Cell Biochem Biophys. 2025 Mar 26. doi: 10.1007/s12013-025-01725-2. Online ahead of print.

ABSTRACT

The kynurenine pathway (KP) plays a pivotal role in dampening the immune response in many types of cancer, including TNBC. The intricate involvement of tryptophan degradation via KP serves as a critical regulator in mediating immunosuppression in the tumor microenvironment. The key enzymes that facilitate this mechanism and contribute to tumor progression are indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). Despite attempts to use navoximod as a dual-specific inhibitor, its poor bioavailability and lack of clinical efficacy have hampered its utility. To date, no FDA-approved drugs have advanced for dual targeting of these enzymes. Therefore, this study aimed to repurpose the approved drugs from the DrugBank database as novel IDO1/TDO inhibitors. Initially, 2588 FDA-approved compounds were screened by employing molecular docking and pharmacokinetic profiling. Subsequently, methods such as MM-GBSA calculations and machine learning based analysis precisely identified 20 potential lead compounds. The resultant compounds were then assessed for various toxicity endpoints and anticancer activity. The PaccMann server revealed potent anticancer activity, with sensitivities ranging from 0.203 to 24.119 μM against MDA-MB-231 TNBC cell lines. Alongside, the interaction profile with critical residues, strongly reinforced DB06292 (Dapagliflozin) as a compelling hit candidate. Finally, the reliability of the result was corroborated through a rigorous 200 ns molecular dynamics simulation, ensuring the stable binding of the hit against the target proteins. Considering the promising outcomes, we speculate that the proposed hit compound holds strong potential for the management of TNBC.

PMID:40133710 | DOI:10.1007/s12013-025-01725-2

Sci Rep. 2025 Mar 25;15(1):10298. doi: 10.1038/s41598-025-95372-5.

ABSTRACT

Drug repositioning utilizes existing drugs for new therapeutic applications, driven by the rapid increase in disease and drug-related data. However, organizing knowledge in this field and integrating the complex and scattered data from multiple systems into a cohesive knowledge network have become urgent problems to address. In this paper, we propose a drug repositioning model based on knowledge graph embedding. The model employs multivariate relational data to embed entities and relationships in a low-dimensional vector space. It also innovatively introduces the attention mechanism into translation and bilinear models, forming new models such as Attranse, Attdismult, and Attrescal. This model's feature extraction does not rely on a single approach, instead, it integrates multiple models and combines their screening results to enhance drug screening quality. The model's effectiveness was validated using COVID-19 data, yielding results consistent with 7 clinically approved drugs for COVID-19 treatment, indicating high accuracy in identifying new drug indications. The successful application of this model to COVID-19 suggests its potential for broader use in emerging infectious diseases and complex conditions, providing valuable insights for future drug development.

PMID:40133375 | DOI:10.1038/s41598-025-95372-5

PeerJ Comput Sci. 2025 Mar 5;11:e2664. doi: 10.7717/peerj-cs.2664. eCollection 2025.

ABSTRACT

The internet has been inundated with an ocean of information, and hence, information retrieval systems are failing to provide optimal results to the user. In order to meet the challenge, query expansion techniques have emerged as a game-changer and are improving the results of information retrieval significantly. Of late, semantic query expansion techniques have attracted increased interest among researchers since these techniques offer more pertinent and practical results to the users. These allow the user to retrieve more meaningful and useful information from the web. Currently, few research works provide a comprehensive review on semantic query expansion; usually, they cannot provide a full view on recent advances, diversified data application, and practical challenges. Therefore, it is imperative to go deep in review in order to explain these advances and assist researchers with concrete insights for future development. This article represents the comprehensive review of the query expansion methods, with a particular emphasis on semantic approaches. It overviews the recent frameworks that have been developed within a period of 2015-2024 and reviews the limitations of each approach. Further, it discusses challenges that are inherent in the semantic query expansion field and identifies some future research directions. This article emphasizes that the linguistic approach is the most effective and flexible direction for researchers to follow, while the ontology approach better suits domain-specific search applications. This, in turn, means that development of the ontology field may further open new perspectives for semantic query expansion. Moreover, by employing artificial intelligence (AI) and making most of the query context without relying on user intervention, improvements toward the optimal expanded query can be achieved.

