Cell Syst. 2024 Aug 30:S2405-4712(24)00212-6. doi: 10.1016/j.cels.2024.08.004. Online ahead of print.

ABSTRACT

Most cancer types lack targeted therapeutic options, and when first-line targeted therapies are available, treatment resistance is a huge challenge. Recent technological advances enable the use of assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA sequencing (RNA-seq) on patient tissue in a high-throughput manner. Here, we present a computational approach that leverages these datasets to identify drug targets based on tumor lineage. We constructed gene regulatory networks for 371 patients of 22 cancer types using machine learning approaches trained with three-dimensional genomic data for enhancer-to-promoter contacts. Next, we identified the key transcription factors (TFs) in these networks, which are used to find therapeutic vulnerabilities, by direct targeting of either TFs or the proteins that they interact with. We validated four candidates identified for neuroendocrine, liver, and renal cancers, which have a dismal prognosis with current therapeutic options.

PMID:39236711 | DOI:10.1016/j.cels.2024.08.004

Mol Genet Metab. 2024 Aug 18;143(1-2):108567. doi: 10.1016/j.ymgme.2024.108567. Online ahead of print.

ABSTRACT

While the identification and diagnosis of congenital disorders of glycosylation (CDG) have rapidly progressed, the available treatment options are still quite limited. Mostly, we are only able to manage the disease symptoms rather than to address the underlying cause. However, recent years have brought about remarkable advances in treatment approaches for some CDG. Innovative therapies, targeting both the root cause and resulting manifestations, have transitioned from the research stage to practical application. The present paper aims to provide a detailed overview of these exciting developments and the rising concepts that are used to treat these ultra-rare diseases.

PMID:39236565 | DOI:10.1016/j.ymgme.2024.108567

PLoS Pathog. 2024 Sep 5;20(9):e1012475. doi: 10.1371/journal.ppat.1012475. eCollection 2024 Sep.

ABSTRACT

Drug-resistant parasitic nematodes pose a grave threat to plants, animals, and humans. An innovative paradigm for treating parasitic nematodes is emphasized in this opinion. This approach relies on repurposing methuosis (a death characterized by accumulation of large vacuoles) inducing anticancer drugs as anthelmintics. We review drugs/chemicals that have shown to kill nematodes or cancerous cells by inducing multiple vacuoles that eventually coalesce and rupture. This perspective additionally offers a succinct summary on Structure-Activity Relationship (SAR) of methuosis-inducing small molecules. This strategy holds promise for the development of broad-spectrum anthelmintics, shedding light on shared molecular mechanisms between cancer and nematodes in response to these inducers, thereby potentially transforming both therapeutic domains.

PMID:39235992 | DOI:10.1371/journal.ppat.1012475

Curr Neuropharmacol. 2024;22(12):1942-1959. doi: 10.2174/1570159X22666240426091311.

ABSTRACT

Alzheimer's disease (AD) is a severe progressive neurodegenerative condition associated with neuronal damage and reduced cognitive function that primarily affects the aged worldwide. While there is increasing evidence suggesting that mitochondrial dysfunction is one of the most significant factors contributing to AD, its accurate pathobiology remains unclear. Mitochondrial bioenergetics and homeostasis are impaired and defected during AD pathogenesis. However, the potential of mutations in nuclear or mitochondrial DNA encoding mitochondrial constituents to cause mitochondrial dysfunction has been considered since it is one of the intracellular processes commonly compromised in early AD stages. Additionally, electron transport chain dysfunction and mitochondrial pathological protein interactions are related to mitochondrial dysfunction in AD. Many mitochondrial parameters decline during aging, causing an imbalance in reactive oxygen species (ROS) production, leading to oxidative stress in age-related AD. Moreover, neuroinflammation is another potential causative factor in AD-associated mitochondrial dysfunction. While several treatments targeting mitochondrial dysfunction have undergone preclinical studies, few have been successful in clinical trials. Therefore, this review discusses the molecular mechanisms and different therapeutic approaches for correcting mitochondrial dysfunction in AD, which have the potential to advance the future development of novel drug-based AD interventions.

