Int J Mol Sci. 2025 Jun 6;26(12):5445. doi: 10.3390/ijms26125445.

ABSTRACT

Acute Myeloid Leukemia (LAML) is a life-threatening hematological malignancy, and the DEAD-box helicase 3 X-linked (DDX3X) gene is a potential yet underexplored target gene for LAML. Biomolecules derived from medicinal plants like Aerva javanica offer a great source of therapeutic candidates. This study aimed to investigate the role of DDX3X in LAML and identify plant-derived biomolecules that could inhibit DDX3X using computational approaches. Pan-cancer mutational profiling, a transcriptomic analysis, survival, protein-protein interaction networks, and a principal component analysis (PCA) were employed to elucidate functional associations and transcriptomic divergence. Subsequently, biomolecules from A. javanica were subjected to in silico screening using molecular docking and ADMET profiling. The docking protocol was validated using RK-33, a known DDX3X inhibitor. DDX3X was found to be linked to key leukemogenic pathways, including Wnt/β-catenin and MAPK signaling, indicating it to be a potential target. Molecular docking of A. javanica compounds revealed CIDs 15559724, 5490003, and 74819331 as potent DDX3X inhibitors with strong binding affinity and favorable pharmacokinetic and toxicity profiles compared to RK-33. This study highlights the importance of DDX3X in LAML pathogenesis and suggests targeting it using plant-derived inhibitors, which may require further in vitro and in vivo validation.

PMID:40564907 | DOI:10.3390/ijms26125445

Animals (Basel). 2025 Jun 19;15(12):1811. doi: 10.3390/ani15121811.

ABSTRACT

This preclinical study investigated the efficacy and safety of fenbendazole, a broad-spectrum benzimidazole anthelmintic, for the treatment of Gyrodactylus kobayashii in goldfish (Carassius auratus). In vivo bath treatments demonstrated potent, dose-dependent anthelmintic efficacy, achieving 98.58% efficacy at a concentration of 0.02 mg/L and a 48 h EC50 of 0.006 mg/L. A short-duration (6 h) bath at 0.06 mg/L, followed by an 18 h recovery period in dechlorinated water, resulted in complete parasite elimination. However, acute toxicity assay indicated a relatively narrow safety margin for prolonged bath treatments, with a 96 h LC50 of 0.039 mg/L, highlighting the need for caution when employing extended bath treatments. Oral administration of fenbendazole at 20 mg/kg body weight for three consecutive days resulted in an efficacy of 83.35%, which increased to 96.28% by seven days post-treatment. Safety evaluations revealed this regimen induced transient oxidative stress and mild, reversible histopathological alterations in the liver and gills. Biochemical and histological markers indicated a recovery trend, approaching baseline levels by 15 days post-treatment. These findings suggested that oral fenbendazole is an effective and relatively safe anthelmintic treatment against G. kobayashii in goldfish. This study underscores the potential of drug repurposing as an effective strategy for developing novel anthelmintic agents in aquaculture.

PMID:40564366 | DOI:10.3390/ani15121811

Brain Sci. 2025 Jun 13;15(6):637. doi: 10.3390/brainsci15060637.

ABSTRACT

BACKGROUND: Glioblastoma (GBM) remains a significant challenge in oncology due to its resistance to standard treatments including temozolomide. This study aimed to develop and validate an integrated model for predicting GBM sensitivity to alternative chemotherapeutics and identifying new drugs and combinations with therapeutic potential.

RESEARCH DESIGN AND METHODS: We analyzed drug sensitivity data for 272 compounds from CancerRxTissue and employed in silico algorithms to assess blood-brain barrier permeability. The model was used to predict GBM sensitivity to various drugs, which was then validated using GBM cellular models. Alternative drugs targeting overexpressed and negative prognostic biomarkers in GBM were experimentally validated.

