINION: COPD remains a challenging area, with a significant unmet medical need. Despite previous efforts, few effective therapies exist. Innovative in vitro models, targeted molecular therapies, and drug repurposing strategies are showing promise. Emphasizing advanced preclinical models and repurposing existing drugs could transform treatment paradigms, promoting more effective therapies for complex diseases like COPD. These innovations hold potential for enhancing drug discovery efficiency, leading to personalized and precision medicine approaches.

PMID:40223433 | DOI:10.1080/17460441.2025.2490251

Clin Exp Med. 2025 Apr 13;25(1):117. doi: 10.1007/s10238-025-01631-0.

ABSTRACT

Glioblastoma (GBM) is an aggressive Grade IV brain tumor with a poor prognosis. It results from genetic mutations, epigenetic changes, and factors within the tumor microenvironment (TME). Traditional treatments like surgery, radiotherapy, and chemotherapy provide limited survival benefits due to the tumor's heterogeneity and resistance mechanisms. This review examines novel approaches for treating GBM, focusing on repurposing existing medications such as antipsychotics, antidepressants, and statins for their potential anti-GBM effects. Advances in molecular profiling, including next-generation sequencing, artificial intelligence (AI), and nanotechnology-based drug delivery, are transforming GBM diagnosis and treatment. The TME, particularly GBM stem cells and immune evasion, plays a key role in therapeutic resistance. Integrating multi-omics data and applying precision medicine show promise, especially in combination therapies and immunotherapies, to enhance clinical outcomes. Addressing challenges such as drug resistance, targeting GBM stem cells, and crossing the blood-brain barrier is essential for improving treatment efficacy. While current treatments offer limited benefits, emerging strategies such as immunotherapies, precision medicine, and drug repurposing show significant potential. Technologies like liquid biopsies, AI-powered diagnostics, and nanotechnology could help overcome obstacles like the blood-brain barrier and GBM stem cells. Ongoing research into combination therapies, targeted drug delivery, and personalized treatments is crucial. Collaborative efforts and robust clinical trials are necessary to translate these innovations into effective therapies, offering hope for improved survival and quality of life for GBM patients.

PMID:40223032 | DOI:10.1007/s10238-025-01631-0

Reprod Biol. 2025 Apr 12;25(2):101017. doi: 10.1016/j.repbio.2025.101017. Online ahead of print.

ABSTRACT

PCOS is an endocrine disorder that affects women of reproductive age. The root of PCOS is ovarian dysfunction, which presents as hormonal disturbances affecting normal ovarian function to cause the symptoms and complications of the disease. This dysfunction causes symptoms like impaired maturation of follicles and disorders of various origins with multiple treatment regimens that are not always clear. Therefore, the present review mainly concentrates on the genetic level of ovarian dysfunction of PCOS. The articles were identified through a vigorous literature search where search engines such as PubMed, Google Scholar, databases, and Science Direct were used, and the articles published from 2015 to 2025 were referred. We identified that the key genes involved in the ovarian dysfunctions in PCOS include CYP11A1, CYP17A1, CYP19A1, AR, FSHR, LHCGR, AMH, INSR, SHBG, IRS1, GATA4, ADIPOQ, YAP1, TCF7L2, and DENND1A, which play a role in gonadotropin action, steroidogenesis, and folliculogenesis. Furthermore, epigenetic factors and miRNAs miR-93, 222, 155, 146a, 132, 320, 27a, 483, 21, 378, 17-92 Cluster, and 375, 221 are also involved in it. Abnormal expression of these genes is known to play a critical role in the etiology and pathogenesis of PCOS. Present treatment includes the use of oral contraceptives, anti-androgen agents, insulin-sensitizing agents, and ovulation-inducing agents, and future treatment may consist of miRNA therapy, drug repositioning, and genetic markers that might be used for early identification and better management of ovarian dysfunction. Thus, the current review discusses ovarian dysfunction in PCOS, the involvement of potential genes and epigenetic factors, and miRNAs concerning ovulation and its therapeutic implications.

PMID:40222066 | DOI:10.1016/j.repbio.2025.101017

Sci Rep. 2025 Apr 12;15(1):12698. doi: 10.1038/s41598-025-96284-0.