PMID:39234772 | DOI:10.2174/1570159X22666240426091311

Med Pharm Rep. 2024 Jul;97(3):243-248. doi: 10.15386/mpr-2641. Epub 2024 Jul 30.

ABSTRACT

COVID-19 pandemic has taught many lessons regarding drug discovery and development. This review covers these aspects of drug discovery and research for COVID-19 which might be used as a tool for future. It summarizes the positives such as progresses in antiviral drug discovery, drug repurposing, adaptations of clinical trial and its regulations, as well as the negative points such as the need to develop more collaboration among stakeholders and future directions. It also discusses the benefits and limitations of finding new indications for existing drugs, and the lessons learned regarding rigorous and robust clinical trials, pharmacokinetic/pharmacodynamic modelling, as well as combination therapy. The pandemic has also revealed some gaps regarding global collaboration and coordination, data sharing and transparency and equitable distribution. Finally, the review enumerates the future directions and implications of drug discovery and research for COVID-19 and other infectious diseases such as preparedness and resilience, interdisciplinary and integrative approaches, diversity and inclusion, and personalized and precision medicine.

PMID:39234462 | PMC:PMC11370851 | DOI:10.15386/mpr-2641

Bioinformatics. 2024 Sep 1;40(Supplement_2):ii190-ii197. doi: 10.1093/bioinformatics/btae386.

ABSTRACT

MOTIVATION: Effective molecular representation is critical in drug development. The complex nature of molecules demands comprehensive multi-view representations, considering 1D, 2D, and 3D aspects, to capture diverse perspectives. Obtaining representations that encompass these varied structures is crucial for a holistic understanding of molecules in drug-related contexts.

RESULTS: In this study, we introduce an innovative multi-view contrastive learning framework for molecular representation, denoted as MolMVC. Initially, we use a Transformer encoder to capture 1D sequence information and a Graph Transformer to encode the intricate 2D and 3D structural details of molecules. Our approach incorporates a novel attention-guided augmentation scheme, leveraging prior knowledge to create positive samples tailored to different molecular data views. To align multi-view molecular positive samples effectively in latent space, we introduce an adaptive multi-view contrastive loss (AMCLoss). In particular, we calculate AMCLoss at various levels within the model to effectively capture the hierarchical nature of the molecular information. Eventually, we pre-train the encoders via minimizing AMCLoss to obtain the molecular representation, which can be used for various down-stream tasks. In our experiments, we evaluate the performance of our MolMVC on multiple tasks, including molecular property prediction (MPP), drug-target binding affinity (DTA) prediction and cancer drug response (CDR) prediction. The results demonstrate that the molecular representation learned by our MolMVC can enhance the predictive accuracy on these tasks and also reduce the computational costs. Furthermore, we showcase MolMVC's efficacy in drug repositioning across a spectrum of drug-related applications.

AVAILABILITY AND IMPLEMENTATION: The code and pre-trained model are publicly available at https://github.com/Hhhzj-7/MolMVC.

PMID:39230706 | DOI:10.1093/bioinformatics/btae386

Nanomedicine (Lond). 2024 Sep 4:1-14. doi: 10.1080/17435889.2024.2390349. Online ahead of print.