RESULTS: The model predicted that GBM is more sensitive to Etoposide and Cisplatin compared to Temozolomide, which was confirmed by experimental validation in GBM cells. We also identified novel drugs with high predicted sensitivity in GBM. Daporinad, a NAMPT inhibitor that permeates the blood-brain barrier was selected for further preclinical evaluation. This evaluation supported the in silico predictions of high potential efficacy and safety in GBM.

CONCLUSIONS: Our findings using different cellular models suggest that this computational prediction model could constitute a valuable tool for drug repurposing in GBM and potentially in other tumors, which could accelerate the development of more effective cancer treatments.

PMID:40563807 | DOI:10.3390/brainsci15060637

Pharmacol Ther. 2025 Jun 23:108903. doi: 10.1016/j.pharmthera.2025.108903. Online ahead of print.

ABSTRACT

In recent years, the emergence of new viruses and the re-emergence of old ones have posed a significant challenge to global Public Health. Viruses characterised by high morbidity and mortality rates have the potential to spread rapidly, causing large epidemic outbreaks and even pandemics. In this context, viral infections still lacking effective treatments represent a serious threat to human health. For this reason, sustained development and implementation of countermeasures are urgently needed against these infections, as they are for diseases for which the emergence of drug resistance is rapidly increasing. In this regard, compared to de novo drug discovery, drug repurposing could represent a highly efficient, faster, and more affordable strategy to develop new drugs. Here, we provide a comprehensive review of the different experimental and computational approaches used for drug repurposing and discuss their advantages and limitations in comparison with other drug discovery strategies. In addition, as an example of the successful application of drug repurposing, we present the case of approved antifungal drugs that could be repurposed to counteract viral infections.

PMID:40562104 | DOI:10.1016/j.pharmthera.2025.108903

PLoS One. 2025 Jun 25;20(6):e0325707. doi: 10.1371/journal.pone.0325707. eCollection 2025.

ABSTRACT

The global pandemic, due to the emergence of COVID-19, has created a public health crisis. It has a huge morbidity rate that was never comprehended in the recent decades. Despite numerous efforts, potent antiviral drugs are lacking. Repurposing of drugs presents a low-cost and rapid solution for finding new drugs by exploiting known drugs. In this study, we employed an integrated In-Silico approach using molecular docking and machine learning regression models to explore the potential inhibitors against key proteins of SARS-CoV-2. A library of 5903 drugs from the ZINC database was retrieved and screened against three crucial viral targets: Spike glycoprotein (7LM9), main protease 3CLpro (7JSU), and Nucleocapsid protein (7DE1). Binding affinities were predicted by using molecular docking, and subsequent predictive regression models, Decision Tree Regression (DTR), Gradient Boosting, XGBoost, Extra Trees, KNNR, and MLP, were constructed employing MACCS molecular fingerprints. Among them, the DTR model had better predictive performance, as indicated by the highest R² and lowest RMSE. The highest ranked compounds possessed good binding affinities (-12.6 to -19.7 kcal/mol) and favorable pharmacokinetics. Importantly, five novel candidate compounds, namely ZINC003873365, ZINC085432544, ZINC008214470, ZINC085536956, and ZINC261494640, had multi-target potential and optimal binding interaction. This computational analysis yields useful information for lead prioritization and sets the stage for additional in vitro and in vivo confirmation of these drug candidates to combat COVID-19.

PMID:40561178 | DOI:10.1371/journal.pone.0325707

Life Sci. 2025 Jun 22:123814. doi: 10.1016/j.lfs.2025.123814. Online ahead of print.

ABSTRACT

Overexpression of the spleen tyrosine kinase (SYK) has been found associated with different cancer types. Despite the investigation of inhibitors of SYK including fostamatinib, entospletinib, cerdulatinib, and TAK-659 for cancer therapy, their lack of specificity and potential off-target effects remain significant concerns. Addressing the need for targeted and non-toxic SYK inhibitors, this study integrates machine learning with structure-based drug design. Using bioactivity data, we employed machine learning algorithms random forest, to screen an FDA-approved drug library. Molecular docking and dynamics simulations were then conducted to assess binding affinities and stability of identified compounds. Rifabutin, darunavir, and sildenafil were found as promising SYK inhibitors, showing strong interactions and stable conformations. Analysis of RMSD, RMSF, RoG, hydrogen bonding, PCA, and MMGBSA/MM-PBSA supported their efficacy as safer alternatives to current inhibitors. Our findings underscore the value of computational methods in drug discovery and advocate for further experimental validation of these compounds as SYK-targeted therapies. This study aims to advance the development of more effective and safer treatments for cancers associated with SYK overexpression.

