Parasitol Int. 2025 Feb 11:103041. doi: 10.1016/j.parint.2025.103041. Online ahead of print.

ABSTRACT

The malarial parasite Plasmodium falciparum has evolved resistance to several antimalarial drugs, posing a significant challenge to the effective management and treatment of malaria in endemic areas. Drug repurposing has emerged as a potential alternative strategy for addressing this issue. This study aimed to identify an FDA-approved microbicidal agent, zinc pyrithione (ZPT), against mixed blood-stage parasites of P. falciparum chloroquine-sensitive (Pf3D7) and resistant strains (PfINDO). Based on the time-inhibition kinetics assay, the parasite viability was significantly inhibited by ZPT treatment for 96 (0.77 μM and 0.37 μM) and 72 h (0.63 μM and 0.61 μM), followed by 48 h (0.76 μM and 1.32 μM) and moderate inhibitory effects for 12 and 24 h in both Pf3D7 and PfINDO culture. Stage-specific treatment revealed that trophozoites and schizonts exposed to ZPT were more susceptible than ring-stage parasites. Phenotypic assays revealed that trophozoites and schizonts failed to mature and exhibited aberrant morphologies such as condensed nuclei, as determined by Giemsa staining. Furthermore, ZPT in combination with dihydroartemisinin and chloroquine demonstrated additive interactions in both Pf3D7 and PfINDO parasites. At therapeutic dosages, ZPT failed to cause hemolysis in human erythrocytes. Overall, this study demonstrated a time-dependent effect of ZPT on the blood stages of human P. falciparum in culture, suggesting its utility in clinical settings.

PMID:39947389 | DOI:10.1016/j.parint.2025.103041

Int J Mol Sci. 2025 Feb 2;26(3):1287. doi: 10.3390/ijms26031287.

ABSTRACT

Space exploration has progressed from contemporary discoveries to current endeavors, such as space tourism and Mars missions. As human activity in space accelerates, understanding the physiological effects of microgravity on the human body is becoming increasingly critical. This study analyzes transcriptomic data from human cell lines exposed to microgravity, investigates its effects on gene expression, and identifies potential therapeutic interventions for health challenges posed by spaceflight. Our analysis identified five under-expressed genes (DNPH1, EXOSC5, L3MBTL2, LGALS3BP, SPRYD4) and six over-expressed genes (CSGALNACT2, CSNK2A2, HIPK1, MBNL2, PHF21A, RAP1A), all of which exhibited distinct expression patterns in response to microgravity. Enrichment analysis highlighted significant biological functions influenced by these conditions, while in silico drug repurposing identified potential modulators that could counteract these changes. This study introduces a novel approach to addressing health challenges during space missions by repurposing existing drugs and identifies specific genes and pathways as potential biomarkers for microgravity effects on human health. Our findings represent the first systematic effort to repurpose drugs for spaceflight, establishing a foundation for the development of targeted therapies for astronauts. Future research should aim to validate these findings in authentic space environments and explore broader biological impacts.

PMID:39941055 | DOI:10.3390/ijms26031287

Cancers (Basel). 2025 Jan 27;17(3):439. doi: 10.3390/cancers17030439.

ABSTRACT

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine the therapeutic efficacy. These include challenges in suboptimal drug delivery through the blood-brain barrier (BBB), marked intra-tumoral molecular heterogeneity, and the elusive tumor microenvironment. Drug repurposing or re-tasking FDA-approved drugs with evidence of penetration into the CNS, using newer methods of intracranial drug delivery facilitating optimal drug exposure, has been an area of intense research. This could be a valuable tool, as most of these agents have already gone through the lengthy process of drug development and the evaluation of safety risks and the optimal pharmacokinetic profile. They can now be used and tested in clinics with an accelerated and different approach. Conclusions: The next-generation therapeutic strategy should prioritize repurposing oncologic and non-oncologic drugs that have been used for other indication, and have demonstrated robust preclinical activity against pediatric brain tumors. In combination with novel drug delivery techniques, these drugs could hold significant therapeutic promise in pediatric neurooncology.

PMID:39941807 | DOI:10.3390/cancers17030439

Int J Mol Sci. 2025 Feb 6;26(3):1389. doi: 10.3390/ijms26031389.