ABSTRACT

Aim: Amitriptyline (AMI) has been used to treat neuropathic pain. However, the clinical outcomes remain unsatisfactory, presumably due to a limited understanding of the underlying molecular mechanisms. Here, we investigated a drug repositioning strategy using a low-dose of AMI encapsulated in poly (D, L lactic-co-glycolic acid) (PLGA) nanoparticles (AMI NPs) for neuropathic pain, since PLGA nanoparticles are known to enhance delivery to microglia.Methods: We evaluated the anti-allodynic effects of AMI and AMI NPs on neuropathic pain by assessing behaviors and inflammatory responses in a rat model of spinal nerve ligation (SNL). While the anti-allodynic effect of AMI (30 μg) drug injection on SNL-induced neuropathic pain persisted for 12 h, AMI NPs significantly alleviated mechanical allodynia for 3 days.Results: Histological and cytokine analyses showed AMI NPs facilitated the reduction of microglial activation and pro-inflammatory mediators in the spinal dorsal horn. This study suggests that AMI NPs can provide a sustained anti-allodynic effect by enhancing the targeting of microglia and regulating the release of pro-inflammatory cytokines from activated microglia.Conclusion: Our findings suggest that the use of microglial-targeted NPs continuously releasing AMI (2 μg) as a drug repositioning strategy offers long-term anti-allodynic effects.

PMID:39229790 | DOI:10.1080/17435889.2024.2390349

medRxiv [Preprint]. 2024 Aug 21:2024.08.20.24312181. doi: 10.1101/2024.08.20.24312181.

ABSTRACT

BACKGROUND: Patients with post-traumatic stress disorder (PTSD) experience higher risk of adverse cardiovascular (CV) outcomes. This study explores shared loci, and genes between PTSD and CV conditions from three major domains: CV diagnoses from electronic health records (CV-EHR), cardiac and aortic imaging, and CV health behaviors defined in Life's Essential 8 (LE8).

METHODS: We used genome-wide association study (GWAS) of PTSD (N=1,222,882), 246 CV diagnoses based on EHR data from Million Veteran Program (MVP; N=458,061), UK Biobank (UKBB; N=420,531), 82 cardiac and aortic imaging traits (N=26,893), and GWAS of traits defined in the LE8 (N = 282,271 ∼ 1,320,016). Shared loci between PTSD and CV conditions were identified using local genetic correlations (rg), and colocalization (shared causal variants). Overlapping genes between PTSD and CV conditions were identified from genetically regulated proteome expression in brain and blood tissues, and subsequently tested to identify functional pathways and gene-drug targets. Epidemiological replication of EHR-CV diagnoses was performed in AllofUS cohort (AoU; N=249,906).

RESULTS: Among the 76 PTSD-susceptibility risk loci, 33 loci exhibited local rg with 45 CV-EHR traits (|rg|≥0.4), four loci with eight heart imaging traits(|rg|≥0.5), and 44 loci with LE8 factors (|rg|≥0.36) in MVP. Among significantly correlated loci, we found shared causal variants (colocalization probability > 80%) between PTSD and 17 CV-EHR (in MVP) at 11 loci in MVP, that also replicated in UKBB and/or other cohorts. Of the 17 traits, the observational analysis in the AoU showed PTSD was associated with 13 CV-EHR traits after accounting for socioeconomic factors and depression diagnosis. PTSD colocalized with eight heart imaging traits on 2 loci and with LE8 factors on 31 loci. Leveraging blood and brain proteome expression, we found 33 and 122 genes, respectively, shared between PTSD and CVD. Blood proteome genes were related to neuronal and immune processes, while the brain proteome genes converged on metabolic and calcium-modulating pathways (FDR p <0.05). Drug repurposing analysis highlighted DRD2, NOS1, GFAP, and POR as common targets of psychiatric and CV drugs.

CONCLUSION: PTSD-CV comorbidities exhibit shared risk loci, and genes involved in tissue-specific regulatory mechanisms.

PMID:39228734 | PMC:PMC11370495 | DOI:10.1101/2024.08.20.24312181

Parasit Vectors. 2024 Sep 3;17(1):373. doi: 10.1186/s13071-024-06456-6.

ABSTRACT

BACKGROUND: Cystic echinococcosis (CE) is a zoonotic disease caused by the larval stage of the dog tapeworm Echinococcus granulosus sensu lato (E. granulosus), with a worldwide distribution. The current treatment strategy for CE is insufficient. Limited drug screening models severely hamper the discovery of effective anti-echinococcosis drugs.

