iScience. 2025 Feb 28;28(3):112126. doi: 10.1016/j.isci.2025.112126. eCollection 2025 Mar 21.

ABSTRACT

Integrating enzyme parameters into constraint-based models have significantly improved the prediction of physiological and molecular traits. To further improve these models, we integrated promiscuous enzyme activities that jointly comprise the so-called underground metabolism by developing the CORAL toolbox, which increases the resolution of modeled enzyme resource allocation. Applying CORAL to a protein-constrained model of Escherichia coli revealed that underground metabolism resulted in larger flexibility of metabolic fluxes and enzyme usage. Simulating metabolic defects where the main activity of a promiscuous enzyme was blocked but promiscuous activities remained functional showed a small enzyme redistribution to the side activities. Further, blocking pairs of main activities showed that non-promiscuous enzymes exhibited larger impact on growth than promiscuous enzymes. These simulations showed that promiscuous enzymes can compensate for these defects, in line with experimental evidence. Together, our results indicated that promiscuous enzyme activities are vital to maintain robust metabolic function and growth.

PMID:40160425 | PMC:PMC11951047 | DOI:10.1016/j.isci.2025.112126

Bioessays. 2025 Mar 31:e70004. doi: 10.1002/bies.70004. Online ahead of print.

ABSTRACT

Recent studies show the importance of mesoscale changes to plasma membrane (PM) topography during cell shape change. Local folding and flattening of the cell surface is mechanosensitive, changing in response to both microenvironment structural elements and intracellular cytoskeletal activities. These topography changes elicit local mechanical signaling events that act in conjunction with molecular signal transduction pathways to remodel the cell cortex. Experimental manipulations of local PM curvature show its sufficiency for recruiting Arp2/3 actin network induction pathways. Additionally, studies of diverse cell shape changes-ranging from neutrophil migration to early Drosophila embryo cleavage to neural stem cell asymmetric division-show that local generation of PM folding is linked with local Arp2/3 actin network induction, which then remodels the PM topography during dynamic control of cell structure. These examples are reviewed in detail, together with known and potential causes of PM topography changes, downstream effects, and higher-order feedback.

PMID:40159841 | DOI:10.1002/bies.70004

Drug Des Devel Ther. 2025 Mar 26;19:2243-2252. doi: 10.2147/DDDT.S486562. eCollection 2025.

ABSTRACT

PURPOSE: To evaluate pharmacokinetics (PK) and safety of fezolinetant after single-dose and multiple-dose administration of 15, 30, and 60 mg in healthy Chinese women.

PATIENTS AND METHODS: This was a fixed-sequence crossover study in 16 healthy Chinese female subjects, 18-45 years old. All received single doses of fezolinetant 15 mg, 30 mg or 60 mg with a 3-day washout. From Day 10, subjects received multiple doses of 30 mg fezolinetant once-daily for 7 days. PK parameters were obtained during the single- and multiple-dose periods. Safety assessments were based on adverse events, vital signs, and laboratory tests.

RESULTS: Fezolinetant exhibited rapid absorption, with median time of the maximum concentration (tmax) 1.50 to 1.75 hours after single-dose administration of fezolinetant tablets in the fasted state, followed by a decline in plasma levels, with a mean t1/2 of 6.12-7.69 hours at dose levels of 15, 30 and 60 mg. There was a dose-proportional increase in maximum concentration and total exposure for fezolinetant across the doses studied. Mean peak concentration (Cmax) values were 221, 439 and 834 ng/mL, for the 15, 30, and 60 mg doses, respectively. The drug exposure parameters had a low-to-moderate variability (21.1-39.7%). Minimum accumulation was observed after multiple doses. Metabolite ES259564 showed rapid formation following a single dose of fezolinetant, with a median tmax of 1.50-2.00 hours. Plasma levels then declined, with mean t1/2 ranging from 5.72-6.31 hours. Dose-proportional increases in Cmax and AUCinf were observed following single-doses of fezolinetant. Steady state was achieved on the second day after starting multiple-dose administration. In total, 3 (18.8%) subjects experienced 4 drug-related treatment-emergent adverse events; all mild in severity.