ABSTRACT

Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with advanced melanoma, treatment resistance, their side effect profiles, and the prohibitive cost remain a challenge, and the survival outcomes remain suboptimal. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, recurrence, metastasis, and treatment resistance. CSCs reside within the tumor microenvironment (TME) regulated by the immune system, and the paracrine renin-angiotensin system, which is expressed in many cancer types, including melanoma. This narrative review discusses the role of CSCs and the paracrine renin-angiotensin system in the melanoma TME, and its implications on the current treatment of advanced melanoma with targeted therapy and immune checkpoint blockers. It also highlights the regulation of the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways by the renin-angiotensin system via pro-renin receptors, and how this may relate to CSCs and treatment resistance, underscoring the potential for improving the efficacy of targeted therapy and immunotherapy by concurrently modulating the renin-angiotensin system.

PMID:39941158 | DOI:10.3390/ijms26031389

Int J Mol Sci. 2025 Jan 23;26(3):925. doi: 10.3390/ijms26030925.

ABSTRACT

Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) continue to be global public health issues. Globally, about 39.9 million persons live with HIV in 2023, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2024 Fact Sheet. Consequently, the World Health Organisation (WHO) reported that about 1.5 million new cases of HBV occur, with approximately 820 thousand mortalities yearly. Conversely, the lower percentage of HBV (30%) cases that receive a diagnosis is a setback in achieving the WHO 2030 target for zero HBV globally. This has necessitated a public health concern to repurpose antiretroviral (ARV) drugs for the treatment of HBV diseases. This review provides an introductory background, including the pros and cons of repurposing antiretrovirals (ARVs) for HBV treatment. We examine the similarities in replication mechanisms between HIV and HBV. We further investigate some clinical studies and trials of co-infected and mono-infected patients with HIV-HBV. The topical keywords including repurposing ARV drugs, repurposing antiretroviral therapy, Hepatitis B drugs, HBV therapy, title, and abstracts are searched in PubMed, Web of Science, and Google Scholar. The advanced search includes the search period 2014-2024, full text, clinical trials, randomized control trials, and review. The search results filtered from 361 to 51 relevant articles. The investigations revealed that HIV and HBV replicate via a common route known as 'reverse transcription'. Clinical trial results indicate that an early initiation of ARVs, particularly with tenofovir disoproxil fumarate (TDF) as part of a regimen, significantly reduced the HBV viral load in co-infected patients. In mono-infected HBV, timely and correct precise medication is essential for HBV viral load reduction. Therefore, genetic profiling is pivotal for successful ARV drug repurposing in HBV treatment. Pharmacogenetics enables the prediction of the right dosages, specific individual responses, and reactions. This study uniquely explores the intersection of pharmacogenetics and drug repurposing for optimized HBV therapy. Additional in vivo, clinical trials, and in silico research are important for validation of the potency, optimum dosage, and safety of repurposed antiretrovirals in HBV therapy. Furthermore, a prioritization of research collaborations comprising of regulators and funders to foster clinically adopting and incorporating repurposed ARVs for HBV therapy is recommended.

PMID:39940695 | DOI:10.3390/ijms26030925

Int J Mol Sci. 2025 Jan 21;26(3):888. doi: 10.3390/ijms26030888.

ABSTRACT

Classic galactosemia is a rare disease with long-term consequences that seriously affect the quality of life of patients. To date, various therapeutic approaches are being developed, but treatments that target the molecular defects in the mutant galactose-1-phosphate uridylyltransferase (GALT) gene are lacking. We conducted a computational search for putative pharmacochaperones by applying a drug repurposing strategy, and we found that one compound, already active as a pharmacochaperone in another pathology, doubled the enzymatic activity of the purified mutant enzyme in an in vitro test. Furthermore, an extensive computational search in a database of known active molecules found another compound able in its turn to improve in vitro enzymatic activity. Both compounds are predicted to interact with a cavity at the enzyme interface previously supposed to be an allosteric site for the GALT enzyme. In vitro tests confirmed also the reduced accumulation of galactose-1-phosphate (G1P) in fibroblasts of patients. Although these results must be considered preliminary, our findings pave the way for future research lines focused on the search for promising pharmacochaperones that can directly rescue the activity of the enzyme.