PMID:40555292 | DOI:10.1016/j.lfs.2025.123814

Gynecol Oncol. 2025 Jun 18;199:57-63. doi: 10.1016/j.ygyno.2025.06.012. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and all-cause mortality in women with ovarian cancer, using real-world data from a global federated health database.

METHODS: We conducted a retrospective cohort study using the TriNetX global health records network. Female patients diagnosed with ovarian cancer between 2014 and 2023 were included. Patients were divided into two cohorts based on GLP-1RA exposure. A 1:1 propensity score matching was performed to balance demographics, comorbidities, medications, and cancer stage. Kaplan-Meier survival curves and Cox proportional hazards models were used to estimate overall survival. Subgroup and sensitivity analyses were performed.

RESULTS: After matching, 1023 patients were included in each group. GLP-1RA users had a significantly lower all-cause mortality rate compared with non-users (7.94 % vs. 19.71 %; hazard ratio [HR], 0.45; 95 % confidence intervals [CI], 0.35-0.59; log-rank P < 0.001). The survival benefit was consistent across most subgroups, including patients receiving chemotherapy or Poly(ADP-ribose) polymerase (PARP) inhibitors. No significant benefit was observed in patients with heart failure or chronic kidney disease. Sensitivity analysis supports the primary analysis.

CONCLUSIONS: Use of GLP-1RA was associated with substantially improved overall survival in women with ovarian cancer. Given their widespread clinical use and favorable safety profile, GLP-1RA may represent a promising adjunctive strategy for improving outcomes in women with ovarian cancer, particularly those with coexisting metabolic disorders. Further prospective studies are warranted.

PMID:40554181 | DOI:10.1016/j.ygyno.2025.06.012

Methods Mol Biol. 2025;2952:169-192. doi: 10.1007/978-1-0716-4690-8_10.

ABSTRACT

Artificial intelligence is emerging as an important domain in the scientific field with the potential to provide advancements in molecular biology and cell engineering to improve the quality of life of human beings. The convergence of AI and related technologies linked with biology can lower the technical and knowledge barriers in numerous areas, such as diagnostics and forecasting. Artificial intelligence (AI) and machine learning tools are revolutionizing life science research and biomedical applications. Examples include understanding ecosystems across space and time, designing new drugs, deciphering molecular data and biomedical images, and predicting the 3D structures of proteins. Cellular engineering is a new field that has arisen as biomedical engineering has moved from the organ and tissue level to the cellular and subcellular level. Through the automated and programmatically enabled finding of tissue-level patterns and design principles, AI presents a radically new paradigm for tissue engineering research.Molecular biology delves into the intricate mechanisms governing life at its most fundamental level-the molecular scale, exploring the structure, function, and interactions of biological molecules such as DNA, RNA, proteins, and lipids. AI has spearheaded remarkable advancements in molecular biology, fundamentally transforming numerous facets of research, including drug discovery, protein structure prediction, genomic analysis, drug repurposing, synthetic biology, and disease diagnosis and prognosis. Moreover, this chapter demonstrates the fundamental potentials of AI and their applications focusing on molecular biology and cellular engineering.

PMID:40553333 | DOI:10.1007/978-1-0716-4690-8_10

Blood Neoplasia. 2024 Aug 28;1(4):100036. doi: 10.1016/j.bneo.2024.100036. eCollection 2024 Dec.

NO ABSTRACT

PMID:40552135 | PMC:PMC12182841 | DOI:10.1016/j.bneo.2024.100036

Biochimie. 2025 Jun 21:S0300-9084(25)00125-7. doi: 10.1016/j.biochi.2025.06.012. Online ahead of print.