METHODS: In the present study, using high-content screening technology, we developed a novel high-throughput screening (HTS) assay by counting the ratio of propidium iodide-stained dead protoscoleces (PSCs) to the total number of PSCs. In vitro and ex vivo cyst viability assays were utilized to determine the effect of drugs on cyst viability.

RESULTS: Using the newly established HTS assay, we screened approximately 12,000 clinical-stage or The Food and Drug Administration (FDA)-approved small molecules from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library, as well as the LOPAC1280 and SelleckChem libraries, as a strategic approach to facilitate the drug discovery process. Initial screening yielded 173 compounds with anti-echinococcal properties, 52 of which demonstrated dose-response efficacy against E. granulosus PSCs in vitro. Notably, two agents, omaveloxolone and niclosamide, showed complete inhibition upon further validation in cyst and microcyst viability assays in vitro after incubation for 3 days, and in an ex vivo cyst viability assay using cysts isolated from the livers of mice infected with E. granulosus, as determined by morphological assessment.

CONCLUSIONS: Through the development of a novel HTS assay and by repurposing libraries, we identified omaveloxolone and niclosamide as potent inhibitors against E. granulosus. These compounds show promise as potential anti-echinococcal drugs, and our strategic approach has the potential to promote drug discovery for parasitic infections.

PMID:39227942 | DOI:10.1186/s13071-024-06456-6

J Transl Med. 2024 Sep 3;22(1):818. doi: 10.1186/s12967-024-05561-5.

ABSTRACT

BACKGROUND: Dengue virus (DENV) is the most widespread arbovirus. The World Health Organization (WHO) declared dengue one of the top 10 global health threats in 2019. However, it has been underrepresented in bibliometric analyses. This study employs bibliometric analysis to identify research hotspots and trends, offering a comprehensive overview of the current research dynamics in this field.

RESULTS: We present a report spanning from 1995 to 2023 that provides a unique longitudinal analysis of Dengue virus (DENV) research, revealing significant trends and shifts not extensively covered in previous literature. A total of 10,767 DENV-related documents were considered, with a notable increase in publications, peaking at 747 articles in 2021. Plos Neglected Tropical Diseases has become the leading journal in Dengue virus research, publishing 791 articles in this field-the highest number recorded. Our bibliometric analysis provides a comprehensive mapping of DENV research across multiple dimensions, including vector ecology, virology, and emerging therapies. The study delineates a complex network of immune response genes, including IFNA1, DDX58, IFNB1, STAT1, IRF3, and NFKB1, highlighting significant trends and emerging themes, particularly the impacts of climate change and new outbreaks on disease transmission. Our findings detail the progress and current status of key vaccine candidates, including the licensed Dengvaxia, newer vaccines such as Qdenga and TV003, and updated clinical trials. The study underscores significant advancements in antiviral therapies and vector control strategies for dengue, highlighting innovative drug candidates such as AT-752 and JNJ-1802, and the potential of drug repurposing with agents like Ribavirin, Remdesivir, and Lopinavir. Additionally, it discusses biological control methods, including the introduction of Wolbachia-infected mosquitoes and gene-editing technologies.

CONCLUSION: This bibliometric study underscores the critical role of interdisciplinary collaboration in advancing DENV research, identifying key trends and areas needing further exploration, including host-virus dynamics, the development and application of antiviral drugs and vaccines, and the use of artificial intelligence. It advocates for strengthened partnerships across various disciplines to effectively tackle the challenges posed by DENV.

PMID:39227968 | DOI:10.1186/s12967-024-05561-5

Biomed Pharmacother. 2024 Sep 2;179:117325. doi: 10.1016/j.biopha.2024.117325. Online ahead of print.