PMID:40134880 | PMC:PMC11935759 | DOI:10.7717/peerj-cs.2664

Am J Psychiatry. 2025 Mar 26:appiajp20240295. doi: 10.1176/appi.ajp.20240295. Online ahead of print.

ABSTRACT

OBJECTIVE: The authors provide recommendations on incorporating recent advances in psychiatric genetics into clinical practice for mental health clinicians.

METHOD: The International Society for Psychiatric Genetics Education Committee met monthly to come to a consensus on priority topics in psychiatric genetics. Topics were then assigned to small teams of subspecialty experts to summarize the current knowledge base and create an illustrative clinical case. Topics included, familial aggregation, common and rare genetic variants, epigenetics, gene-environment interactions, pharmacogenomics, genetic counseling, and ethical and social implications. Each section was reviewed and revised by all committee members and then finalized by the Committee Chair.

RESULTS: Key findings highlight the importance of understanding the genetic architecture of psychiatric disorders, the potential applications of genetic information in risk assessment, diagnosis, treatment selection, and patient education, as well as the ethical and social considerations surrounding the use of genetic data. The committee emphasizes the need for a nuanced approach that integrates genetic factors with environmental and experiential factors in a holistic model of care.

CONCLUSION: As psychiatric genetics continues to evolve rapidly, mental health clinicians must stay informed about the latest findings and their clinical implications. Ongoing education, collaboration with genetics professionals, and effective communication strategies are crucial to harness the power of genetics while avoiding potential pitfalls such as genetic determinism and stigma. The committee recommends a balanced perspective that recognizes the complex interplay of genetic and non-genetic factors in shaping mental health outcomes.

PMID:40134266 | DOI:10.1176/appi.ajp.20240295

Nat Commun. 2025 Mar 25;16(1):2913. doi: 10.1038/s41467-025-58152-3.

ABSTRACT

Electronic health records (EHRs) coupled with large-scale biobanks offer great promises to unravel the genetic underpinnings of treatment efficacy. However, medication-induced biomarker trajectories stemming from such records remain poorly studied. Here, we extract clinical and medication prescription data from EHRs and conduct GWAS and rare variant burden tests in the UK Biobank (discovery) and the All of Us program (replication) on ten cardiometabolic drug response outcomes including lipid response to statins, HbA1c response to metformin and blood pressure response to antihypertensives (N = 932-28,880). Our discovery analyses in participants of European ancestry recover previously reported pharmacogenetic signals at genome-wide significance level (APOE, LPA and SLCO1B1) and a novel rare variant association in GIMAP5 with HbA1c response to metformin. Importantly, these associations are treatment-specific and not associated with biomarker progression in medication-naive individuals. We also found polygenic risk scores to predict drug response, though they explained less than 2% of the variance. In summary, we present an EHR-based framework to study the genetics of drug response and systematically investigated the common and rare pharmacogenetic contribution to cardiometabolic drug response phenotypes in 41,732 UK Biobank and 14,277 All of Us participants.

PMID:40133288 | DOI:10.1038/s41467-025-58152-3

Respirol Case Rep. 2025 Mar 24;13(3):e70146. doi: 10.1002/rcr2.70146. eCollection 2025 Mar.

ABSTRACT

Hepatotoxicity due to Elexacaftor/Tezacaftor/Ivacaftor (ETI) use has been well documented. There are no dose adjustments or increased-frequency monitoring algorithms recommended for people who experience elevated transaminases without cirrhosis, only suggested treatment interruption or withdrawal depending on the severity of the derangement. Here we describe a patient with non-cirrhotic hepatic steatosis who experienced persistently elevated liver function tests due to modulator therapy but demonstrated a remarkable response to a notably low dose of ETI.

PMID:40134928 | PMC:PMC11932953 | DOI:10.1002/rcr2.70146

Adv Healthc Mater. 2025 Mar 26:e2500681. doi: 10.1002/adhm.202500681. Online ahead of print.