CONCLUSION: Linear PK was confirmed within the dose range of 15 to 60 mg in healthy Chinese women.

PMID:40160966 | PMC:PMC11955179 | DOI:10.2147/DDDT.S486562

Int Cancer Conf J. 2024 Dec 28;14(2):91-96. doi: 10.1007/s13691-024-00742-x. eCollection 2025 Apr.

ABSTRACT

A 70-year-old woman with the breast cancer exhibited interstitial lung disease 20 months after the administration with anastrozole, which was performed as the post-operative adjuvant therapy. The drug-induced lymphocyte stimulation test revealed that anastrozole was responsible for the development of interstitial lung disease in this patient. The interstitial lung disease was effectively treated by prednisolone. Then, tamoxifen was used as an alternative therapy, resulting in the occurrence of agranulocytosis 24 days after the administration with tamoxifen. Both anastrozole and tamoxifen are widely used and are highly effective drugs for the treatment of breast cancer. However, the current patient shows that both drugs could cause, albeit very rare, serious side effects in some patients.

PMID:40160876 | PMC:PMC11950607 | DOI:10.1007/s13691-024-00742-x

Drug Discov Today. 2025 Apr;30(4):104346. doi: 10.1016/j.drudis.2025.104346. Epub 2025 Mar 28.

ABSTRACT

Ultra-rare diseases, particularly those that affect a few hundred patients worldwide, are of little commercial interest to the pharmaceutical industry. Patient-led organizations have made remarkable progress in funding the early-stage, academic development of therapies for such neglected ultra-rare conditions. But the long and difficult path to translate most academic proof-of-concept studies into approved medicines means that very few therapies ever reach patients. Here, we discuss some of the roadblocks to the development of therapeutics for conditions of limited commercial interest and propose ways to overcome these obstacles.

PMID:40158837 | DOI:10.1016/j.drudis.2025.104346

Biochem Biophys Res Commun. 2025 Mar 25;760:151701. doi: 10.1016/j.bbrc.2025.151701. Online ahead of print.

ABSTRACT

The histone deacetylase group of proteins, which includes the sirtuins, contributes to several cellular processes and is intimately involved in cancer development. Sirtuins type two (SIRT2) is a constituent of the human sirtuin family, which modulates a range of biological functions and is recognized as a potential biomarker for numerous cancers. The impact of SIRT2 knockout on tumorigenesis is debated and varies with the type of tumor; nonetheless, pharmacological inhibition of SIRT2 results exclusively in growth inhibition of diverse cancer cell lines. As a result, SIRT2 regulation is thought to be a viable protein for treating cancer. Herein, the DrugBank database, containing >14,000 drug molecules, was repurposed to find potential anticancer medications that have the capacity to inhibit the SIRT2 protein utilizing in-silico techniques. In light of the experimental findings, the capability of AutoDock Vina1.1.2 software to anticipate the docking scores and poses of the SIRT2 inhibitors was assessed. SirReal2, a potential SIRT2 inhibitor, was the controller for this study. Notably, drugs with docking scores less than SiReal2 were chosen and introduced to molecular dynamics (MD) simulations, accompanied by binding affinities estimations utilizing the MM-GBSA approach. Interestingly, MM-GBSA calculations demonstrated that five drugs, namely DB11526, DB11977, DB15133, DB04739, and DB04632, revealed potential affinities as SIRT2 inhibitors exhibiting ΔGbinding less than -50.0 kcal/mol. The post-MD analyses were inspected for DB11526, DB11977, DB15133, DB04739, and DB04632, indicating excellent steadiness of these drugs bound to SIRT2 protein throughout the 200 ns MD. The ADMET features were also examined and were acceptable. These findings suggested that more attention should be paid to DB11526, DB11977, DB15133, DB04739, and DB04632 as SIRT2 inhibitors utilizing in-vitro/in-vivo assays to treat cancer disease.

