Drugs. 2024 Apr 4. doi: 10.1007/s40265-024-02022-7. Online ahead of print.

ABSTRACT

The quest for medications to reduce intra-pancreatic fat deposition is now quarter a century old. While no specific medication has been approved for the treatment of fatty change of the pancreas, drug repurposing shows promise in reducing the burden of the most common disorder of the pancreas. This leading article outlines the 12 classes of medications that have been investigated to date with a view to reducing intra-pancreatic fat deposition. Information is presented hierarchically-from preclinical studies to retrospective findings in humans to prospective interventional studies to randomised controlled trials. This lays the grounds for shepherding the most propitious drugs into medical practice through well-designed basic science studies and adequately powered randomised controlled trials.

PMID:38573485 | DOI:10.1007/s40265-024-02022-7

Pharmacol Res Perspect. 2024 Apr;12(2):e1194. doi: 10.1002/prp2.1194.

ABSTRACT

The SARS-CoV-2 caused COVID-19 pandemic has posed a global health hazard. While some vaccines have been developed, protection against viral infection is not perfect because of the urgent approval process and the emergence of mutant SARS-CoV-2 variants. Here, we employed UDCA as an FXR antagonist to regulate ACE2 expression, which is one of the key pathways activated by SARS-CoV-2 Delta variant infection. UDCA is a well-known reagent of liver health supplements and the only clinically approved bile acid. In this paper, we investigated the protective efficacy of UDCA on Omicron variation, since it has previously been verified for protection against Delta variant. When co-housing with an Omicron variant-infected hamster group resulted in spontaneous airborne transmission, the UDCA pre-supplied group was protected from weight loss relative to the non-treated group at 4 days post-infection by more than 5%-10%. Furthermore, UDCA-treated groups had a 3-fold decrease in ACE2 expression in nasal cavities, as well as reduced viral expressing genes in the respiratory tract. Here, the data show that the UDCA serves an alternative option for preventive drug, providing SARS-CoV-2 protection against not only Delta but also Omicron variant. Our results of this study will help to propose drug-repositioning of UDCA from liver health supplement to preventive drug of SARS-CoV-2 infection.

PMID:38573021 | DOI:10.1002/prp2.1194

Assay Drug Dev Technol. 2024 Apr 4. doi: 10.1089/adt.2023.141. Online ahead of print.

ABSTRACT

Gastric cancer is one of the most common and deadly types of cancer in the world. To develop new biomarkers and drugs to diagnose and treat this cancer, it is necessary to identify the differences between the transcriptome profiles of gastric cancer and healthy individuals, identify critical genes associated with these differences, and make potential drug predictions based on these genes. In this study, using two gene expression datasets related to gastric cancer (GSE19826 and GSE79973), 200 genes that were ready for machine learning were selected, and their expression levels were analyzed. The best 100 genes for the model were chosen with the permutation feature importance method, and central genes, such as SCARB1, ETV3, SPATA17, FAM167A-AS1, and MTBP, which were shown to be associated with gastric cancer, were identified. Then, using the drug repurposing method with the Connectivity Map CLUE Query tools, potential drugs such as Forskolin, Gestrinone, Cediranib, Apicidine, and Everolimus, which showed a highly negative correlation with the expression levels of the selected genes, were identified. This study provides a method to develop new approaches to diagnosing and treating gastric cancer by comparing the transcriptome profiles of patients gastric cancer and performing a feature engineering-assisted drug repurposing analysis based on cancer data.

PMID:38572922 | DOI:10.1089/adt.2023.141

Acta Pharm Sin B. 2024 Apr;14(4):1711-1725. doi: 10.1016/j.apsb.2024.01.001. Epub 2024 Jan 4.

ABSTRACT

Drug repurposing offers an efficient approach to therapeutic development. In this study, our bioinformatic analysis first predicted an association between obesity and lansoprazole (LPZ), a commonly prescribed drug for gastrointestinal ulcers. We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity, insulin resistance, and hepatic steatosis in mice. Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes, and induced cold tolerance in cold-exposed mice, suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism. Mechanistically, LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1 (PHOSPHO1) and produces metabolic benefits in a PHOSPHO1-dependent manner. Our results suggested that LPZ may stimulate adipose thermogenesis by inhibiting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid (2-AG-LPA) to 2-arachidonoylglycerol (2-AG) and reduce the activity of the thermogenic-suppressive cannabinoid receptor signaling. In summary, we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome, and identified a potential metabolic basis by which LPZ improves energy metabolism.