ABSTRACT

Direct-acting antivirals ledipasvir (LDV) and daclatasvir (DCV) are widely used as part of combination therapies to treat Hepatitis C infections. Here we show that these compounds inhibit the proliferation, invasion, and colony formation of triple-negative MDA-MB-231 breast cancer cells, SRC-transduced SW620 colon cancer cells and SRC- transduced NIH3T3 fibroblasts. DCV also inhibits the expression of PDL-1, which is responsible for resistance to immunotherapy in breast cancer cells. The demonstrated low toxicity in many Hepatitis C patients suggests LDV and DCV could be used in combination therapies for cancer patients. At the molecular level, these direct-acting antivirals inhibit the phosphorylation of Akt and the ephrin type A receptor 2 (EPHA2) by destabilizing a Src-EPHA2 complex, although they do not affect the general kinase activity of Src. Thus, LDV and DCV could be effective drugs for Src-associated cancers without the inherent toxicity of classical Src inhibitors.

PMID:39226729 | DOI:10.1016/j.biopha.2024.117325

EBioMedicine. 2024 Sep 2;107:105277. doi: 10.1016/j.ebiom.2024.105277. Online ahead of print.

ABSTRACT

BACKGROUND: Global cyclical outbreaks of human enterovirus infections has positioned human enterovirus A71 (EV-A71) as a neurotropic virus of clinical importance. However, there remains a scarcity of internationally approved antivirals and vaccines.

METHODS: In pursuit of repurposing drugs for combating human enteroviruses, we employed a comprehensive pharmacophore- and molecular docking-based virtual screen targeting EV-A71 capsid protein VP1-4, 3C protease, and 3D polymerase proteins. Among 15 shortlisted ligand candidates, we dissected the inhibitory mechanism of Tanomastat in cell-based studies and evaluated its in vivo efficacy in an EV-A71-infected murine model.

FINDINGS: We demonstrated that Tanomastat exerts dose-dependent inhibition on EV-A71 replication, with comparable efficacy profiles in enterovirus species A, B, C, and D in vitro. Time-course studies suggested that Tanomastat predominantly disrupts early process(es) of the EV-A71 replication cycle. Mechanistically, live virus particle tracking and docking predictions revealed that Tanomastat specifically impedes viral capsid dissociation, potentially via VP1 hydrophobic pocket binding. Bypassing its inhibition on entry stages, we utilized EV-A71 replication-competent, 3Dpol replication-defective, and bicistronic IRES reporter replicons to show that Tanomastat also inhibits viral RNA replication, but not viral IRES translation. We further showed that orally administered Tanomastat achieved 85% protective therapeutic effect and alleviated clinical symptoms in EV-A71-infected neonatal mice.

INTERPRETATION: Our study establishes Tanomastat as a broad-spectrum anti-enterovirus candidate with promising pre-clinical efficacy, warranting further testing for potential therapeutic application.

FUNDING: MOE Tier 2 grants (MOE-T2EP30221-0005, R571-000-068-592, R571-000-076-515, R571-000-074-733) and A∗STARBiomedical Research Council (BMRC).

PMID:39226680 | DOI:10.1016/j.ebiom.2024.105277

Reprod Fertil. 2024 Sep 1:RAF-24-0022. doi: 10.1530/RAF-24-0022. Online ahead of print.