PMID:39940658 | DOI:10.3390/ijms26030888

Pharmacol Res Perspect. 2025 Feb;13(1):e70076. doi: 10.1002/prp2.70076.

ABSTRACT

Drug repurposing provides a cost-effective and time-saving approach to cancer therapy. Aripiprazole (ARI), a third-generation antipsychotic, has shown potential anticancer properties by modulating pathways central to tumor progression and resistance. This scoping review systematically examines evidence on ARI's anticancer effects, mechanisms of action, and translational potential. A systematic search of PubMed, EMBASE, SCOPUS, and Web of Science was conducted following PRISMA-ScR guidelines. Eligible studies included in vitro, in vivo, and clinical investigations. Data on cancer types, pathways, assays, and outcomes were extracted and synthesized to identify trends and gaps. Of 588 screened studies, 23 met inclusion criteria, spanning cancer types such as breast, colorectal, lung, and brain cancers. ARI modulates key pathways like PI3K/AKT/mTOR and Wnt/β-catenin, induces apoptosis through mitochondrial dysfunction and ER stress, and overcomes drug resistance by inhibiting P-glycoprotein activity and expression. It exhibits tumor-suppressive effects in vivo and synergizes with chemotherapy and radiotherapy. Retrospective population studies suggest ARI's prolactin-sparing properties may reduce the risk of hormone-sensitive cancers such as breast and endometrial cancer compared to antipsychotics with stronger dopamine receptor blockade. Additionally, ARI's ability to target multiple Hallmarks of Cancer highlights its promise as a repurposed anticancer agent. However, current evidence is primarily preclinical and observational, with limited clinical validation. Large-scale cohort studies and prospective trials are essential to confirm its efficacy and address translational challenges. By bridging these gaps, ARI could emerge as a valuable adjunctive therapy in oncology, leveraging its safety profile and versatility to address unmet needs in cancer treatment.

PMID:39939172 | DOI:10.1002/prp2.70076

Curr Res Transl Med. 2025 Feb 4;73(2):103498. doi: 10.1016/j.retram.2025.103498. Online ahead of print.

ABSTRACT

SARS-CoV-2 infection has been associated with long-term cardiovascular complications including myocarditis and heart failure, as well as central nervous system sequelae such as cognitive dysfunction and neuropathy. Proprotein convertase subtilisin/Kexin type 9 (PCSK9), a hepatic protease involved in cholesterol regulation, has shown associations with a spectrum of diseases potentially relevant to these Covid-19 complications, such as atherosclerosis. To identify novel human PCSK9 inhibitors, a custom virtual screening pipeline was developed employing (1) a convolutional neural network-based deep learning model, (2) molecular docking using Schrödinger with Glide scoring function, and (3) molecular dynamics (MD) simulations with Gibbs Free Energy Landscape analysis. The deep learning model was trained on a dataset of known central nervous system, cardiovascular, and anti-inflammatory acting drugs and used to screen the CMNPD database. Docking simulations were performed on shortlisted candidates, followed by MD simulations and free energy landscape analysis to evaluate binding affinities and identify key interaction residues. This multi-step in-silico approach identified promising PCSK9 inhibitor candidates with favorable binding profiles, suggesting that AI-assisted virtual screening can be a powerful tool for discovering novel therapeutic agents.

PMID:39938184 | DOI:10.1016/j.retram.2025.103498

ACS Infect Dis. 2025 Feb 12. doi: 10.1021/acsinfecdis.4c00666. Online ahead of print.

ABSTRACT

Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against Trypanosoma cruzi and Leishmania donovani, and the latter were progressed into the murine model of infection. Despite the potent in vitro activity, there was no effect on parasitemia, necessitating further work to improve the pharmacokinetic properties of this series. Nonetheless, valuable insights have been obtained into the structure-activity and structure-property relationships of this compound series.

PMID:39936822 | DOI:10.1021/acsinfecdis.4c00666

Mem Inst Oswaldo Cruz. 2025 Feb 7;120:e240183. doi: 10.1590/0074-02760240183. eCollection 2025.