ABSTRACT

Elimination of the Neglected Tropical Disease Visceral Leishmaniasis (VL) is a Sustainable Development Goal. It is caused by Leishmania donovani. The therapeutic options for the treatment of VL are limited due problems such as drug resistance and toxicities. Drug repurposing can be a promising alternative in this case. In this work, the antileishmanial potential of FDA approved anti-arrhythmic drug propafenone has been evaluated for repurposing. It reduced the viability of L. donovani promastigotes and intracellular amastigotes with an IC50 of 8.25 ± 2.48 μM and 11.19 ± 0.01 μM respectively. In the macrophages, the IC50 was 32 ± 7.07 μM. Propafenone treatment altered morphology of parasites and induced damage to the body and flagellum. The cell membrane became damaged and more permeable when the promastigotes were treated with this drug. However, no change in the cell membrane potential was detected. Treatment with propafenone was detrimental to mitochondrial health of L. donovani. It significantly depolarized the mitochondrial membrane and decreased the ATP levels in the promastigotes. Propafenone also induced oxidative stress in the parasites. Cell cycle arrest was detected at the G2/M stage. The data suggests that propafenone has antileishmanial potential and can be evaluated further in an experimental VL model.

PMID:40550412 | DOI:10.1016/j.biochi.2025.06.012

Inflammopharmacology. 2025 Jun 23. doi: 10.1007/s10787-025-01805-y. Online ahead of print.

ABSTRACT

Drug repurposing has emerged as a cost-efficient strategy for neurodegenerative disorders (NDDs), leveraging existing preclinical, safety, and tolerability data to identify therapeutic candidates. NDDs, including epilepsy, Parkinson's disease (PD), Alzheimer's disease (AD), and traumatic brain injury (TBI), are characterized by neuroinflammation, oxidative stress, and neuronal degeneration, with key signaling pathways such as HMGB1, TRPA1, NF-κB, MAPK, and PI3K/Akt-GSK3β playing pivotal roles in their pathogenesis. Given the established link between type 2 diabetes mellitus and neurodegeneration, Saroglitazar, a dual PPAR-α/γ agonist, holds promise in modulating insulin signaling, oxidative stress, neuroinflammation, and key pathways, including HMGB1, TRPA1, NF-κB, MAPK, and PI3K/Akt-GSK3β. This is the first comprehensive review to examine the effects of Saroglitazar in modulating multiple pathways associated with NDDs, thereby addressing existing gaps in the literature. The review explores the mechanistic interplay among these pathways and emphasizes the potential of Saroglitazar as a neuroprotective agent, highlighting the need for further studies to validate its clinical efficacy and disease-modifying capabilities in NDDs. All supporting data were obtained from peer-reviewed literature accessed via PubMed, Web of Science, and Scopus.

PMID:40549317 | DOI:10.1007/s10787-025-01805-y

Mol Divers. 2025 Jun 23. doi: 10.1007/s11030-025-11253-z. Online ahead of print.

ABSTRACT

Renin, an aspartyl protease enzyme, is a crucial part of the renin-angiotensin-aldosterone system (RAAS) that regulates blood pressure. However, numerous renin inhibitors, including Aliskiren, Zankiren, Enalkiren, Fasidotril, and Remikiren, are in the clinical arena of managing hypertension, but they are associated with numerous drawbacks. The important one includes modest efficacy in contrast to other antihypertensive agents, which reduces their use as monotherapy; secondly, the related side effects, including hyperkalemia and renal impairment. Thus, considering the unmet need to identify new renin inhibitors, we applied the drug repurposing technique on an 1880 US FDA-approved small molecules database. The research was achieved by performing the structure-based virtual screening (SBVD) on FDA-approved drugs, which was well supported by molecular docking, dynamics, and mechanics studies. This work identified Panobinostat as a possible lead renin inhibitor. The in vitro Elisa-based assay revealed Panobinostat has the potential to inhibit the renin enzyme at the half-maximal concentration (IC50) of 201.27 nM, while standard renin inhibitor Aliskiren portrayed an IC50 of 162.22 nM. The comparable potency to clinical renin inhibitors presents this HDAC inhibitor as a dual-functioning ligand. The findings are significant and well correlated with the plethora of evidence suggesting the role of HDACs in regulating RAAS and cardiovascular functions via the post-translational level modulation of chromatins' structures and functions.