ABSTRACT

Infertility is estimated to affect more than 50 million couples around the world, with male factor accounting for half of these cases, yet there is a notable absence of effective treatment options for men, other than in-vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). This review considers unlicensed and empirical treatments used for male subfertility, including hormonal therapy, phosphodiesterase inhibitors, and antioxidants. Compounds generally demonstrate variable improvements in sperm function but benefits for fertility are less clear. There is a pressing need for effective treatment options for subfertile men, however, our knowledge of sperm function is limited, restricting the identification of precise treatment targets. The traditional drug discovery pathway is also notorious for its extensive resource and time requirements, often extending over decades and demanding significant financial investment. Unfortunately, a substantial number of potential therapies fail before reaching the marketplace. Furthermore, reliance on mammalian models is not possible in the drug development process for male subfertility, due to significant variability between animals and man. We review recent breakthroughs and highlight novel methods aimed at improving the effectiveness and efficiency of drug discovery for male subfertility. High-throughput screening, combinatorial chemistry, and the repurposing of established medications have great potential. These strategies offer the promise of accelerating the pace of drug development, curbing the extensive demand for resources, and, in the case of drug repurposing, diminish the demand for comprehensive pharmacokinetic and pharmacodynamic studies. As these innovative approaches are adopted, the feasibility of addressing male subfertility through scientific advancements appears to be increasingly attainable.

PMID:39226216 | DOI:10.1530/RAF-24-0022

J Gynecol Oncol. 2024 Aug 27. doi: 10.3802/jgo.2025.36.e28. Online ahead of print.

ABSTRACT

OBJECTIVE: Chemoresistant-epithelial ovarian cancer (EOC) has a poor prognosis, prompting the search for new therapeutic drugs. The diphenylbutylpiperidine (DPBP) class of antipsychotic drugs used in schizophrenia has shown anticancer effects. This study aimed to investigate the preclinical efficacy of penfluridol, fluspirilene, and pimozide (DPBP) using in vitro and in vivo models of EOC.

METHODS: Human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with penfluridol, fluspirilene, and pimozide, and cell proliferation, apoptosis, and migration were assessed. The preclinical efficacy of DPBP was also investigated using in vivo mouse models, including cell lines and patient-derived xenografts (PDX) of EOC.

RESULTS: DPBP drugs significantly decreased cell proliferation in chemosensitive (A2780, HeyA8, and SKOV3ip1) and chemoresistant (A2780-CP20, HeyA8-MDR, and SKOV3-TR) cell lines. Among these drugs, penfluridol exerted a relatively stronger cytotoxic effect on all cell lines. Penfluridol significantly increased apoptosis and inhibited migration of EOC cells. In the cell line xenograft mouse model with HeyA8, the penfluridol group showed significantly decreased tumor weight compared with the control group. In the paclitaxel-resistant model with HeyA8-MDR, the penfluridol group had significantly decreased tumor weight compared with the paclitaxel or control groups. Penfluridol exerted anticancer effects on the PDX model.

CONCLUSION: Penfluridol exerted significant anticancer effects on EOC cells and xenograft models, including PDX. Thus, penfluridol therapy, as a drug repurposing strategy, might be a potential therapeutic for EOCs.

PMID:39223944 | DOI:10.3802/jgo.2025.36.e28

Enzymes. 2024;55:383-411. doi: 10.1016/bs.enz.2024.05.006. Epub 2024 Jul 3.

ABSTRACT

Acetazolamide, methazolamide, ethoxzolamide and dorzolamide, classical sulfonamide carbonic anhydrase (CA) inhibitors (CAIs) designed for targeting human enzymes, were also shown to effectively inhibit bacterial CAs and were proposed for repurposing as antibacterial agents against several infective agents. CAs belonging to the α-, β- and/or γ-classes from pathogens such as Helicobacter pylori, Neisseria gonorrhoeae, vacomycin resistant enterococci (VRE), Vibrio cholerae, Mycobacterium tuberculosis, Pseudomonas aeruginosa and other bacteria were considered as drug targets for which several classes of potent inhibitors have been developed. Treatment of some of these pathogens with various classes of such CAIs led to an impairment of the bacterial growth, reduced virulence and for drug resistant bacteria, a resensitization to clinically used antibiotics. Here I will discuss the strategies and challenges for obtaining CAIs with enhanced selectivity for inhibiting bacterial versus human enzymes, which may constitute an important weapon for addressing the drug resistance to β-lactams and other clinically used antibiotics.