ABSTRACT

The dengue virus, a member of the arbovirus family, can cause a variety of clinical symptoms. However, there are currently no Food and Drug Administration-approved drugs are currently available for its treatment. We have used RNA-dependent RNA polymerase to identify drug candidates against dengue virus 2 or dengue virus 3. The Smina molecular docking program was used to screen natural compounds and FDA-approved drugs. This study used the pkCSM web server for pharmacokinetic profiling, OSIRIS Data Warrior for physicochemical property assessment, Data Warrior software for cytotoxicity profiling, and molecular dynamics simulations to evaluate the stability of ligand-RdRp interactions. Specifically, the drugs and compounds with the highest negative binding energy and most hydrogen bonds are chlorthalidone, valdecoxib, and ZINC14824819, which interact with the RdRp domain of dengue virus 2, and empagliflozin, netarsudil, and ZINC13375652, which interact with the RdRp domain of dengue virus 3. We propose several FDA-approved drugs and natural compounds that can bind to the RdRp of dengue virus serotypes 2 and 3 and prevent the virus from infecting cells. These compounds show a high level of safety and strong skin and intestinal absorption. Further in vitro and in vivo testing is needed to verify these predictions and assess therapeutic potential.

PMID:40221558 | DOI:10.1038/s41598-025-96284-0

Rev Neurol (Paris). 2025 Apr 10:S0035-3787(25)00495-3. doi: 10.1016/j.neurol.2025.04.003. Online ahead of print.

ABSTRACT

In recent years, the increasing availability of antiseizure medications has not reduced the incidence of drug-resistant epilepsy. Precision medicine offers the potential for mechanism-driven treatments for rare pediatric epilepsies. The concept of precision medicine is not new in the field of epilepsy, as demonstrated by the use of pyridoxine for antiquitin deficiency (pyridoxine-dependent epilepsy) and the ketogenic diet for GLUT1 deficiency syndrome. More recently, preclinical evidence has led to phase 3 clinical trials, such as the use of everolimus to inhibit the mTOR pathway in tuberous sclerosis complex. However, preclinical findings do not always translate into effective treatments, as illustrated by the heterogeneous effects of quinidine in KCNT1-related epilepsy. Currently, an exponential increase in compounds identified at the preclinical level will require clinical trial validation. However, it remains uncertain whether these developments will lead to improved efficacy in drug-resistant epilepsy or have any disease-modifying effects. This article does not explicitly address antisense oligonucleotides or gene therapy.

PMID:40221358 | DOI:10.1016/j.neurol.2025.04.003

Neurobiol Dis. 2025 Apr 10:106909. doi: 10.1016/j.nbd.2025.106909. Online ahead of print.

ABSTRACT

BACKGROUND: Previous studies have shown significant sex differences in AD with regarding its epidemiology, pathophysiology, clinical presentation, and treatment response. However, the transcriptome variances associated with sex in AD remain unclear.

METHODS: RNA sequencing (RNA-seq) and transcriptomic analyses were performed on peripheral blood samples from total of 54 patients, including male AD patients (n = 15), female AD patients (n = 10), male MCI patients (n = 7), female MCI patients (n = 11), male healthy controls (n = 6), female healthy controls (n = 5). The snRNA-seq dataset (GSE167494, GSE157827) of prefrontal cortex tissues was obtained from the Gene Expression Omnibus (GEO). We conducted an investigation into differentially expressed genes and pathways in the peripheral blood cells as well as prefrontal cortex tissues of both male and female AD patients with consideration to sex-related factors. Additionally, we analyzed the distribution and characteristics of cells in the cerebral cortex as well as the interaction and communication between cells of male and female AD patients. Connectivity Map (CMap) was utilized for predicting and screening potential sex-specific drugs for AD.

RESULTS: The transcriptome profile and associated biological processes in the peripheral blood of male and female AD and MCI patients exhibit discernible differences, including upregulation of BASP1 in AD male patients and arousing TNS1 in AD female patients. The distribution of various cell types in the prefrontal cortex tissues differs between male and female AD patients, like neuron and oligodendrocyte decreased and endothelial cell and astrocyte increased in female compared with male, while a multitude of genes exhibit significant differential expression. The results of cell communication analysis, such as collagen signaling pathway, suggest that sex disparities impact intercellular interactions within prefrontal cortex tissues among individuals with AD. By drug repositioning, several drugs, including torin-2 and YM-298198, might have the potential to therapeutic value of MCI or AD, while drugs like homoharringtonine and teniposide have potential opposite effects in different sexes.