ABSTRACT

BACKGROUND: The neglected illness Chagas disease is treated with limited efficacy and adverse effects by old drugs. Due to the low interest of pharmaceutical industry in targeting economically depressed-patients, repurposing is a tool that should be applied because it can introduce new anti-Chagas entities into the clinic at reduced costs.

OBJECTIVES: To investigate the repurposing/combination of medicines strategies as anti-Chagas treatment.

METHODS: Epimastigotes, trypomastigotes and amastigotes of Trypanosoma cruzi were in vitro exposed to 28 Uruguayan-approved medicines not previously tested, 28 FDA-approved medicines previously evaluated, and three reference agents. Parasite inhibition was assessed and for the best drugs, in pairs-isobolographic studies, looking for synergism/additivity/antagonism, were done. Macrophages were used to study selectivity. For some relevant agents, we analysed whether medicines mammals´ action mechanisms are operative in epimastigotes-T. cruzi.

FINDINGS: From the anti-epimastigotes monotherapy-screening, we found that 18% of them showed better/comparable activities than references. Additionally, for the binary-combinations 8% were additive, 4% were synergic and the rest showed antagonism. Favourably, in macrophages-cytotoxicity four of the binary-combinations were antagonists. Naftazone and pinaverium bromide, not previously tested against T. cruzi, maintained their activity against trypomastigotes and amastigotes. The identified action mechanisms open the door to new strategies designing anti-T. cruzi drugs.

MAIN CONCLUSIONS: Using approved-medicines is a good strategy for new anti-Chagas treatments.

PMID:39936704 | DOI:10.1590/0074-02760240183

Curr Neuropharmacol. 2025 Feb 6. doi: 10.2174/011570159X327908241121062335. Online ahead of print.

ABSTRACT

Neurodegenerative diseases represent a prevalent category of age-associated diseases. As human lifespans extend and societies become increasingly aged, neurodegenerative diseases pose a growing threat to public health. The lack of effective therapeutic drugs for both common and rare neurodegenerative diseases amplifies the medical challenges they present. Current treatments for these diseases primarily offer symptomatic relief rather than a cure, underscoring the pressing need to develop efficacious therapeutic interventions. Drug repositioning, an innovative and data-driven approach to research and development, proposes the re-evaluation of existing drugs for potential application in new therapeutic areas. Fueled by rapid advancements in artificial intelligence and the burgeoning accumulation of medical data, drug repositioning has emerged as a promising pathway for drug discovery. This review comprehensively examines drug repositioning for neurodegenerative diseases through the lens of translational informatics, encompassing data sources, computational models, and clinical applications. Initially, we systematized drug repositioning-related databases and online platforms, focusing on data resource management and standardization. Subsequently, we classify computational models for drug repositioning from the perspectives of drug-drug, drug-target, and drug-disease interactions into categories such as machine learning, deep learning, and networkbased approaches. Lastly, we highlight computational models presently utilized in neurodegenerative disease research and identify databases that hold potential for future drug repositioning efforts. In the artificial intelligence era, drug repositioning, as a data-driven strategy, offers a promising avenue for developing treatments suited to the complex and multifaceted nature of neurodegenerative diseases. These advancements could furnish patients with more rapid, cost-effective therapeutic options.

PMID:39936420 | DOI:10.2174/011570159X327908241121062335

Front Med (Lausanne). 2025 Jan 28;12:1492709. doi: 10.3389/fmed.2025.1492709. eCollection 2025.

ABSTRACT

OBJECTIVE: To systematically map the knowledge landscape and development trends in artificial intelligence (AI) applications for antimicrobial resistance (AMR) research through bibliometric analysis, providing evidence-based insights to guide future research directions and inform strategic decision-making in this dynamic field.

METHODS: A comprehensive bibliometric analysis was performed using the Web of Science Core Collection database for publications from 2014 to 2024. The analysis integrated multiple bibliometric approaches: VOSviewer for visualization of collaboration networks and research clusters, CiteSpace for temporal evolution analysis, and quantitative analysis of publication metrics. Key bibliometric indicators including co-authorship patterns, keyword co-occurrence, and citation impact were analyzed to delineate research evolution and collaboration patterns in this domain.