PMID:39222998 | DOI:10.1016/bs.enz.2024.05.006

Basic Clin Pharmacol Toxicol. 2024 Sep 1. doi: 10.1111/bcpt.14074. Online ahead of print.

ABSTRACT

Over the past decade, increasing off-label use of quetiapine has been reported worldwide from various sources. We wanted to investigate how this is reflected in therapeutic drug monitoring (TDM) data. Requisitions for serum concentration measurements of quetiapine from a TDM service in Central Norway during 2001-2019 were obtained and analysed for age, gender, trends in quetiapine doses, serum concentrations and indicators of diagnoses. There were 19 759 requisitions from 7459 individuals. Daily doses of quetiapine decreased by 24 mg per year (95% CI: -25.61 to -21.48, p < 0.001, N = 4505). A corresponding decrease in quetiapine serum concentrations was not seen. The proportion of requisitions with diagnoses indicating reimbursable use was 13% for the whole study period. Mean daily doses were slightly higher in the reimbursable group, but declined over time in these samples, as well. To our understanding, these results signal a trend towards lower prescribed doses of quetiapine, possibly reflecting drug repurposing and/or off-label use. The discrepancy in the decrease of doses versus serum concentrations may reflect the intake of higher doses than prescribed and/or inappropriate TDM sampling. Our findings show that TDM data have limitations when it comes to making inferences about the use of quetiapine based on serum concentrations and clinical information on the requisitions.

PMID:39219150 | DOI:10.1111/bcpt.14074

Yakugaku Zasshi. 2024;144(9):857-863. doi: 10.1248/yakushi.24-00120.

ABSTRACT

Less than 10% of the candidate drug compounds are associated with male reproductive toxicity. Genetic and/or epigenetic information on sperm may be crucial for fetal development. Therefore, developmental toxicity, such as paternally transmitted birth defects, is possible if genetic abnormalities in the male germ line persist and accumulate in the sperm during spermatogenesis. First, this study provides an overview of chemical and male reproductive toxicity, which may lead to developmental toxicity from the perspective of male reproduction. Second, we demonstrate methods for evaluating male reproductive toxicity to anticipate male-mediated developmental toxicity. We developed a novel staining technique for evaluating sperm quality, as well as a noninvasive imaging analysis of male reproductive toxicity. The former is a mammalian male germ cell-specific staining method using reactive blue 2 dye (RB2), as previously confirmed in human sperm, and a method for detecting the early-stage DNA fragmentation in a single nucleus from mouse spermatozoa using single-cell pulsed-field gel electrophoresis. The latter is a new, ready-to-use, and compact magnetic resonance imaging (MRI) platform utilizing a high-field permanent magnet to evaluate male reproductive toxicity. The histopathological analysis supported the suitability of the MRI platform. The present study, for the first time, revealed a rapid, noninvasive evaluation of male reproductive toxicity in vivo using compact MRI. These novel toxicity assessments can help predict male-mediated developmental toxicity, contributing to accelerated drug discovery and drug repositioning.

PMID:39218652 | DOI:10.1248/yakushi.24-00120

Methods. 2024 Aug 30:S1046-2023(24)00189-0. doi: 10.1016/j.ymeth.2024.08.008. Online ahead of print.

ABSTRACT

Accurately predicting drug-target affinity is crucial in expediting the discovery and development of new drugs, which is a complex and risky process. Identifying these interactions not only aids in screening potential compounds but also guides further optimization. To address this, we propose a multi-perspective feature fusion model, MFF-DTA, which integrates chemical structure, biological sequence, and other data to comprehensively capture drug-target affinity features. The MFF-DTA model incorporates multiple feature learning components, each of which is capable of extracting drug molecular features and protein target information, respectively. These components are able to obtain key information from both global and local perspectives. Then, these features from different perspectives are efficiently combined using specific splicing strategies to create a comprehensive representation. Finally, the model uses the fused features to predict drug-target affinity. Comparative experiments show that MFF-DTA performs optimally on the Davis and KIBA data sets. Ablation experiments demonstrate that removing specific components results in the loss of unique information, thus confirming the effectiveness of the MFF-DTA design. Improvements in DTA prediction methods will decrease costs and time in drug development, enhancing industry efficiency and ultimately benefiting patients.