PMID:40158406 | DOI:10.1016/j.bbrc.2025.151701

Echocardiography. 2025 Apr;42(4):e70142. doi: 10.1111/echo.70142.

ABSTRACT

Left main coronary artery atresia (LMCAA) is a rare congenital coronary anomaly and sometimes presents with non-specific clinical symptoms that make the diagnosis challenging. We are presenting an interesting case that required multimodality imaging to establish the diagnosis.

PMID:40159450 | DOI:10.1111/echo.70142

Respiration. 2025 Mar 28:1-10. doi: 10.1159/000545552. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene. A minority of people with CF carry two heterozygous CFTR mutations other than the common Phe508del, complicating diagnosis and treatment.

CASE PRESENTATION: We report the case of a 25-year-old South American male diagnosed with CF respiratory disease, characterized by a history of recurrent infections, pulmonary Mycobacterium abscessus infection, airway disease on high-resolution CT, and an elevated sweat chloride level (74 mmol/L). Exome sequencing identified a unique combination of CFTR mutations: a pathogenic frameshift variant (c.2052dup) and a variant of unknown clinical significance (c.710A>C). Notably, there were no signs of pancreatic insufficiency. Rectal mucosal organoid cultures demonstrated residual CFTR function with responsiveness to ivacaftor and the combination of elexacaftor, tezacaftor, and ivacaftor.

CONCLUSION: This case highlights a unique combination of heterozygous CFTR variants in a person with late-onset CF respiratory disease, which may be amenable to CFTR modulation therapy.

PMID:40159410 | DOI:10.1159/000545552

J Gene Med. 2025 Apr;27(4):e70018. doi: 10.1002/jgm.70018.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an unknown etiology and complex pathophysiology that are not fully understood. The disease involves intricate cellular interplay, particularly among various immune cells. Currently, there is no treatment capable of reversing the fibrotic process or aiding lung regeneration. Hepatocyte growth factor (HGF) has demonstrated antifibrotic properties, whereas the adoptive transfer of modified T cells is a well-established treatment for various malignancies. We aimed to understand the dynamics of T cells in the progression of lung fibrosis and to study the therapeutic benefit of adoptive T cell transfer in a bleomycin-injured mouse lung (BLM) model.

METHODS: T cells were isolated from the spleen of naïve mice and transfected in vitro with mouse HGF plasmid and were administered intratracheally to the mice lungs 7 days post-bleomycin injury to the lung. Lung tissue and bronchoalveolar lavage were collected and analyzed using flow cytometry, histology, qRT-PCR, ELISA, and hydroxyproline assay.

RESULTS: Our findings demonstrate the successful T cell therapy of bleomycin-induced lung injury through the adoptive transfer of HGF-transfected T cells in mice. This treatment resulted in decreased collagen deposition and a balancing of immune cell exhaustion and cytokine homeostasis compared with untreated controls. In vitro testing showed enhanced apoptosis in myofibroblasts induced by HGF-overexpressing T cells.

CONCLUSIONS: Taken together, our data highlight the great potential of adoptive T cell transfer as an emerging therapy to counteract lung fibrosis.

PMID:40159455 | DOI:10.1002/jgm.70018

Respiration. 2025 Mar 28:1-10. doi: 10.1159/000545165. Online ahead of print.