PMID:40549296 | DOI:10.1007/s11030-025-11253-z

Microbiol Spectr. 2025 Jun 23:e0075825. doi: 10.1128/spectrum.00758-25. Online ahead of print.

ABSTRACT

The obligate human pathogen Streptococcus pyogenes (also known as GAS; Group A Streptococcus) carries high morbidity and mortality, primarily in impoverished or resource-poor regions. The failure rate of monotherapy with conventional antibiotics is high, and invasive infections by this bacterium frequently require extensive supportive care and surgical intervention. Thus, it is important to find new compounds with adjunctive therapeutic benefits. The conserved secreted protease streptopain (Streptococcal pyogenic exotoxin B; SpeB) directly contributes to disease pathogenesis by inducing pathological inflammation, degrading tissue, and promoting the evasion of antimicrobial host defense proteins. This study screened 400 diverse off-patent drugs and drug-like compounds for inhibitors of streptopain proteolysis. Lead compounds were tested for activity at lower concentrations and anti-virulence activities during in vitro infection. Significant inhibition of streptopain was seen for pentamidine, an anti-protozoal drug approved for the treatment of Pneumocystis pneumonia, leishmaniasis, and trypanosomiasis. Streptopain inhibition rendered GAS susceptible to killing by human innate immune cells. These studies identify unexploited molecules as new starting points for drug discovery and a potential for repurposing existing drugs for the treatment of infections by GAS.IMPORTANCEStreptococcus pyogenes is a common cause of severe invasive infections. Repeated infections can trigger autoimmune diseases such as acute rheumatic fever and rheumatic heart disease. This study examines how targeting a specific, highly conserved virulence factor of the secreted cysteine protease streptopain can sensitize a serious pathogen to killing by the immune system. Manipulating the host-pathogen interaction, rather than attempting to directly kill a microbe, is a promising therapeutic strategy. Notably, its benefits include limiting off-target effects on the microbiota. Streptopain inhibitors, including the antifungal and antiparasitic drug pentamidine as identified in this work, may therefore be useful in the treatment of S. pyogenes infection.

PMID:40548752 | DOI:10.1128/spectrum.00758-25

J Biomed Inform. 2025 Jun 20:104857. doi: 10.1016/j.jbi.2025.104857. Online ahead of print.

ABSTRACT

OBJECTIVE: Drug repurposing offers a cost-effective strategy to accelerate drug development by identifying new therapeutic uses for approved medications. Knowledge graphs (KGs) that capture large amounts of biomedical knowledge have recently been used for drug repurposing, however, KGs are inherently incomplete due to our limited biomedical knowledge.

METHODS: We propose KGiA, an inductive graph augmentation method that supports semi-inductive reasoning-allowing models to generalize to previously unseen biomedical entities. KGiA enhances KGs using counterfactual relationships mined from disease-specific topological patterns. We apply it to a state-of-art biomedical KG constructed from six datasets including biomedical relationships extracted from biomedical literature, which comprised 1,614,801 triples and 100,563 entities, including 30,006 diseases.

RESULTS: Across five augmented architectures, KGiA improves generalizability by up to 24×in Mean Reciprocal Rank (MRR) and outperforms the state-of-the-art KG-based drug repurposing model by up to 32%. We applied KGiA in four case studies of diseases including Alzheimer's Disease and showed its promise in identifying novel repurposed candidate drugs.

CONCLUSION: We showed that leveraging counterfactual relationships derived from disease-specific graph structures to augment existing knowledge graphs improved performance in KG-based drug repurposing.