PMID:39218169 | DOI:10.1016/j.ymeth.2024.08.008

J Ethnopharmacol. 2024 Aug 30:118764. doi: 10.1016/j.jep.2024.118764. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal formulae have been used in China for thousands of years but have unclear clinical positioning and unknown characteristic indications make it difficult to determine their specific application in various diseases, which seriously hamper their clinical value. Identifying the precise clinical positioning and clinical advantages of similar formulae for related diseases is a critical issue.

AIM OF THIS STUDY: To develop a methodology based on modular pharmacology to determine the clinical advantages and precise clinical position of similar formulae.

MATERIALS AND METHODS: In this study, we proposed a modular-based network proximity approach to explore drug repositioning and clinical advantages of three formulae, Shirebi tablets (SRB), Yuxuebi capsules (YXB), and Wangbifukang granules (WBFK), for rheumatic disease. First, we constructed a rheumatology target network, and modules were obtained using the cluster tool molecular complex detection (MCODE). Based on the modular interaction map established by a quantitative approach for inter-module coordination and its transition (IMCC), using a targeting rate (TR) matrix to identify targeted modules of three formulae. Moreover, the network proximity Z-score and Jaccard similarity coefficient were used to identify potential optimal symptomatic indications and related diseases using three formulae. At the same time, the driver genes for SRB and gouty arthritis were identified by flow centrality and shortest distance, and the epresentative driver genes were validated by in vivo experiments.

RESULTS: 32 modules were obtained using the MCODE method. 4, 4, and 14 characteristic targeted modules of SRB, YXB, and WBFK, respectively, were identified using a targeting rate (TR) matrix. Module 2, 16, and 19 were targeted by both SRB and WBFK. The common effects of SRB and WBFK focused on inflammatory response and innate immune response, YXB was found to be involved in the collagen catabolic process, transmembrane receptor protein serine/threonine kinase signaling pathway. Moreover, potential optimal symptomatic indications and representative related diseases were identified for three formulae: SRB was significantly associated with GA (Z=-20.26) ; YXB was significantly associated with AS (Z=-4.532) , MI (Z=-29.11) , RhFv (Z=-6.945) , OA (Z=-39.97) , and GA (Z=-13.03) ; and WBFK was significantly associated with MI (Z=-205.5), SLE (Z=-37.65), RhFv (Z=-42.45), and GA (Z=-17.24). Finally, 8 driver genes for SRB and gouty arthritis were identified,the representative driver genes TRAF6 and NFE2L1 were validated by in vivo experiments.

CONCLUSIONS: The modular-based network proximity approach proposed in this study may provide a new perspective for the precise drug repositioning and clinical advantages of similar formulae in disease treatment.

PMID:39218127 | DOI:10.1016/j.jep.2024.118764

Sci Rep. 2024 Aug 31;14(1):20298. doi: 10.1038/s41598-024-71240-6.

ABSTRACT

Statins, widely used cardiovascular drugs that lower cholesterol by inhibiting HMG-CoA reductase, have been increasingly recognized for their potential anticancer properties. This study elucidates the underlying mechanism, revealing that statins exploit Synthetic Lethality, a principle where the co-occurrence of two non-lethal events leads to cell death. Our computational analysis of approximately 37,000 SL pairs identified statins as potential drugs targeting genes involved in SL pairs with metastatic genes. In vitro validation on various cancer cell lines confirmed the anticancer efficacy of statins. This data-driven drug repurposing strategy provides a molecular basis for the anticancer effects of statins, offering translational opportunities in oncology.

PMID:39217242 | DOI:10.1038/s41598-024-71240-6