ABSTRACT

The extracellular matrix (ECM) plays a pivotal role in immunomodulation, providing structural and biochemical cues that shape immune cell function. In pathological conditions like cancer and chronic inflammation, dysregulated remodeling often results in altered ECM composition and architecture, with fibrillar alignment being a hallmark linked to disease progression. Here, how ECM alignment influences dendritic cell (DC) behavior using 3D biomimetic collagen matrices with controlled fibril anisotropy is investigated. This results show that immature DCs in aligned matrices exhibited increased expression of CD86 and HLA-DR with elevated secretion of CXCL8 and CCL2 chemokines, which may enhance immune cell recruitment. However, transcriptomic and metabolomic analysis revealed significant downregulation of oxidative phosphorylation and an insufficient compensatory shift toward glycolysis, resulting in reduced ATP production. This metabolic constraint correlated with impaired/reduced DC migratory speed and distance. In contrast, mature DCs displayed minimal sensitivity to ECM alignment, maintaining uniform differentiation and functional profiles across matrix conditions. T-cell coculture experiments revealed that ECM alignment dampens T-cell activation and proliferation, likely through direct modulation of T-cell behavior. These findings highlight the stage-specific effects of ECM alignment on DC function, highlighting its role in DC immunomodulation, with implications for therapeutic development in cancer and other pathological contexts.

PMID:40134371 | DOI:10.1002/adhm.202500681

Nat Med. 2025 Mar 25. doi: 10.1038/s41591-025-03526-9. Online ahead of print.

ABSTRACT

The 2022 global mpox epidemic was caused by transmission of MPXV clade IIb, lineage B.1 through sexual contact networks, with New York City (NYC) experiencing the first and largest outbreak in the United States. By performing phylogeographic analysis of MPXV genomes sampled from 757 individuals in NYC between April 2022 and April 2023, and 3,287 MPXV genomes sampled around the world, we identify over 200 introductions of MPXV into NYC with at least 84 leading to onward transmission. These infections primarily occurred among men who have sex with men, transgender women and nonbinary individuals. Through a comparative analysis with HIV in NYC, we find that both MPXV and HIV genomic cluster sizes are best fit by scale-free distributions, and that people in MPXV clusters are more likely to have previously received an HIV diagnosis and be a member of a recently growing HIV transmission cluster. We model MPXV transmission through sexual contact networks and show that highly connected individuals would be disproportionately infected at the start of an epidemic, which would likely result in the exhaustion of the most densely connected parts of the network, and, therefore, explain the rapid expansion and decline of the NYC outbreak. By coupling the genomic epidemiology of MPXV and HIV with epidemic modeling, we demonstrate that the transmission dynamics of MPXV in NYC can be understood by general principles of sexually transmitted pathogens.

PMID:40133528 | DOI:10.1038/s41591-025-03526-9

Sci Rep. 2025 Mar 25;15(1):10296. doi: 10.1038/s41598-025-88571-7.

ABSTRACT

Lignin is composed of phenylpropanoid monomers linked by ether and carbon-carbon bonds to form a complex heterogeneous structure. Bond-specific studies of lignin-modifying enzymes (LMEs; e.g., laccases and peroxidases) are limited by the polymerization of model lignin substrates and repolymerization of cleavage products. Here we present a high throughput platform to screen LME activities on four tagged model lignin compounds that represent the β-O-4', β-β', 5-5', and 4-O-5' linkages in lignin. We utilized nanostructure-initiator mass spectrometry (NIMS) and model lignin compounds with tags containing perfluorinated and cationic moieties, which effectively limit polymerization and condensation of the substrates and their degrading products. Sub-microliter sample droplets were printed on the NIMS chip with a novel robotics method. This rapid platform enabled characterization of LMEs across a range of pH 3-10 and relative quantification of modified (typically oxidized), cleaved, and polymerized products. All tested enzymes oxidized the four substrates and cleaved the β-O-4' and β-β' substrates to monomeric products. We discovered that the active pH range depended on both the substrate and the enzyme type. This has important applications for biomass conversion to biofuels and bioproducts, where the relative percentages of different bond types in lignin varies depending on feedstock and chemical pretreatment methods.

PMID:40133407 | DOI:10.1038/s41598-025-88571-7

Cell Discov. 2025 Mar 25;11(1):31. doi: 10.1038/s41421-025-00771-7.