RESULTS: A collection of 2,408 publications was analyzed, demonstrating significant annual growth with publications increasing from 4 in 2014 to 549 in 2023 (22.7% of total output). The United States (707), China (581), and India (233) were the leading contributors in international collaborations. The Chinese Academy of Sciences (53), Harvard Medical School (43), and University of California San Diego (26) were identified as top contributing institutions. Citation analysis highlighted two major breakthroughs: AlphaFold's protein structure prediction (6,811 citations) and deep learning approaches to antibiotic discovery (4,784 citations). Keyword analysis identified six enduring research clusters from 2014 to 2024: sepsis, artificial neural networks, antimicrobial resistance, antimicrobial peptides, drug repurposing, and molecular docking, demonstrating the sustained integration of AI in antimicrobial therapy development. Recent trends show increasing application of AI technologies in traditional approaches, particularly in MALDI-TOF MS for pathogen identification and graph neural networks for large-scale molecular screening.

CONCLUSION: This bibliometric analysis shows the importance of artificial intelligence in enhancing the progress in the discovery of antimicrobial drugs especially toward the fight against AMR. From enhancing the fast, efficient and predictive performance of drug discovery methods, current AI capabilities have revealed observable potential to be proactive in combating the ever-growing challenge of AMR worldwide. This study serves not only an identification of current trends, but also, and especially, offers a strategic approach to further investigations.

PMID:39935800 | PMC:PMC11810743 | DOI:10.3389/fmed.2025.1492709

Clin Pharmacol Ther. 2025 Feb 11. doi: 10.1002/cpt.3583. Online ahead of print.

ABSTRACT

We evaluated whether drugs approved for other indications that also target metabolic drivers of Alzheimer's disease and related dementia (ADRD) pathogenesis are associated with delayed onset of ADRD. Using routinely collected healthcare data from two population-based data sources from the US (Medicare) and UK (CPRD), we conducted active comparator, new-user cohort studies. Four alternate analytic and design specifications were implemented: (1) an as-treated follow-up approach, (2) an as-started follow-up approach incorporating a 6-month induction period, (3) incorporating a 6-month symptom to diagnosis period to account for misclassification of ADRD onset, and (4) identifying ADRD through symptomatic prescriptions and diagnosis codes. Of the 10 drug pairs evaluated, hydrochlorothiazide vs. dihydropyridine CCBs showed meaningful reductions in 3 out of 4 analyses that addressed specific biases including informative censoring, reverse causality, and outcome misclassification (pooled hazard ratios [95% confidence intervals] across Medicare and CPRD: 0.81 [0.75-0.88] in Analysis 1, 0.98 [0.92-1.06] in Analysis 2, 0.83 [0.75-0.91] in Analysis 3, 0.75 [0.65-0.85] in Analysis 4). Amiloride vs. triamterene, although less precise, also suggested a potential reduction in risk in 3 out of 4 analyses (0.86 [0.66-1.11] in Analysis 1, 0.98 [0.79-1.23] in Analysis 2, 0.74 [0.54-1.00] in Analysis 3, 0.61 [0.36-1.05] in Analysis 4). Other analyses suggested likely no major differences in risk (probenecid, salbutamol, montelukast, propranolol/carvedilol, and anastrozole) or had limited precision precluding a definitive conclusion (semaglutide, ciloztozol, levetiracetam). Future replication studies should be considered to validate our findings.

PMID:39935003 | DOI:10.1002/cpt.3583

Cancer Metastasis Rev. 2025 Feb 11;44(1):31. doi: 10.1007/s10555-025-10249-3.

ABSTRACT

Cellular plasticity and the ability to avoid terminal differentiation are hallmarks of cancer. Here, we review the evidence that tumor cells themselves can take on properties of neurons of the central nervous system, which can regulate tumor growth and metastasis. We discuss recent evidence that axon guidance molecules and regulators of electrical activity and synaptic transmission, such as ion channels and neurotransmitters, can drive the oncogenic and invasive properties of tumor cells from a range of cancers. We also review how FDA-approved treatments for neurological disorders are being tested in pre-clinical models and clinical trials for repurposing as anti-cancer agents, offering the potential for new therapies for cancer patients that can be accessed more quickly.