PMID:38572109 | PMC:PMC10985025 | DOI:10.1016/j.apsb.2024.01.001

Mol Divers. 2024 Apr 3. doi: 10.1007/s11030-024-10834-8. Online ahead of print.

ABSTRACT

Dengue virus, an arbovirus, leads to millions of infections every year ultimately leading to a high rate of mortality. Highly effective and specific therapeutic option is not available till date to combat viral infection. One of the first stages in the virus lifecycle encompasses the viral entry into the host cell which is mediated by the interaction between heparan sulphate and the Dengue virus envelope protein in turn leading to the interaction between the envelope protein receptor binding domain and host cell receptors. The heparan sulphate binding site on the envelope protein was established using literature survey and the result validated using ColDock simulations. We have performed virtual screening against the heparan sulphate binding site using DrugBank database and short-listed probable inhibitors based on binding energy calculation following Molecular Dynamics (MD) simulations in this study. Two compounds (PubChem IDS 448062 and 656615) were selected for further analyses on which RAMD simulations were performed to quantitate the binding stability of both the molecules in the protein binding pocket which ultimately led to the selection of ZK-806450 molecule as the final selected compound. Competitive binding MD simulation against dengue virus envelope protein was performed for this molecule and heparan sulphate in order to ascertain the efficiency of binding of this molecule to the dengue virus envelope protein in the presence of its natural ligand molecule and found that this molecule has a higher affinity for the dengue virus envelope protein GAG binding site than heparan sulphate. This study may help in the use of this inhibitor molecule to combat dengue virus infection in foreseeable future and open a new avenue for drug repurposing methodology using competitive binding MD simulation.

PMID:38570391 | DOI:10.1007/s11030-024-10834-8

ACS Infect Dis. 2024 Apr 3. doi: 10.1021/acsinfecdis.3c00737. Online ahead of print.

ABSTRACT

Due to the widespread abuse of antibiotics, drug resistance in Enterococcus has been increasing. However, the speed of antibiotic discovery cannot keep pace with the acquisition of bacterial resistance. Thus, drug repurposing is a proposed strategy to solve the crises. Lusutrombopag (LP) has been approved as a thrombopoietin receptor agonist by the Food and Drug Administration. This study demonstrated that LP exhibited significant antimicrobial activities against vancomycin-resistant Enterococcus in vitro with rare resistance occurrence. Further, LP combined with tobramycin exhibited synergistic antimicrobial effects in vitro and in vivo against Enterococcus. No in vitro or in vivo detectable toxicity was observed when using LP. Mechanism studies indicated that the disrupted proton motive force may account for LP's antimicrobial activity. In summary, these results demonstrate that LP has the previously undocumented potential to serve as an antibacterial agent against refractory infections caused by Enterococcus.

PMID:38567846 | DOI:10.1021/acsinfecdis.3c00737

Front Neurosci. 2024 Mar 19;18:1375484. doi: 10.3389/fnins.2024.1375484. eCollection 2024.

ABSTRACT

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels generate electrical rhythmicity in various tissues although primarily heart, retina and brain. The HCN channel blocker compound, Ivabradine (Corlanor), is approved by the US Food and Drug Administration (FDA) as a medication to lower heart rate by blocking hyperpolarization activated inward current in the sinoatrial node. In addition, a growing body of evidence suggests a role for HCN channels in regulation of sleep/wake behavior. Zebrafish larvae are ideal model organisms for high throughput drug screening, drug repurposing and behavioral phenotyping studies. We leveraged this model system to investigate effects of three HCN channel blockers (Ivabradine, Zatebradine Hydrochloride and ZD7288) at multiple doses on sleep/wake behavior in wild type zebrafish. Results of interest included shorter latency to daytime sleep at 0.1 μM dose of Ivabradine (ANOVA, p: 0.02), moderate reduction in average activity at 30 μM dose of Zatebradine Hydrochloride (ANOVA, p: 0.024) in daytime, and increased nighttime sleep at 4.5 μM dose of ZD7288 (ANOVA, p: 0.036). Taken together, shorter latency to daytime sleep, decrease in daytime activity and increased nighttime sleep indicate that different HCN channel antagonists affected different parameters of sleep and activity.