PMID:40544900 | DOI:10.1016/j.jbi.2025.104857

J Mol Recognit. 2025 May;38(3):e70005. doi: 10.1002/jmr.70005.

ABSTRACT

Cancer cells exhibit elevated levels of reactive oxygen species, resulting in oxidative stress and DNA damage. To counteract this, many cancers upregulate the expression of MTH1 (MutT Homolog-1), a crucial enzyme that detoxifies oxidised nucleotide pools. Consequently, inhibiting MTH1 is a potential therapeutic strategy for managing DNA damage and cancer cell death. Here, we conducted a comprehensive computational screening of 3800 FDA-approved drugs to identify potential MTH1 inhibitors. Among these, Lumacaftor and Nilotinib were selected based on their strong binding affinity and pharmacokinetic profiles. Molecular dynamics simulations over 500 ns further validated the stable binding of these drugs to MTH1, suggesting their potential as effective inhibitors. Nilotinib, a well-known tyrosine kinase inhibitor (TKI), displayed strong binding affinity (Ka = 2.5 × 104) and potent MTH1 inhibitory activity (IC50: 37.2 μM). Notably, this study is the first to establish the interaction between Nilotinib and MTH1, highlighting the dual potential of Nilotinib as an MTH1 inhibitor. The findings suggest that Nilotinib could be repurposed to enhance cancer therapy, particularly in combating drug resistance through the novel mechanism of MTH1 inhibition. This approach provides new avenues for tackling chemoresistance and improving therapeutic outcomes in cancer patients.

PMID:40544353 | DOI:10.1002/jmr.70005

Clin Epigenetics. 2025 Jun 21;17(1):108. doi: 10.1186/s13148-025-01900-5.

ABSTRACT

BACKGROUND: Glioblastoma multiforme (GBM) is a lethal brain tumor. With the current gold standard chemotherapy treatment, temozolomide (TMZ), many patients do not survive beyond one year. While the urgency of researching novel treatments is understandable, the prohibitively high costs and the prolonged duration of research and clinical trials significantly delay the availability of medical advancements to the general public. This highlights the urgent need for adjuvant therapies to enhance treatment effectiveness.

MAIN BODY: Recent research has suggested the potential of repurposing FDA-approved drugs such as temozolomide (TMZ), disulfiram (DSF), and aspirin for the treatment of glioblastoma, with encouraging evidence particularly for DSF and aspirin. Additionally, compounds like histone deacetylase inhibitors (e.g., vorinostat) are being investigated for their impact on non-coding RNA (ncRNA) modulation, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Combining traditional therapies with ncRNA modulation has shown potential in enhancing therapeutic efficacy and targeting specificity. NcRNAs play a crucial role in regulating gene expression and have been implicated in tumor growth, invasion, and treatment resistance. Recent discoveries, such as cuproptosis, offer new insights into tumor cell death mechanisms.

CONCLUSION: This review focuses on how these molecular insights can serve as novel therapeutic targets and how drug adjuvant therapy may improve GBM treatment strategies. It focuses on how the integration of ncRNA modulation with conventional therapies and the combination strategy of enhancing efficacy of drugs can enhance treatment efficacy and pave the way for innovative approaches in managing GBM. In short, we will explore how non-coding RNAs (ncRNAs) might serve as promising targets and how repurposing TMZ, DSF, and aspirin could help enhance the efficacy of GBM treatment.

PMID:40544306 | PMC:PMC12181852 | DOI:10.1186/s13148-025-01900-5

Microbiol Spectr. 2025 Jun 20:e0071925. doi: 10.1128/spectrum.00719-25. Online ahead of print.