ABSTRACT

Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease that subverts the normal structure of the lungs and finally causes respiratory failure. High flow nasal therapy (HFNT) is currently used in the acute setting for IPF with acute respiratory failure (ARF). Also, acute exacerbation of IPF (AE-IPF) and end-stage disease are common indications. Chronic cough is often an unmet need in IPF because it is partially responsive to common pharmacological treatment. Moreover, opioids have known adverse events. The aim of this paper is to investigate the effects and safety of chronic HFNT on lung function and symptoms of IPF. Methods This is a single center case-control study including patients affected by IPF. We included 35 adult patients with a consistent radiological diagnosis of IPF, clinical history of lung function decline and high prevalence of symptoms. All patients received the standard of treatment, particularly including antifibrotic drugs and conventional oxygen therapy (COT). 18 subjects were assigned to additional treatment with HFNT for 12 months. Results No significant differences were observed after the follow up with HFNT in terms of lung function. Results are showed in Figure 1. The mean FVC was 1.89 ± 0.73 L with HFNT and 2.43 ± 0.87 without HFNT (p=0.09). The mean FVC % of predicted is shown in Fig.1A; the mean FVC decline per year was 190 with HFNT vs 200 ml with standard of care. The mean DLCO % of predicted was 28.86 ± 14.51 % of predicted with HFNT and 36.03 ± 19.18 with COT (p=0.276), as shown in Fig.1B. No significant impact was observed on dyspnea, the mean borg scale value was 6.72 ± 2.22 after HFNT and 7.14 with COT (p=0.56) (Fig.1C). The score for cough significantly improved after treatment with a mean score in the HFNT group being 46.67 ± 10.85 vs 73.8 ± 18.43 (p<0.0001) with standard of care. Conclusions Long-term HFNT significantly reduces chronic cough in patients affected by IPF compared to COT. Lung function including FVC and DLCO is not significatively influenced.

PMID:40159397 | DOI:10.1159/000545165

Zhonghua Jie He He Hu Xi Za Zhi. 2025 Apr 12;48(4):389-392. doi: 10.3760/cma.j.cn112147-20240806-00465.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic lung disease of unknown etiology, primarily affecting middle-aged and elderly individuals. Chest imaging and histopathology are characterized by usual interstitial pneumonia (UIP). Without treatment, the median survival of patients is 3-5 years. Disease progression or acute exacerbation in IPF patients indicates a poor survival prognosis. Therefore, identification and establishment of predictive models for assessing IPF disease behavior may allow early prediction of disease progression, facilitating timely intervention or adjustment of therapeutic strategies to improve outcomes. This review aimed to summarized recent advances in IPF predictive models and to highlight key issues that need to be addressed.

PMID:40159060 | DOI:10.3760/cma.j.cn112147-20240806-00465

Zhonghua Jie He He Hu Xi Za Zhi. 2025 Apr 12;48(4):358-364. doi: 10.3760/cma.j.cn112147-20241203-00716.

ABSTRACT

Objective: To explore the clinicopathological characteristics and prognosis of lung cancer arising in the native lung after single lung transplantation for end-stage lung disease. Methods: We conducted a respective analysis of the clinical, pathological, and follow-up data of 12 recipients who developed lung cancer in the native lung after single-lung transplantation at China-Japan Friendship Hospital from September 2017 to June 2021, among a total of 247 single-lung transplantations performed during this period. Eleven were male and 1 was female, with ages ranging from 46-67 (59.25±5.75) years. Results: Of the 12 recipients, 11 had a smoking history before transplantation. The underlying diagnosis of lung diseases before transplantation included 8 cases of idiopathic pulmonary fibrosis, 3 cases of connective tissue disease-associated interstitial lung disease, and 1 case of chronic obstructive pulmonary disease. The time interval from transplantation to the development of lung cancer in the native lung was 3 to 53 months, with an average of (30.0±16.2) months. Eleven patients had elevated levels of serum tumor markers at the time of lung cancer diagnosis. CT/PET-CT showed new nodules or FDG avidity in the native lung. The histological types of lung cancer in the 12 cases included 1 case of small cell carcinoma and 11 cases of non-small cell lung cancer (7 cases of squamous cell carcinoma, 3 cases of adenocarcinoma, and 1 case of SMARCA4-deficient undifferentiated carcinoma). There were 8 cases in clinical stage Ⅳ, 1 case in stage Ⅲ, and 3 cases in stageⅠ. Three patients in stage Ⅰ and one patient in stage Ⅲ underwent surgical treatment, while patients in stage Ⅳ were treated with radiotherapy, chemotherapy, and palliative care. At the end of this study, 10 patients had died, 1 patient survived, and 1 patient was lost to follow-up. The median survival time was 7 months (ranging from 2 to 47 months), and the 1-year cumulative survival rate was 9.2%. Conclusions: The risk of developing lung cancer in the native lung after single lung transplantation is increased. The prognosis is very poor. Most of the histological types are squamous cell carcinoma. Close monitoring of high-risk populations after transplantation for early tumor detection may prolong survival time.