PMID:38567282 | PMC:PMC10986788 | DOI:10.3389/fnins.2024.1375484

Ther Adv Neurol Disord. 2024 Apr 1;17:17562864241241383. doi: 10.1177/17562864241241383. eCollection 2024.

ABSTRACT

BACKGROUND: Several studies have demonstrated that early childhood and adolescent obesity are risk factors for multiple sclerosis (MS) susceptibility. Obesity is thought to share inflammatory components with MS through overproduction of pro-inflammatory adipokines (e.g., leptin) and reduction of anti-inflammatory adipokines (e.g, adiponectin). Recently, drug repurposing (i.e. identifying new indications for existing drugs) has garnered significant attention. The US Food and Drug Administration Adverse Event Reporting System (FAERS) database serves not only as a resource for mining adverse drug reactions and safety signals but also for identifying inverse associations and potential medication repurposing opportunities.

OBJECTIVE: We aimed to explore the association between weight-loss-inducing drugs and MS using real-world reports from the FAERS database.

DESIGN: Secondary analysis of existing data from the FAERS database.

METHODS: We conducted a disproportionality analysis using the FAERS database between the fourth quarter of 2003 and the second quarter of 2023 to explore associations between MS and weight loss-inducing drugs. Disproportionality was quantified using the reporting odds ratio (ROR). An inverse association was defined when the upper limit of the 95% confidence interval for ROR was <1.

RESULTS: We found an inverse association between MS and anti-diabetic weight loss-inducing drugs including semaglutide (ROR: 0.238; 95% CI: 0.132-0.429), dulaglutide (ROR: 0.165; 95% CI: 0.109-0.248), liraglutide (ROR: 0.161; 95% CI: 0.091-0.284), empagliflozin (ROR: 0.234; 95% CI: 0.146-0.377), and metformin (ROR: 0.387; 95% CI: 0.340-0.440). No inverse associations were found for other weight loss-inducing drugs such as phentermine, bupropion, topiramate, zonisamide, and amphetamine. An exception was naltrexone (ROR: 0.556; 95% CI: 0.384-0.806).

CONCLUSION: Our findings suggest a potential consideration for repurposing anti-diabetic weight loss-inducing drugs including semaglutide, dulaglutide, and liraglutide (glucagon-like peptide-1 receptor agonists), empagliflozin (sodium-glucose cotransporter-2 inhibitor), and metformin (biguanide), for MS. This warrants validation through rigorous methodologies and prospective studies.

PMID:38566910 | PMC:PMC10986166 | DOI:10.1177/17562864241241383

Curr Drug Targets. 2024 Apr 2. doi: 10.2174/0113894501290296240327081624. Online ahead of print.

ABSTRACT

Drug repurposing is an emerging approach to reassigning existing pre-approved therapies for new indications. The FDA Adverse Event Reporting System (FAERS) is a large database of over 28 million adverse event reports submitted by medical providers, patients, and drug manufacturers and provides extensive drug safety signal data. In this review, four common drug repurposing strategies using FAERS are described, including inverse signal detection for a single disease, drug-drug interactions that mitigate a target ADE, identifying drug-ADE pairs with opposing gene perturbation signatures and identifying drug-drug pairs with congruent gene perturbation signatures. The purpose of this review is to provide an overview of these different approaches to FAERS-based drug repurposing using existing successful applications in the literature. With the fast expansion of adverse drug event reports, FAERS-based drug repurposing represents a versatile and promising strategy for discovering new uses for existing therapies.

PMID:38566381 | DOI:10.2174/0113894501290296240327081624

Hum Genomics. 2024 Apr 2;18(1):34. doi: 10.1186/s40246-024-00591-y.

ABSTRACT

BACKGROUND: Male-pattern baldness (MPB) is the most common cause of hair loss in men. It can be categorized into three types: type 2 (T2), type 3 (T3), and type 4 (T4), with type 1 (T1) being considered normal. Although various MPB-associated genetic variants have been suggested, a comprehensive study for linking these variants to gene expression regulation has not been performed to the best of our knowledge.