ABSTRACT

An outbreak of mpox has triggered concerns regarding the adequacy of intervention strategies. Passive immunity conferred by neutralizing antibodies exhibits potential in the prophylaxis and treatment of orthopoxvirus infections. Despite this, the investigations of effective antibody therapeutics have been hindered by the varied nature of orthopoxvirus envelope proteins and the intricate mechanisms underpinning viral invasion. Our study involves the production of six mpox virus (MPXV) envelope proteins, which are relatively conservative and considered to play a role in the neutralization process. We employed a synthetic nanobody (Nb) library to derive a broad array of specific Nbs against these viral proteins. We identified a cross-reactive Nb, termed M1R-01, which targets the M1R protein and effectively neutralizes both vaccinia virus (VACV) and MPXV. Notably, the M1R-01-based antibody strategy provided optimal protection against a lethal VACV challenge in mice. Additionally, we determined the crystal structure of the M1R-Nb complex, uncovering novel binding attributes of M1R-01 and detailed conformational epitope information. This work provides a promising candidate for the therapy and prophylaxis of orthopoxvirus infections.

PMID:40133273 | DOI:10.1038/s41421-025-00771-7

Nat Commun. 2025 Mar 25;16(1):2923. doi: 10.1038/s41467-025-58035-7.

ABSTRACT

Macroautophagy/autophagy is a key catabolic-recycling pathway that can selectively target damaged organelles or invading pathogens for degradation. The selective autophagic degradation of the endoplasmic reticulum (hereafter referred to as ER-phagy) is a homeostatic mechanism, controlling ER size, the removal of misfolded protein aggregates, and organelle damage. ER-phagy can also be stimulated by pathogen infection. However, the link between ER-phagy and bacterial infection remains poorly understood, as are the mechanisms evolved by pathogens to escape the effects of ER-phagy. Here, we show that Salmonella enterica serovar Typhimurium inhibits ER-phagy by targeting the ER-phagy receptor FAM134B, leading to a pronounced increase in Salmonella burden after invasion. Salmonella prevents FAM134B oligomerization, which is required for efficient ER-phagy. FAM134B knock-out raises intracellular Salmonella number, while FAM134B activation reduces Salmonella burden. Additionally, we found that Salmonella targets FAM134B through the bacterial effector SopF to enhance intracellular survival through ER-phagy inhibition. Furthermore, FAM134B knock-out mice infected with Salmonella presented severe intestinal damage and increased bacterial burden. These results provide mechanistic insight into the interplay between ER-phagy and bacterial infection, highlighting a key role for FAM134B in innate immunity.

PMID:40133256 | DOI:10.1038/s41467-025-58035-7

Front Pharmacol. 2025 Mar 11;16:1508276. doi: 10.3389/fphar.2025.1508276. eCollection 2025.

ABSTRACT

BACKGROUND: Effective therapies for pulmonary fibrosis caused by coronavirus disease (COVID-19) and other etiologies are lacking. Our previous studies demonstrated that Fuzheng Huayu tablet (FZHY), a traditional Chinese medicine known for its anti-liver fibrotic properties, can improve lung function in patients with chronic obstructive pulmonary disease and attenuate bleomycin-induced pulmonary fibrosis in rats.

PURPOSE: This study aimed to evaluate the efficacy and safety of FZHY in post-COVID-19 pulmonary fibrosis.

METHODS: A multi-center, randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the efficacy of a 24-week treatment with FZHY, combined with vitamin C and respiratory function rehabilitation, for treating pulmonary fibrosis in discharged convalescent COVID-19 patients. The primary outcome was the regression rate of pulmonary fibrosis assessed by the high-resolution computed tomography scores and lung function improvement (forced vital capacity [FVC], forced expiratory volume in one second [FEV1], and FEV1/FVC) after 24 weeks. Secondary outcomes included the 6-min walk distance, improvement in pulmonary inflammation, clinical symptoms, and quality of life.

RESULTS: This study included 142 patients, who were randomized to the FZHY (n = 72) and placebo groups (n = 70). By week 24, the regression rates of pulmonary fibrosis in the FZHY and placebo groups were 71.2% and 49.2%, respectively (p = 0.01). Limited spirometry data revealed higher FEV1/FVC in the FZHY group than in the placebo group at week 8 ([87.7 ± 7.2] % vs. [82.7 ± 6.9] %; p = 0.018). The regression rates in pulmonary inflammation in the FZHY and placebo groups were 83.8% and 68.8%, respectively (p = 0.04). At week 4, the increase in 6-min walking distance was greater in the FZHY group than in the placebo group ([41.4 ± 64.1] m vs. [21.8 ± 50.3] m; p = 0.05). However, no significant differences were observed between the groups in the improvement rate of clinical symptoms, quality of life-BREF, patient health questionnaire-9, or generalized anxiety disorder-7 scores (p > 0.05). No drug-related adverse events were reported in the FZHY group.