PMID:40159054 | DOI:10.3760/cma.j.cn112147-20241203-00716

Commun Biol. 2025 Mar 30;8(1):522. doi: 10.1038/s42003-025-07906-2.

ABSTRACT

The Hsp70 chaperone system is capable of disassembling pathological aggregates such as amyloid fibres associated with serious degenerative diseases. Here we examine the role of the J-domain protein co-factor in amyloid disaggregation by the Hsc70 system. We used cryo-EM and tomography to compare the assemblies with wild-type DNAJB1 or inactive mutants. We show that DNAJB1 binds regularly along α-synuclein amyloid fibrils and acts in a 2-step recruitment of Hsc70, releasing DNAJB1 auto-inhibition before activating Hsc70 ATPase. The wild-type DNAJB1:Hsc70:Apg2 complex forms dense arrays of chaperones on the fibrils, with Hsc70 on the outer surface. When the auto-inhibition is removed by mutating DNAJB1 (ΔH5 DNAJB1), Hsc70 is recruited to the fibrils at a similar level, but the ΔH5 DNAJB1:Ηsc70:Apg2 complex is inactive, binds less regularly to the fibrils and lacks the ordered clusters. Therefore, we propose that 2-step activation of DNAJB1 regulates the ordered assembly of Hsc70 on the fibril. The localised, dense packing of chaperones could trigger a cascade of recruitment and activation to give coordinated, sequential binding and disaggregation from an exposed fibril end, as previously observed in AFM videos. This mechanism is likely to be important in maintaining a healthy cellular proteome into old age.

PMID:40159506 | DOI:10.1038/s42003-025-07906-2

Tree Physiol. 2025 Mar 30:tpaf038. doi: 10.1093/treephys/tpaf038. Online ahead of print.

ABSTRACT

Phosphorus (P) deficiency is critical to the renewal barrier of she-oak (Casuarina equisetifolia), an important tree species used for coastal protection. However, the response of she-oak to P deficiency remains unclear. In this study, we compared the phenotypes of two she-oak cultivars, the P deficiency-sensitive 'Chihu219' and the insensitive 'Chihu397', and found that P deficiency significantly increased root growth, P concentration and P absorption efficiency (PAE) in Chihu219, but not in Chihu397. We also analyzed the transcriptome and metabolome of these cultivars under different P conditions and showed that trans-zeatin riboside (tZR) levels were highly suppressed by P deficiency in Chihu219, but not in Chihu397. Furthermore, exogenous tZR suppressed both root P concentration and PAE while promoting phosphorus use efficiency (PUE). We also identified CeIPT5 (isopentenyltransferase 5) as a key regulatory gene of tZR biosynthesis and found that its expression was more highly induced by P deficiency in Chihu219 than in Chihu397. We also showed that overexpression of CeIPT5 in insensitive she-oak lines reduced tZR concentration and increased root P concentration compared to the vector control. Taken together, P deficiency can greatly reduce tZR accumulation in P deficiency-insensitive she-oak at least by activating the tZR accumulation regulatory gene, CeIPT5, thereby promoting root elongation and P concentration. This study not only provides a genetic basis for enhancing PAE in woody plants, but also establishes a theoretical basis for optimizing root structure and improving nutrient utilization efficiency, thereby promoting sustainable forestry development.

PMID:40159239 | DOI:10.1093/treephys/tpaf038

Gut Microbes. 2025 Dec;17(1):2485326. doi: 10.1080/19490976.2025.2485326. Epub 2025 Mar 30.