CONCLUSION: The characteristics of the transcriptome in peripheral blood and single-cell transcriptome in the prefrontal cortex exhibit significant differences between male and female patients with AD, which providing a basis for future sex stratified treatment of AD.

PMID:40220916 | DOI:10.1016/j.nbd.2025.106909

Int Immunopharmacol. 2025 Apr 11;155:114622. doi: 10.1016/j.intimp.2025.114622. Online ahead of print.

ABSTRACT

The lysosomal cysteine protease cathepsin S supports host defence by promoting the maturation of MHC class-II proteins. In contrast, increased cathepsin S activity mediates tissue destructive immune responses in autoimmune and inflammatory diseases. Therefore, cathepsin S is a key target in drug discovery programs. Here, we critically reviewed the specific mechanisms by which cathepsin S mediates autoimmune and hyperinflammatory responses to identify new targets for therapeutic immunomodulation. To this end, we performed literature review utilizing PubMed, drug database of US FDA, European Medicines Agency and the Drug-Gene Interaction Database. Cathepsin S destroys T cell epitopes and reduces endogenous antigen diversity, impairing negative selection of autoreactive T cells that could recognize these epitopes. Moreover, cathepsin S critically regulates inflammatory disease severity by generating proinflammatory molecules (PAR-1, PAR-2, IL-36γ, Fractalkine, Endostatin, Ephrin-B2), inactivating anti-inflammatory mediators (SLPI) and degrading molecules involved in antimicrobial and immunomodulatory responses (surfactant protein-A, LL-37, beta-defensins), inter-endothelial/-epithelial barrier function, gene repair and energy homeostasis. These pathways could be targeted by repositioning of existing drugs. These findings suggest that inhibiting cathepsin S or a specific downstream target of cathepsin S by repositioning of existing drugs could be a promising strategy for treating autoimmune and inflammatory diseases. Current cathepsin S inhibitors in clinical trials face challenges, highlighting the need for innovative inhibitors that function effectively in various cellular compartments with differing pH levels, without targeting the shared catalytic site of cysteine cathepsins.

PMID:40220622 | DOI:10.1016/j.intimp.2025.114622

NPJ Antimicrob Resist. 2025 Apr 11;3(1):25. doi: 10.1038/s44259-025-00097-0.

ABSTRACT

Slow- and non-growing bacterial populations, along with intracellular pathogens, often evade standard antibacterial treatments and are linked to persistent and recurrent infections. This necessitates the development of therapies specifically targeting nonproliferating bacteria. To identify compounds active against non-growing uropathogenic Escherichia coli (UPEC) we performed a drug-repurposing screen of 6454 approved drugs and drug candidates. Using dilution-regrowth assays, we identified 39 compounds that either kill non-growing UPEC or delay its regrowth post-treatment. The hits include fluoroquinolones, macrolides, rifamycins, biguanide disinfectants, a pleuromutilin, and anti-cancer agents. Twenty-nine of the hits have not previously been recognized as active against non-growing bacteria. The hits were further tested against non-growing Pseudomonas aeruginosa and Staphylococcus aureus. Ten compounds - solithromycin, rifabutin, mitomycin C, and seven fluoroquinolones-have strong bactericidal activity against non-growing P. aeruginosa, killing >4 log10 of bacteria at 2.5 µM. Solithromycin, valnemulin, evofosfamide, and satraplatin are unique in their ability to selectively target non-growing bacteria, exhibiting poor efficacy against growing bacteria. Finally, 31 hit compounds inhibit the growth of intracellular Shigella flexneri in a human enterocyte infection model, indicating their ability to permeate the cytoplasm of host cells. The identified compounds hold potential for treating persistent infections, warranting further comparative studies with current standard-of-care antibiotics.

PMID:40216902 | DOI:10.1038/s44259-025-00097-0

Exp Cell Res. 2025 Apr 9:114551. doi: 10.1016/j.yexcr.2025.114551. Online ahead of print.