CONCLUSION: FZHY attenuates post-COVID-19 pulmonary fibrosis, with good safety profiles.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04279197, identifier NCT04279197.

PMID:40135237 | PMC:PMC11933019 | DOI:10.3389/fphar.2025.1508276

Case Rep Anesthesiol. 2025 Mar 18;2025:1303993. doi: 10.1155/cria/1303993. eCollection 2025.

ABSTRACT

Acute liver injury can be precipitated by several factors perioperatively. One of the rare factors identified intraoperatively is the use of sevoflurane, an inhalational anesthetic agent which can cause significant acute hepatotoxicity. The report presents a case of acute liver injury followed by graft loss in a patient who underwent kidney transplantation. The patient developed several complications which resulted in graft loss. Close postoperative monitoring of patients following kidney transplantation is crucial. The case supports the current literature describing sevoflurane as a hepatotoxic agent. Medication side effects should be closely monitored both intraoperatively and postoperatively in those with renal dysfunction.

PMID:40134944 | PMC:PMC11936524 | DOI:10.1155/cria/1303993

Sci Rep. 2025 Mar 26;15(1):10359. doi: 10.1038/s41598-025-95021-x.

ABSTRACT

To use the FDA Adverse Event Reporting System (FAERS) database to identify drugs associated with orthostatic hypotension. Adverse event reports of orthostatic hypotension from Q1 2004 to Q3 2024 were obtained from the FAERS and JADER databases. We employed algorithms such as the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) for signal detection. JADER database was used to validate the findings from FAERS analysis. We identified 15,737 adverse events associated with orthostatic hypotension, involving 15,480 patients for analysis. The patient demographic included 6,745 males (43.5%) and 7,248 females (46.8%), with the largest group comprising adults over 65 years (7,654 cases, 49.4%). The three drugs with the highest ROR risk signals were terazosin [ROR (95% CI): 153.96 (124.57-190.28)], rasagiline [ROR (95% CI): 37.46 (29.99-46.78)], and doxazosin [ROR (95% CI): 37.06 (31.32-43.86)]. Apomorphine, abalopatine and levodopa were associated with the shortest onset time of orthostatic hypotension. Most of the signal detection results from the FAERS database were verified in the JADER database. Drugs associated with orthostatic hypertension still focused on cardiovascular and nervous system drugs. This study employed the FAERS database to identify 33 drugs that may be potentially linked to orthostatic hypotension. Medical workers should remain vigilant regarding the risk of these drugs causing orthostatic hypotension.

PMID:40133436 | DOI:10.1038/s41598-025-95021-x

Metabolites. 2025 Feb 27;15(3):159. doi: 10.3390/metabo15030159.

ABSTRACT

Background: Aging is characterized by shared cellular and molecular processes, and aging-related diseases might co-exist in a cluster of comorbidities, particularly in vulnerable individuals whose phenotype meets the criteria for frailty. Whilst the multidimensional definition of frailty is still controversial, there is an increasing understanding of the common pathways linking metabolic syndrome, cognitive decline, and sarcopenia, frequent conditions in frail elderly patients. Methods: We performed a systematic search in the electronic databases Cochrane Library and PubMed and included preclinical studies, cohort and observational studies, and trials. Discussion: Metabolic syndrome markers, such as insulin resistance and the triglyceride/HDL C ratio, correlate with early cognitive impairment. Insulin resistance is a cause of synaptic dysfunction and neurodegeneration. Conversely, fasting and fasting-mimicking agents promote neuronal resilience by enhancing mitochondrial efficiency, autophagy, and neurogenesis. Proteins acting as cellular metabolic sensors, such as SIRT1, play a pivotal role in aging, neuroprotection, and metabolic health. In AD, β-amyloid accumulation and hyperphosphorylated tau in neurofibrillary tangles can cause metabolic reprogramming in brain cells, shifting from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect in cancer. The interrelation of metabolic syndrome, sarcopenia, and cognitive decline suggests that targeting these shared metabolic pathways could mitigate all the conditions. Pharmacological interventions, including GLP-1 receptor agonists, metformin, and SIRT 1 inducers, demonstrated neuroprotective effects in animals and some preliminary clinical models. Conclusions: These findings encourage further research on the prevention and treatment of neurodegenerative diseases as well as the drug-repurposing potential of molecules currently approved for diabetes, dyslipidemia, and metabolic syndrome.