ABSTRACT

Mycobacterium abscessus presents significant clinical challenges due to its intrinsic and acquired resistance to antibiotics, resulting in prolonged treatments and poor patient outcomes. Addressing the urgent need for novel therapeutics, this study explores the antimicrobial potential of VLX600, originally developed as an anticancer agent, against M. abscessus. Screening a library of 3,200 clinically evaluated compounds identified VLX600 as a potent antimicrobial with minimal cytotoxicity. VLX600 demonstrated inhibitory effects against various strains of M. abscessus with minimum inhibitory concentrations of 4 µg/mL-16 µg/mL. It also remained effective in intracellular M. abscessus in host cells and exhibited broad-spectrum activity against other bacterial species, including Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The antimicrobial activity of VLX600 was abrogated by supplemental iron, indicating a mechanism dependent on iron chelation. VLX600 significantly reduced bacterial burdens and inflammation in a murine model of pulmonary M. abscessus infection. Additionally, synergistic effects were observed when VLX600 was combined with conventional antibiotics such as amikacin and clarithromycin in vitro. These findings highlight VLX600 as a promising candidate for repurposing as an antimicrobial agent against M. abscessus, warranting further clinical investigations.IMPORTANCEMycobacterium abscessus is an opportunistic pathogen that commonly causes pulmonary infections in cystic fibrosis patients. These infections are notoriously difficult to treat due to high levels of antibiotic resistance of M. abscessus, resulting in low cure rates. In this study, we identified a novel antibiotic candidate, VLX600, through high-throughput screening of 3,200 clinical compounds and demonstrated that VLX600 inhibits the growth of M. abscessus by depriving it of ferric and ferrous ions. This study highlights the potential of iron chelators as antimicrobial agents against M. abscessus infections. Since iron is an essential nutrient for the growth of many bacteria, the use of iron chelators could be extended to other infectious diseases. We hope this research will inspire further studies aimed at developing iron chelators as a novel class of antimicrobial agents.

PMID:40539807 | DOI:10.1128/spectrum.00719-25

Oncol Rep. 2025 Aug;54(2):97. doi: 10.3892/or.2025.8930. Epub 2025 Jun 20.

ABSTRACT

STAT3 is abnormally activated in several types of cancer, and elevated nuclear levels of STAT3 are strongly associated with poor prognosis in oral squamous cell carcinoma (OSCC). Despite ongoing progress in developing targeted therapies, there is no Food and Drug Administration‑approved drug currently targeting STAT3 in OSCC. To evaluate the anticancer effects of BBI608, a potent STAT3 inhibitor, in two human OSCC cell lines (HSC‑3 and HSC‑4), various two‑dimensional (2D) or 3D in vitro analyses were performed, including western blot analysis, colony formation assay, DAPI staining, sub‑G1 population analysis and Annexin V/PI staining. The molecular mechanisms of BBI608 were also determined using cross‑linking assay, nuclear and cytoplasmic fractionation assay, reverse transcription‑quantitative PCR and chromatin immunoprecipitation assay. In the present study, it was observed that human HSC‑3 and HSC‑4 OSCC cells exhibited higher levels of phosphorylated (p)‑STAT3 compared with those in immortalized oral keratinocytes (iHOK cells). BBI608 inhibited cell proliferation in a concentration‑dependent manner and triggered caspase 3‑dependent apoptosis in HSC‑3 and HSC‑4 cells. Additionally, BBI608 reduced the nuclear translocation of p‑STAT3 in HSC‑3 and HSC‑4 cells compared with that in DMSO‑treated cells. Mechanistically, BBI608 modulated anti‑apoptotic STAT3 downstream genes: Survivin expression was regulated at the transcriptional level, while myeloid cell leukemia‑1 expression was modulated post‑translation via proteasomal degradation. Consistent with the results from 2D culture, BBI608 showed effective anticancer effects against OSCC spheroids in 3D culture. These results suggest that BBI608 effectively inhibits STAT3 activation in both 2D and 3D models, offering a promising therapeutic strategy and supporting its potential for repurposing in patients with OSCC who exhibit elevated STAT3 activity.

PMID:40539433 | DOI:10.3892/or.2025.8930

Transl Psychiatry. 2025 Jun 20;15(1):207. doi: 10.1038/s41398-025-03418-z.