RESULTS: In this study, we prioritized MPB-related tissue panels using tissue-specific enrichment analysis and utilized single-tissue panels from genotype-tissue expression version 8, as well as cross-tissue panels from context-specific genetics. Through a transcriptome-wide association study and colocalization analysis, we identified 52, 75, and 144 MPB associations for T2, T3, and T4, respectively. To assess the causality of MPB genes, we performed a conditional and joint analysis, which revealed 10, 11, and 54 putative causality genes for T2, T3, and T4, respectively. Finally, we conducted drug repositioning and identified potential drug candidates that are connected to MPB-associated genes.

CONCLUSIONS: Overall, through an integrative analysis of gene expression and genotype data, we have identified robust MPB susceptibility genes that may help uncover the underlying molecular mechanisms and the novel drug candidates that may alleviate MPB.

PMID:38566255 | DOI:10.1186/s40246-024-00591-y

J Neurooncol. 2024 Apr 2. doi: 10.1007/s11060-024-04654-x. Online ahead of print.

ABSTRACT

PURPOSE: Triple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD.

METHODS: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry.

RESULTS: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model.

CONCLUSIONS: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.

PMID:38563850 | DOI:10.1007/s11060-024-04654-x

Front Hum Neurosci. 2024 Mar 18;18:1352118. doi: 10.3389/fnhum.2024.1352118. eCollection 2024.

ABSTRACT

COVID-19's effects on the human brain reveal a multifactorial impact on cognition and the potential to inflict lasting neuronal damage. Type I interferon signaling, a pathway that represents our defense against pathogens, is primarily affected by COVID-19. Type I interferon signaling, however, is known to mediate cognitive dysfunction upon its dysregulation following synaptopathy, microgliosis and neuronal damage. In previous studies, we proposed a model of outside-in dysregulation of tonic IFN-I signaling in the brain following a COVID-19. This disruption would be mediated by the crosstalk between central and peripheral immunity, and could potentially establish feed-forward IFN-I dysregulation leading to neuroinflammation and potentially, neurodegeneration. We proposed that for the CNS, the second-order mediators would be intrinsic disease-associated molecular patterns (DAMPs) such as proteopathic seeds, without the requirement of neuroinvasion to sustain inflammation. Selective vulnerability of neurogenesis sites to IFN-I dysregulation would then lead to clinical manifestations such as anosmia and cognitive impairment. Since the inception of our model at the beginning of the pandemic, a growing body of studies has provided further evidence for the effects of SARS-CoV-2 infection on the human CNS and cognition. Several preclinical and clinical studies have displayed IFN-I dysregulation and tauopathy in gene expression and neuropathological data in new cases, correspondingly. Furthermore, neurodegeneration identified with a predilection for the extended olfactory network furthermore supports the neuroanatomical concept of our model, and its independence from fulminant neuroinvasion and encephalitis as a cause of CNS damage. In this perspective, we summarize the data on IFN-I as a plausible mechanism of cognitive impairment in this setting, and its potential contribution to Alzheimer's disease and its interplay with COVID-19.

PMID:38562226 | PMC:PMC10982434 | DOI:10.3389/fnhum.2024.1352118

Mol Neurobiol. 2024 Apr 1. doi: 10.1007/s12035-024-04137-0. Online ahead of print.

ABSTRACT

Krabbe disease (KD) is a rare demyelinating disorder characterized by demyelination caused by mutations in the GALC gene, resulting in toxic accumulation of psychosine. Psychosine has been identified as detrimental to oligodendrocytes, leading to demyelination through diverse hypothesized pathways. Reducing demyelination is essential to maintain neurological function in KD; however, therapeutic interventions are currently limited. Acetylcholinesterase inhibitors (AChEi) are commonly used for symptomatic management of Alzheimer's Disease and are suggested to have potential disease-modifying effects, including regulating myelin state. In particular, donepezil, an AChEi, has demonstrated promising effects in cellular and animal models, including promotion of the expression of myelin-related genes and reduction of glial cell reactivity. This drug also acts as an agonist for sigma-1 receptors (Sig-1R), which are implicated in demyelination diseases. In the context of drug repurposing, here, we demonstrate that administration of donepezil has protective effects in the twitcher mouse model of KD. We provide data showing that donepezil preserves myelin and reduces glial cell reactivity in the brains of twitcher mice. Moreover, donepezil also improves behavioral phenotypes and increases lifespan in twitcher animals. These findings suggest that donepezil, with its dual activity as an AChE inhibitor and Sig-1R agonist, may hold promise as a therapeutic candidate for demyelinating diseases, including KD.