PMID:39934425 | DOI:10.1007/s10555-025-10249-3

Cancer Immunol Immunother. 2025 Feb 11;74(3):104. doi: 10.1007/s00262-025-03955-y.

ABSTRACT

The response rates of PD-1/PD-L1 blockade in cancer immunotherapy are relatively low, necessitating the development of novel immune checkpoint inhibitors. Compared with other immune checkpoints, VISTA interacts with its ligand PSGL-1 only under acidic conditions in the tumor microenvironment to suppress the function of CD8+ T cells. On the other hand, drug repurposing offers advantages such as time efficiency and high safety. However, the development of VISTA/PSGL-1 inhibitor based on drug repurposing is still infancy. Here, by screening a library of marketed drugs, we identified Chidamide had a strong binding affinity toward VISTA (KD = 5 nM) and blocked VISTA/PSGL-1 under acidic conditions, thereby significantly enhancing the function of CD8+ T cells and inhibiting the tumor growth in immunocompetent murine CT26 tumor model. This study represents the first discovery of Chidamide as VISTA/PSGL-1 blocker for cancer immunotherapy.

PMID:39932560 | DOI:10.1007/s00262-025-03955-y

Curr Drug Discov Technol. 2025 Feb 10. doi: 10.2174/0115701638364199250123062248. Online ahead of print.

ABSTRACT

Drug design and development are crucial areas of study for chemists and pharmaceutical companies. Nevertheless, the significant expenses, lengthy process, inaccurate delivery, and limited effectiveness present obstacles and barriers that affect the development and exploration of new drugs. Moreover, big and complex datasets from clinical trials, genomics, proteomics, and microarray data also disrupt the drug discovery approach. The integration of Artificial Intelligence (AI) into drug design is both timely and crucial due to several pressing challenges in the pharmaceutical industry, including the escalating costs of drug development, high failure rates in clinical trials, and the in-creasing complexity of disease biology. AI offers innovative solutions to address these challenges, promising to improve the efficiency, precision, and success rates of drug discovery and development. Artificial intelligence (AI) and machine learning (ML) technology are crucial tools in the field of drug discovery and development. More precisely, the field has been revolutionized by the utilization of deep learning (DL) techniques and artificial neural networks (ANNs). DL algorithms & ML have been employed in drug design using various approaches such as physiochemical activity, polyphar-macology, drug repositioning, quantitative structure-activity relationship, pharmacophore modeling, drug monitoring and release, toxicity prediction, ligand-based virtual screening, structure-based vir-tual screening, and peptide synthesis. The use of DL and AI in this field is supported by historical evidence. Furthermore, management strategies, curation, and unconventional data mining aided as-sistance in modern modeling algorithms. In summary, the progress made in artificial intelligence and deep learning algorithms offers a promising opportunity for the development and discovery of effec-tive drugs, ultimately leading to significant benefits for humanity. In this review, several tools and algorithmic programs have been discussed which are being used in drug design along with the de-scriptions of the patents that have been granted for the use of AI in this field, which constitutes the main focus of this review and differentiates it fromalready published materials.

PMID:39931986 | DOI:10.2174/0115701638364199250123062248

Curr Opin Pediatr. 2025 Feb 11. doi: 10.1097/MOP.0000000000001448. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Neonatal and infantile epilepsies represent a diverse group of disorders with significant neurodevelopmental impact, necessitating early diagnosis, and tailored treatment. Recent advancements in genetic research, phenotyping, and therapeutic development have reshaped the understanding and management of these conditions, making this review both timely and relevant.

RECENT FINDINGS: Next-generation sequencing has emerged as a cornerstone for diagnosing neonatal and infantile epilepsies, offering high diagnostic yields and enabling identification of etiology-specific phenotypes. Precision therapies, including sodium channel blockers, ganaxolone, and mammalian target of rapamycin (mTOR) inhibitors, target specific molecular mechanisms. Early initiation of treatment in conditions with a high risk of progressing to epilepsy, like vigabatrin in tuberous sclerosis complex, lower the incidence of infantile spasms and improve developmental outcomes. Drug repurposing has also provided effective options, such as fenfluramine in Dravet syndrome, with promising outcomes. Gene-based therapies, including antisense oligonucleotides and gene replacement, represent the new frontier for addressing the root causes of these disorders.