ABSTRACT

Gastrointestinal symptoms are common during infancy, including infantile colic. Colic can be loosely defined as prolonged and recurrent crying without obvious cause. The cause indeed remains unclear despite much research. Results on infant nutrition are inconclusive, but prior work has linked maternal mental health to infant crying. Recently, several small studies have described associations between gut microbiota and colic. We used a larger cohort to examine the role of the microbiota in infant gastrointestinal health, while also accounting for other biopsychosocial factors. Using fecal 16S rRNA gene amplicon sequencing data from 1,012 infants in the KOALA birth cohort, we examined associations between the 1-month gut microbiota and parent-reported functional gastrointestinal symptoms throughout infancy, including colic, constipation, and cramps. These analyses were adjusted for biopsychosocial factors that were associated with symptoms in a broader analysis involving 2,665 participants. In 257 infants, we also explored associations between breastmilk human milk oligosaccharides (HMOs) and gastrointestinal symptoms. Higher relative abundance of Staphylococcus at one month was associated with less constipation in the first three months of life. Conversely, Ruminococcus gnavus group abundance was associated with more colicky symptoms, particularly between four and seven months. Breastmilk concentrations of the HMOs lacto-N-hexaose (LNH) and lacto-N-neohexaose (LNnH) were associated with less constipation in the first three months. Our results support the conclusion that gut microbiota are relevant in infantile colic and constipation. However more work is needed to elucidate the underlying mechanisms, and explore their interplay with other relevant biopsychosocial factors such as maternal mental health.

PMID:40159147 | DOI:10.1080/19490976.2025.2485326

Antiviral Res. 2025 Mar 28:106154. doi: 10.1016/j.antiviral.2025.106154. Online ahead of print.

ABSTRACT

IPB29 is a lipopeptide-based coronavirus fusion inhibitor with the potent, broad-spectrum antiviral activity, and it has already been advanced to phase III clinical trials for the treatment of SARS-CoV-2 infection. We recently reported its design strategy and initial preclinical characterization; herein, we focused on characterizing its efficacies against newly-emerged Omicron variants, as well as its chronic general toxicity, toxicokinetics, immunogenicity, and reproductive toxicity in animal models. As anticipated, IPB29 demonstrated improved activity in inhibiting JN.1 and KP.2 variants, effectively blocking cell fusion and pseudovirus infections. Nebulized inhalation of IPB29 exhibited high therapeutic efficacy against live BA.5 and EG.5.1 infections in Syrian hamsters. The 26-week toxicity studies revealed that nebulized IPB29 has a favorable safety profile, with well-characterized toxicokinetics in SD rats and Beagle dogs. Notably, short-term nebulization of IPB29 did not elicit anti-drug antibody (ADA) responses in either species. However, IPB29-specific antibodies were detected after long-term administration. Finally, a three-stage reproductive toxicity study in SD rats indicated that IPB29 had no significant toxic effects on fertility, embryo-fetal development, or the development of offspring. In summary, our findings demonstrate that IPB29 is a safe and effective SARS-CoV-2 inhibitor with promising potential for clinical applications.

PMID:40158858 | DOI:10.1016/j.antiviral.2025.106154

Biomed Environ Sci. 2025 Feb 20;38(2):230-247. doi: 10.3967/bes2025.010.

ABSTRACT

The structure of intestinal tissue is complex. In vitro simulation of intestinal structure and function is important for studying intestinal development and diseases. Recently, organoids have been successfully constructed and they have come to play an important role in biomedical research. Organoids are miniaturized three-dimensional (3D) organs, derived from stem cells, which mimic the structure, cell types, and physiological functions of an organ, making them robust models for biomedical research. Intestinal organoids are 3D micro-organs derived from intestinal stem cells or pluripotent stem cells that can successfully simulate the complex structure and function of the intestine, thereby providing a valuable platform for intestinal development and disease research. In this article, we review the latest progress in the construction and application of intestinal organoids.

PMID:40159175 | DOI:10.3967/bes2025.010

Cell Rep. 2025 Mar 28;44(4):115476. doi: 10.1016/j.celrep.2025.115476. Online ahead of print.