PMID:40137124 | DOI:10.3390/metabo15030159

Metabolites. 2025 Feb 25;15(3):156. doi: 10.3390/metabo15030156.

ABSTRACT

BACKGROUND/OBJECTIVES: Neutrophil cells' lysis forms the extracellular traps (NETs) to counter the foreign body during insults to the body. Peptidyl arginine deiminase (PAD) participates in this process and is then released into the extracellular fluid with the lysed cell components. In some diseases, patients with abnormal function of PADs, especially PAD 4, tend to form autoantibodies against the abnormal citrullinated proteins that are the result of PAD activity on arginine side chains. Those antibodies, which are highly distinct in RA, are distinctly anti-citrullinated protein antibodies (ACPA). This study used an in-silico drug repurposing approach of FDA-approved medications to identify potential alternative medications that can inhibit this process and address solutions to the current limitations of existing therapies.

METHODS: We utilized Maestro Schrödinger as a computational tool for preparing and docking simulations on the PAD 4 enzyme crystal structure that is retrieved from RCSB Protein Data Bank (PDB ID: 4X8G) while the docked FDA-approved medications are obtained from the Zinc 15 database. The protein was bound to GSK 199-an investigational compound-as a positive control for the docked molecules. Preparation of the protein was performed by Schrödinger Protein Preparation Wizard tool. Binding pocket determination was performed by Glide software (Schrödinger Release 2021-3:Schrödinger, LLC., New York, NY, USA, 2021). and validation of molecular docking was carried out through the redocking of GSK 199 and superimposition. After that, standard and induced fit docking were performed.

RESULTS/CONCLUSIONS: Among the four obtained hits Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol, which showed the highest XP scores providing favorable binding interactions. The induced-fit docking (IFD) results displayed the strong binding affinities of Ioversol, Pemetrexed, Leucovorin, Chlordiazepoxide in the order IFD values -11.617, -10.599, -10.521, -9.988, respectively. This research investigates Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol as potential repurposing agents in the treatment of rheumatoid arthritis (RA) as they are identified as PAD4 inhibitors.

PMID:40137121 | DOI:10.3390/metabo15030156

Curr Issues Mol Biol. 2025 Feb 26;47(3):153. doi: 10.3390/cimb47030153.

ABSTRACT

Metastatic endometrial cancer continues to be a common cause of death as of 2024, even after maximal use of all currently available standard treatments. To address this problem of metastatic cancer generally in 2025, the drug repurposing movement within oncology identifies medicines in common general medical use that have clinical or preclinical experimental data indicating that they interfere with or inhibit a specific growth driving element identified in a given cancer. The drug repurposing movement within oncology also uses data from large scale in vitro screens of thousands of drugs, looking for simple empirical growth inhibition in a given cancer type. This paper outlines the data showing that five drugs from general medical practice meet these evidence criteria for inhibition of endometrial cancer growth, the EC5 regimen. The EC5 regimen uses the osteoporosis treatment drug, alendronate; the analgesic drug, celecoxib; the antifungal drug, itraconazole; the sleep aid, ramelteon; and the cholesterol lowering drug, simvastatin. Side effects seen with these drugs are usually minimal and easily tolerated by patients.

PMID:40136407 | DOI:10.3390/cimb47030153

mBio. 2025 Mar 26:e0020525. doi: 10.1128/mbio.00205-25. Online ahead of print.