ABSTRACT

Due to the expensive and lengthy process of drug design and approval, drug repurposing (or repositioning) has become another option for identifying preexisting molecules that may be used for alternative purposes. Recently, some antimalarial compounds have been shown to display efficacy against cancer cell proliferation. In this study, we provide evidence to suggest that multiple preexisting antimalarial drugs can reduce the viability of human cancer cells in culture. Furthermore, we provide the first evidence that one antimalarial, Tafenoquine (LD50=9.6μM in HCT116 cells), is capable of decreasing viability with an efficacy comparable to Etoposide (LD50=15.2μM in HCT116 cells) Further, Tafenoquine induces apoptosis and increases the expression of genes involved in cell cycle arrest and cell death. We also show that cells are sensitized to the apoptotic effects of Tafenoquine following depletion of the heme oxygenase 1 (HMOX-1) gene. Collectively, our studies confirm that antimalarial compounds hold the potential for use as anticancer agents and provide the first evidence to detail the potent efficacy of Tafenoquine against cancer cells in culture.

PMID:40216009 | DOI:10.1016/j.yexcr.2025.114551

Biomed Pharmacother. 2025 Apr 10;186:118031. doi: 10.1016/j.biopha.2025.118031. Online ahead of print.

ABSTRACT

The coagulation system plays a complex role in cancer therapy. Endothelial damage and tissue factor increased by chemotherapy initiate the coagulation cascade, producing active FXa and releasing thrombin. Thrombin triggers tumor growth and metastasis, leading to severe thromboembolic events in cancer patients. Direct thrombin inhibitors do not have the expected anti-metastatic effect as PAR-2 remains active and increases the risk of bleeding. Therefore, dual inhibition of thrombin by FXa inhibition and plasmin inhibition, which converts fibrin to fibrinogen, is targeted. Clinical studies show that the use of tranexamic acid in patients on NOAC therapy may be beneficial without increasing the risk of bleeding. This approach offers a promising strategy to provide an anti-metastatic effect in cancer treatment.

PMID:40215647 | DOI:10.1016/j.biopha.2025.118031

Cells. 2025 Apr 2;14(7):533. doi: 10.3390/cells14070533.

ABSTRACT

Failure in the proliferation, recruitment, mobilization, and/or differentiation of oligodendrocyte precursor cells (OPCs) impedes remyelination in central nervous system (CNS) demyelinating diseases. Our group has recently achieved the generation of functional oligodendroglia through direct lineage conversion by expressing Sox10, Olig2, and Zfp536 genes in adult rat adipose tissue-derived stromal cells. The present study aimed to determine whether various repurposed drugs or molecules could enhance the myelinating capacities of these induced OPCs (iOPCs). We report that kainate, benztropine, miconazole, clobetasol, and baclofen promote in vitro iOPCs migration, differentiation, and ensheathing abilities through mechanisms similar to those observed in rat neural stem cell-derived OPCs. This research supports the potential use of iOPCs as they provide an alternative and reliable cell source for testing the effects of in vitro promyelinating repurposed drugs and for assessing the molecular and cellular mechanisms involved in therapeutic strategies for demyelinating diseases.

PMID:40214487 | DOI:10.3390/cells14070533

Ann Med Surg (Lond). 2025 Feb 28;87(3):1506-1528. doi: 10.1097/MS9.0000000000003043. eCollection 2025 Mar.

ABSTRACT

Cancer is one of the leading causes of death worldwide. In cancer therapy, anti-cancer drugs are the current treatment-of-choice for patients with metastatic cancers, but these drugs present a major drawback: they destroy healthy cells along with cancerous cells. Unfortunately, the drug discovery process for de novo drugs is costly and time-consuming. To address this global problem, our research team has established the concept of "Chemotherapy with a molecular rational basis", which focuses on the identification of molecular targets in tumor cells, whose activation or inhibition induces apoptosis or sensitizes the tumor cells to apoptosis. Here we review the experimental and clinical evidence of pentoxifylline (PTX) in the setting of chemotherapy with a molecular rational basis. A search of the literature was conducted for articles published during the period from 2 January 2003 to 21 October 2024. Articles published in English or Spanish were included. The keywords "Pentoxifylline" OR "BL 191" OR "trental" AND "cancer" were used for in vitro, in vivo, and clinical studies. PTX is an approved, accessible, and relatively safe drug. Furthermore there is a large body of experimental and clinical evidence of the beneficial effects of PTX in cancer therapy, either alone or in combination with antitumor drugs, sometimes even more effective than traditional chemotherapy regimens. However, it is necessary to carry out larger clinical trials in cancer patients to identify the benefits, adverse effects and even pharmacological interactions of PTX with current chemotherapy regimens and thus achieve a new drug repositioning that benefits our patients.

PMID:40213176 | PMC:PMC11981314 | DOI:10.1097/MS9.0000000000003043

Eur J Med Res. 2025 Apr 11;30(1):267. doi: 10.1186/s40001-025-02443-4.