ABSTRACT

The clustering of multiple transcription factor binding sites (TFBSs) for the same TF has proved to be a pervasive feature of cis-regulatory elements in the eukaryotic genome. However, the contribution of binding sites within the homotypic clusters of TFBSs (HCTs) to TF binding and target gene expression remains to be understood. Here, we characterize the CHD4 enhancers that harbor unique functional ZNF410 HCTs genome wide. We uncover that ZNF410 controls chromatin accessibility and activity of the CHD4 enhancer regions. We demonstrate that ZNF410 binds to the HCTs in a collaborative fashion, further conferring transcriptional activation. In particular, three ZNF410 motifs (sub-HCTs) located at 3' end of the distal enhancer act as "switch motifs" to control chromatin accessibility and enhancer activity. Mechanistically, the SWI/SNF complex is selectively required to mediate cooperative ZNF410 binding for CHD4 expression. Together, our findings expose a complex functional hierarchy of homotypic clustered motifs, which cooperate to fine-tune target gene expression.

PMID:40158221 | DOI:10.1016/j.celrep.2025.115476

J Hazard Mater. 2025 Mar 28;492:138044. doi: 10.1016/j.jhazmat.2025.138044. Online ahead of print.

ABSTRACT

Drug-induced osteotoxicity refers to the harmful effects certain pharmaceuticals have on the skeletal system, posing significant safety risks. These toxic effects are critical concerns in clinical practice, drug development, and environmental management. However, current toxicity assessment models lack specialized datasets and algorithms specifically designed to predict osteotoxicity In this study, we compiled a dataset of osteotoxic molecules and used clustering analysis to classify them into four distinct groups Furthermore, target prediction identified key genes (IL6, TNF, ESR1, and MAPK3), while GO and KEGG analyses were employed to explore the complex underlying mechanisms Additionally, we developed prediction models based on molecular fingerprints and descriptors. We further advanced our approach by incorporating models such as Transformer, SVM, XGBoost, and molecular graphs integrated with Weave GNN, ViT, and a pre-trained KPGT model. Specifically, the descriptor-based model achieved an accuracy of 0.82 and an AUC of 0.89; the molecular graph model reached an accuracy of 0.84 and an AUC of 0.86; and the KPGT model attained both an accuracy and an AUC of 0.86. These findings led to the creation of Bonetox, the first online platform specifically designed for predicting osteotoxicity. This tool aids in assessing the impact of hazardous substances on bone health during drug development, thereby improving safety protocols, mitigating skeletal side effects, and ultimately enhancing therapeutic outcomes and public safety.

PMID:40158503 | DOI:10.1016/j.jhazmat.2025.138044

Neurotherapeutics. 2025 Mar 28:e00576. doi: 10.1016/j.neurot.2025.e00576. Online ahead of print.

ABSTRACT

Glioblastoma (GB) is an incurable cancer of the brain, and there is an urgent need to identify effective treatments. This may be achieved by either identifying new molecules or through drug repurposing. To ascertain the therapeutic potential of known GSK-3β and/or PDE7 inhibitors in GB, a drug screening was conducted using a Drosophila melanogaster glioma model. VP3.15, a dual inhibitor with anti-inflammatory and neuroprotective roles in multiple sclerosis, was selected for further investigation. VP3.15 demonstrated robust anti-tumor efficacy against a panel of human and mouse GB cells; however, its capacity to inhibit orthotopic growth was only observed in a wild-type PTEN cell line. The in vivo dependence on PTEN was further suggested with the results in fly gliomas. The analysis of the VP3.15-treated tissues revealed a notable reduction in the number of myeloid cells and in the degree of vascularization. Mechanistic studies indicate that VP3.15 diminishes the production of GAL9, a key molecule that stimulates pro-angiogenic macrophages. Our findings substantiate the pro-tumoral function of GSK-3β, which might depend on the PTEN genetic status. Furthermore, we have delineated the therapeutic potential of VP3.15, which acts through the inhibition of the supportive role of the GB microenvironment. This molecule could be safely and effectively utilized after PTEN characterization in GB patients.

PMID:40157890 | DOI:10.1016/j.neurot.2025.e00576