ABSTRACT

Coccidioidomycosis or valley fever is a treatment-limited fungal infection endemic to the alkaline deserts of North and South America for which two classes of antifungals are typically used: the polyenes and the triazoles. In light of the limited usefulness of the echinocandins and a growing trend of azole resistance, it is essential that we identify novel antifungals. In this study, we have developed and optimized a screening methodology for identifying potential antifungals effective against Coccidioides spherule initials using a metabolic assay, used it to screen four diverse drug libraries with limited drug overlap, and established safety and efficacy data for a majority of the compounds, including the Broad Repurposing Hub, Prestwick Chemicals 1520, Selleck L8200 Anti-parasitic, and MedChemExpress CNS Penetrants libraries. Hits were defined as compounds with strong metabolic inhibition (≥70%), which were significantly different compared to the median plate readout (B-scores ≤ -3). We identified 30 promising hits and found 12 compounds exhibiting half-maximal inhibitory concentrations below 6 µM. Among these, oxethazaine, niclosamide ethanolamine, 10058-F4, niclosamide (NIC), and pentamidine isethionate showed synergy with amphotericin B, suggesting their potential use in combination therapy. Further assessment of lead compounds' effects on spherules was conducted by image flow cytometry. Additionally, we explored the potential to use an attenuated, Biosafety Level 2 containment mutant, C. posadasii ∆cts2/∆ard1/∆cts3 (∆T), as a surrogate model for drug screening. Overall, our findings provide a foundation for future research focused on screening and developing novel coccidioidomycosis treatments.IMPORTANCEThe antifungal treatment arsenal is especially limited against Coccidioides. Due to toxicity concerns, amphotericin B is generally reserved for triazole-recalcitrant infections. Recent laboratory susceptibility tests show an increase in fluconazole resistance, highlighting a need for new treatments. We have developed a large-scale metabolic screening assay under Biosafety Level 3 containment to identify existing drugs with novel activity against Coccidioides spherules. This drug-repurposing approach represents a convenient and cost-effective strategy to increase the available antifungals effective against these infections.

PMID:40135873 | DOI:10.1128/mbio.00205-25

J Biomol Struct Dyn. 2025 Mar 26:1-12. doi: 10.1080/07391102.2025.2483963. Online ahead of print.

ABSTRACT

Poly (ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that plays a pivotal role in DNA repair and has emerged as a promising target for cancer therapy. Repurposing existing FDA-approved drugs for PARP1 inhibition offers an accelerated route to drug discovery. Here, we present an integrated approach to drug repurposing for PARP1 inhibition while utilizing an integrated approach involving structure-based virtual screening and molecular dynamics (MD) simulations. First, a curated library of 3648 FDA-approved drugs from DrugBank was screened to identify potential candidates capable of binding to the PARP1. Our study reveals a subset of drug molecules with favorable binding profiles and stable interactions within the PARP1 active site. The standout candidate, Nilotinib, was selected based on its drug profile and subjected to a detailed analysis, including interaction studies and 500 ns all-atom MD simulations. By integrating multiple computational approaches, we provide a rational framework for the selection of Nilotinib, demonstrating its PARP1 binding features and potential for therapeutic development after further experimentation. This study highlights the power of computational methods in accelerating drug repurposing efforts, offering an efficient strategy for identifying novel therapeutic options for PARP1-associated diseases.

PMID:40135853 | DOI:10.1080/07391102.2025.2483963

Clin Pract. 2025 Mar 7;15(3):54. doi: 10.3390/clinpract15030054.

ABSTRACT

Background/Objectives: During the last decade, there has been an increased interest in phenolic compound-rich natural products as natural therapies for regulating the molecular pathways behind central obesity and associated metabolic disorders. The present scoping review presents the outcomes of clinical and preclinical studies examining the anti-obesity effects of high phenolic extra virgin olive oil (HP-EVOO) and its possible underlying molecular mechanisms. Methods: Studies published between 2014 and 2024 were searched via MEDLINE, Scopus, Cochrane, the Web of Science, Semantic Scholar, Google Scholar, Science.gov, and Clinicaltrials.gov databases. A combination of keywords and Boolean logic was used to search throughout the last decade in all databases, including "hyperglycemia" or "hypertension" or "metabolic syndrome" or "dyslipidemia" or "hyperlipidemia" or "hypoglycemia" or "obesity" or "macrovascular diabetic complications" or "microvascular diabetic complications" or "cardiovascular disease" or "overweight" or "insulin sensitivity" or "insulin resistance" and "extra virgin olive oil" or "high phenolic olive oil" and "human" or "animal model". Results: The 10-year literature survey identified 21 studies in both animal models and humans, indicating that HP-EVOO improves inflammation, glycemic control, oxidative stress and endothelial function, potentially protecting against metabolic syndrome, hypertension and type 2 diabetes, even compared to EVOO. Moreover, HP-EVOO's antiplatelet effect and improvement in HDL functionality reduce cardiovascular risk. Conclusions: The evidence presented in this study demonstrates that HP-EVOO represents an effective preventive and therapeutic dietary approach to cardiometabolic diseases.

PMID:40136590 | DOI:10.3390/clinpract15030054