ABSTRACT

Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P < 10-5) were evaluated in up to 55,744 independent samples in Stage 2. Significant findings (P < 5 × 10-8) were identified based on meta-analyses of the two stages. There were 10,230 variants from 120 loci significantly associated with serum lipids. We identified novel associations for variants in four loci using the 1df test of interaction, and five additional loci using the 2df joint test that were independent of known lipid loci. Of these 9 loci, 7 could not have been detected without modeling the interaction as there was no evidence of association in a standard GWAS model. The genetic diversity of included samples was key in identifying these novel loci: four of the lead variants displayed very low frequency in European ancestry populations. Functional annotation highlighted promising loci for further experimental follow-up, particularly rs73597733 (MACROD2), rs59808825 (GRAMD1B), and rs11702544 (RRP1B). Notably, one of the genes in identified loci (RRP1B) was found to be a target of the approved drug Atenolol suggesting potential for drug repurposing. Overall, our findings suggest that taking interaction between genetic variants and psychosocial factors into account and including genetically diverse populations can lead to novel discoveries for serum lipids.

PMID:40537477 | DOI:10.1038/s41398-025-03418-z

J Cancer. 2025 Jun 12;16(8):2690-2705. doi: 10.7150/jca.110850. eCollection 2025.

ABSTRACT

Background: Antihypertensive drugs represent the most widely used drugs worldwide. However, the association between antihypertensive drugs and the risk of kidney cancer remains unclear. This study innovatively integrates multi-omics and causal inference approaches to investigate the long-term effects and potential mechanisms of 12 antihypertensive drug classes on kidney cancer risk. Methods: In this study, novel approaches including two-sample mendelian randomization (MR), summary-data-based mendelian randomization (SMR), two-step network MR, and single-cell transcriptomic analysis were employed. Single nucleotide polymorphisms (SNPs) were obtained from genome-wide association studies (GWASs) to proxy exposures and outcomes. The cis-expression quantitative trait loci (cis-eQTL) as the proxies of exposure were also obtained. MR estimates were generated using the inverse-variance weighted method or Wald ratio method. Sensitivity analyses were undertaken to interrogate the robustness of the main findings. Two-step network MR and single-cell analysis were specifically designed to dissect pathway-level mediation and expression patterns of identified targets. Results: In the main analysis, genetically proxied calcium-channel blockers (odds ratio [OR]: 0.95, 95% confidence interval [CI]: 0.91-0.99, p=0.021) and vasodilator antihypertensives (OR: 0.86, 95% CI: 0.76-0.97, p=0.018) were suggestively associated with decreased risk of kidney cancer, whereas genetically proxied angiotensin-converting enzyme inhibitors (OR: 1.13, 95% CI: 1.00-1.27, p=0.043) was suggestively associated with increased risk of kidney cancer. Genetically proxied antiadrenergic agents (OR=0.94, 95% CI: 0.90-0.99, p=0.021) and centrally acting antihypertensives (OR=0.93, 95% CI: 0.88-0.98, p=0.010) were suggestively associated with a decreased risk of clear cell renal cell carcinoma. SMR analysis revealed that these suggestively significant associations might be driven by CACNA1C, CALM1, ACE, and LTA4H. Upon two-step network MR analyses, 10 pathways with directional consistency were identified, and the mediation proportion ranged from 3.22% to 7.12%. The influence of antihypertensive drugs on kidney cancer risk might be associated with their regulation of levels of blood cells and lipids. Single-cell analysis further revealed the expression patterns of the four identified targets in peripheral blood and tumor infiltrating immune cells. Conclusion: This study pioneers the integration of causal inference and single-cell omics to demonstrate that antihypertensive drugs modulate kidney cancer risk through target-specific mechanisms involving blood cell and lipid pathways. Our findings provide actionable targets (CACNA1C, CALM1, ACE, and LTA4H) for drug repurposing trials and underscore the clinical importance of personalized antihypertensive therapy in cancer prevention.

PMID:40535814 | PMC:PMC12170992 | DOI:10.7150/jca.110850