SUMMARY: The integration of genetic and molecular advancements is transforming the management of neonatal and infantile epilepsies, fostering precision-driven care. Continued research and innovation are essential to refine these strategies, optimize patient outcomes, and establish new standards of care.

PMID:39931929 | DOI:10.1097/MOP.0000000000001448

J Med Virol. 2025 Feb;97(2):e70229. doi: 10.1002/jmv.70229.

ABSTRACT

The main protease (Mpro) of SARS-CoV-2 is an attractive drug target for antivirals, as this enzyme plays a key role in virus replication. Drug repurposing is a promising option for the treatment of coronavirus disease 2019 (COVID-19). Recently, a number of FDA-approved drugs have been identified as Mpro inhibitors, but stringent hit validation is lacking. In this study, we rigorously reevaluated the in vitro inhibition of the Mpro enzyme by repurposed drugs via combined experiments, including the fluorescence resonance energy transfer (FRET) assay, fluorescence polarization (FP) assay, and protease biosensor cleavage assay. Our results from a set of in vitro assays revealed that boceprevir is a potential Mpro inhibitor, but other repurposed drugs, including atazanavir, dipyridamole, entrectinib, ethacridine, glecaprevir, hydroxychloroquine, ivermectin, meisoindigo, pelitinib, raloxifene, roxatidine acetate, saquinavir, teicoplanin, thonzonium bromide, and valacyclovir, are not. Our research highlights that the use of candidate Mpro inhibitors from primary screening warrants further comprehensive studies before the reporting of new findings.

PMID:39930936 | DOI:10.1002/jmv.70229

Sci Rep. 2025 Feb 10;15(1):4979. doi: 10.1038/s41598-025-87676-3.

ABSTRACT

Hepatocellular Carcinoma (HCC) is a malignancy with high mortality rates and limited treatment options. This study aimed to unearth the repurposable potential of FDA-approved drugs against specific genetic targets governing the HCC pathological pathways. The transcriptomics microarray datasets were explored to retrieve the HCC specific differentially expressed genes, and the significant genes were fed in Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database to capture the protein-protein interactions, which were visualized in Cytoscape. This revealed CCNA2, a cell cycle regulator, as a potential target, which mediates its action by interacting with CDK1 and CDK2. Further, with the intention of identifying inhibitors for CDK1 and CDK2, a drug library was created, and the drugs were virtually screened against their respective targets via molecular docking and dynamics studies. This captured the binding affinity of Steviolbioside towards CDK1 and Etravirine and Fludarabine towards CDK2. In vitro, validation confirmed the cytotoxic potential of Etravirine and Fludarabine in Huh-7 cell lines. Further, enzymatic assays, gene expression analysis, and cell cycle analysis signified the anti-proliferative potential of Etravirine in Huh-7 cells via inhibition of CDK2. In this drug repurposing venture, Etravirine, a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV, emerged as a promising candidate for HCC treatment. The findings warrant further preclinical and clinical investigations to ascertain the repurposable potential of Etravirine against HCC, particularly in patients with viral infections.

PMID:39929880 | DOI:10.1038/s41598-025-87676-3

Cell Death Discov. 2025 Feb 10;11(1):56. doi: 10.1038/s41420-025-02328-9.

ABSTRACT

The phenomenon of cell death has garnered significant scientific attention in recent years, emerging as a pivotal area of research. Recently, novel modalities of cellular death and the intricate interplay between them have been unveiled, offering insights into the pathogenesis of various diseases. This comprehensive review delves into the intricate molecular mechanisms, inducers, and inhibitors of the underlying prevalent forms of cell death, including apoptosis, autophagy, ferroptosis, necroptosis, mitophagy, and pyroptosis. Moreover, it elucidates the crosstalk and interconnection among the key pathways or molecular entities associated with these pathways, thereby paving the way for the identification of novel therapeutic targets, disease management strategies, and drug repurposing.

PMID:39929794 | DOI:10.1038/s41420-025-02328-9