ABSTRACT

Current TB treatment regimens are hindered by drug resistance, numerous adverse effects, and long treatment durations, highlighting the need for 'me-better' treatment regimens. Host-directed therapy (HDT) has gained recognition as a promising approach in TB treatment. It allows the repurposing of existing drugs approved for other conditions and aims to enhance the effectiveness of existing anti-TB therapies, minimize drug resistance, decrease treatment duration, and adverse effects. By modulating the host immune response, HDT ameliorates immunopathological damage and improves overall outcomes by promoting autophagy, antimicrobial peptide production, and other mechanisms. It holds promise for addressing the challenges posed by multiple and extensively drug-resistant Mycobacterium tuberculosis strains, which are increasingly difficult to treat using conventional therapies. This article reviews various HDT candidates, including repurposed drugs, explores their underlying mechanisms such as autophagy promotion and inflammation reduction, while emphasizing their potential to improve TB treatment outcomes and outlining future research directions.

PMID:40211397 | DOI:10.1186/s40001-025-02443-4

Cell Commun Signal. 2025 Apr 10;23(1):179. doi: 10.1186/s12964-025-02185-0.

ABSTRACT

BACKGROUND: About 40% of relapsed or non-responder tumors exhibit therapeutic resistance in the absence of a clear genetic cause, suggesting a pivotal role of intracellular communication. A deeper understanding of signaling pathways rewiring occurring in resistant cells is crucial to propose alternative effective strategies for cancer patients.

METHODS: To achieve this goal, we developed a novel multi-step strategy, which integrates high sensitive mass spectrometry-based phosphoproteomics with network-based analysis. This strategy builds context-specific networks recapitulating the signaling rewiring upon drug treatment in therapy-resistant and sensitive cells.

RESULTS: We applied this strategy to elucidate the BCR::ABL1-independent mechanisms that drive relapse upon therapy discontinuation in chronic myeloid leukemia (CML) patients. We built a signaling map, detailing - from receptor to key phenotypes - the molecular mechanisms implicated in the control of proliferation, DNA damage response and inflammation of therapy-resistant cells. In-depth analysis of this map uncovered novel therapeutic vulnerabilities. Functional validation in patient-derived leukemic stem cells revealed a crucial role of acquired FLT3-dependency and its underlying molecular mechanism.

CONCLUSIONS: In conclusion, our study presents a novel generally applicable strategy and the reposition of FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for CML relapsed patients.

PMID:40211380 | DOI:10.1186/s12964-025-02185-0

J Invest Dermatol. 2025 Apr 8:S0022-202X(25)00396-3. doi: 10.1016/j.jid.2025.03.029. Online ahead of print.

NO ABSTRACT

PMID:40210113 | DOI:10.1016/j.jid.2025.03.029

IEEE J Biomed Health Inform. 2025 Apr 10;PP. doi: 10.1109/JBHI.2025.3559570. Online ahead of print.

ABSTRACT

Drug repositioning, which identifies new therapeutic potential of approved drugs, is instrumental in accelerating drug discovery. Recently, to alleviate the effect of data sparsity on predicting possible drug-disease associations (DDAs), graph contrastive learning (GCL) has emerged as a promising paradigm for learning discriminative representations of drugs and diseases through distilling informative self-supervised signals. However, existing GCLbased methods devised for DDA prediction still encounter two limitations. Firstly, the crucial heterogeneous property, which allows for capturing nuanced interaction semantics between biological entities, is overlooked. The second is how to perform contrastive view augmentation without relying on stochastic perturbation. In this study, we propose a novel multi-view contrastive learning approach for DDA prediction, namely MICLE. To handle the first issue, proteinrelated bipartite graphs are integrated with the original DDA network in advance, thereby composing a heterogeneous biological network (HBN). Besides, heterogeneous graph neural network is applied to mine the rich connectivity patterns implicit in the above HBN. For the second limitation, we design the complementary inter-view and intra-view contrastive learning tasks. Specifically, the former ensures that the mutual information between paired nodes across views is maximized, the latter enhances the agreement between each node and its first-order neighbors on similarity networks. Extensive experiments conducted on three benchmarks under 10-fold cross-validation demonstrate the model effectiveness. Source code and datasets are available at https://github.com/OleCui/paper MICLE.

PMID:40208759 | DOI:10.1109/JBHI.2025.3559570

Biochem Biophys Rep. 2025 Mar 19;42:101957. doi: 10.1016/j.bbrep.2025.101957. eCollection 2025 Jun.

ABSTRACT

Colorectal cancer (CRC) is a multifaceted disease characterized by abnormal cell proliferation in the colon and rectum. The BCL-2 family proteins are implicated in CRC pathogenesis, yet the impacts of genetic variations within these proteins remains elusive. This in-silico study employs diverse sequence- and structure-based bioinformatics tools to identify potentially pathogenic nonsynonymous single nucleotide polymorphisms (nsSNPs) in BCL-2 family proteins. Leveraging computational tools including SIFT, PolyPhen-2, SNPs&GO, PhD-SNP, PANTHER, and Condel, 94 nsSNPs were predicted as deleterious, damaging, and disease-associated by at least five tools. Stability analysis with I-Mutant2.0, MutPred, and PredictSNP further identified 31 nsSNPs that reduce protein stability. Conservation analysis highlighted highly functional, exposed variants (rs960653284, rs758817904, rs1466732626, rs569276903, rs746711568, rs764437421, rs779690846, and rs2038330314) and structural, buried variants (rs376149674, rs1375767408, rs1582066443, rs367558446, rs367558446, rs1319541919, and rs1370070128). To explore the functional effects of these mutations, molecular docking and molecular dynamics simulations were conducted. G233D (rs376149674) and R12G (rs960653284) mutations in the BCL2 protein exhibited the greatest differences in docking scores with d-α-Tocopherol and Tocotrienol, suggesting enhanced protein-ligand interactions. The simulations revealed that d-α-Tocopherol and Tocotrienol (strong binders) contributed to greater stability of BCL-2 family proteins, while Fluorouracil, though weaker, still demonstrated selective binding stability. This work represents the first comprehensive computational analysis of functional nsSNPs in BCL-2 family proteins, providing insights into their roles in CRC pathogenesis. While these findings demand experimental validation, they hold great promise for guiding future large-scale population studies, facilitating drug repurposing efforts, and advancing the development of targeted diagnostic and therapeutic modalities for CRC.

PMID:40207085 | PMC:PMC11979393 | DOI:10.1016/j.bbrep.2025.101957

Front Cell Dev Biol. 2025 Mar 26;13:1505697. doi: 10.3389/fcell.2025.1505697. eCollection 2025.

ABSTRACT

BACKGROUND: Understanding the cell functionality during disease progression or drugs' mechanism are major challenges for precision medicine. Predictive models describing biological phenotypes can be challenging to obtain, particularly in scenarios where sample availability is limited, such as in the case of rare diseases. Here we propose a new method that reproduces the fibroadipogenic expansion that occurs in muscle wasting.

METHODS: We used immortalized fibroadipogenic progenitor cells (FAPs) and differentiated them into fibroblasts or adipocytes. The method successfully identified FAPs cell differentiation fate using accurate measurements of changes in specific proteins, which ultimately constitute a valid cellular in vitro platform for drug screening. Results were confirmed using primary FAPs differentiation as well as comparison with omics data from proteomics and genomic studies.

RESULTS: Our method allowed us to screen 508 different drugs from 2 compounds libraries. Out of these 508, we identified 4 compounds that reduced fibrogenesis and adipogenesis of ≥30% of fibrogenesis and adipogenesis using immortalized cells. After selecting the optimal dose of each compound, the inhibitory effect on FAP differentiation was confirmed by using primary FAPs from healthy subjects (n = 3) and DMD patients (n = 3). The final 4 selected hits reduced fibrogenic differentiation in healthy and DMD samples. The inhibition of adipogenesis was more evident in DMD samples than healthy samples. After creating an inhibitory map of the tested drugs, we validated the signalling pathways more involved in FAPs differentiation analysing data from proteomic and genomic studies.

CONCLUSION: We present a map of molecular targets of approved drugs that helps in predicting which therapeutic option may affect FAP differentiation. This method allows to study the potential effect of signalling circuits on FAP differentiation after drug treatment providing insights into molecular mechanism of action of muscle degeneration. The accuracy of the method is demonstrated by comparing the signal pathway activity obtained after drug treatment with proteomic and genomic data from patient-derived cells.

PMID:40206397 | PMC:PMC11979640 | DOI:10.3389/fcell.2025.1505697