PMID:38558359 | DOI:10.1007/s12035-024-04137-0

Methods Cell Biol. 2024;185:35-48. doi: 10.1016/bs.mcb.2024.02.003. Epub 2024 Mar 5.

ABSTRACT

Childhood cancer is a major cause of death in developed countries, and while treatments and survival rates have improved, long-term side effects remain a challenge. The genetic component of pediatric tumors and their aggressive progression, makes the study of childhood cancer a complex area of research. Here, we introduce the fruit fly Drosophila melanogaster as study model. We emphasize its numerous advantages, including binary gene expression systems that enable precise control over the timing and location of gene expression manipulation, the capacity to combine multiple genes associated with cancer or the testing of human cancer variants within a live, intact animal. As an illustrative example, we focus on the Drosophila cancer paradigm which involves medically relevant genes, the Notch and PI3K/Akt signaling pathways. We describe how this cancer paradigm allows assessing two critical aspects of tumorigenesis during juvenile stages: (1) viability (do animals with particular cancer mutations survive into adulthood?), and (2) tumor burden (what percentage of animals bearing the cancer mutations actually develop cancer and what is the extent of the tumor?). We highlight the potential of Drosophila as a molecular therapeutic tool for drug screening and drug repurposing of medicines already approved to treat other diseases in children, thereby accelerating the potential translation of results into humans. This preclinical animal model sustains huge potential and is cost-effective. It allows screening of thousands of compounds and genes at a relatively low cost and human efforts, opening innovative venues to explore more effective and safer treatments of childhood cancer.

PMID:38556450 | DOI:10.1016/bs.mcb.2024.02.003

Chem Pharm Bull (Tokyo). 2024;72(3):345-348. doi: 10.1248/cpb.c24-00032.

ABSTRACT

Eperisone Hydrochloride was launched in Japan in 1983 and has been used to improve muscle tone and treat spastic paralysis (Originator: Eisai Co., Ltd.). However, its biochemical mechanism of action is unknown. SB Drug Discovery was used to evaluate purinergic P2X (P2X) receptor antagonism using fluorescence. In this study, we discovered that its target protein is the P2X7 receptor. Also, P2X receptor subtype selectivity was high. This finding demonstrates the (Eperisone-P2X7-pain linkage), the validity of P2X7 as a drug target, and the possibility of drug repositioning of Eperisone Hydrochloride.

PMID:38556262 | DOI:10.1248/cpb.c24-00032

Toxicology. 2024 Mar 29:153791. doi: 10.1016/j.tox.2024.153791. Online ahead of print.

ABSTRACT

Bisphenol A (BPA) is a synthetic chemical widely used as a monomer for producing polycarbonate plastics. The present investigation employed an in-silico approach to identify BPA-responsive genes and comprehend the biological functions affected using in vitro studies. A Comparative Toxicogenomics Database search identified 29 BPA-responsive genes in cervical cancer (CC). Twenty-nine genes were screened using published datasets, and thirteen of those showed differential expression between normal and CC samples. Protein-Protein Interaction Networks (PPIN) analysis identified BIRC5, CASP8, CCND1, EGFR, FGFR3, MTOR, VEGFA, DOC2B, WNT5A, and YY1 as hub genes. KM-based survival analysis identified that CCND, EGFR, VEGFA, FGFR3, DOC2B, and YY1 might affect CC patient survival. SiHa and CaSki cell proliferation, migration, and invasion were all considerably accelerated by BPA exposure. Changes in cell morphology, remodelling of the actin cytoskeleton, increased number and length of filopodia, elevated intracellular reactive oxygen species and calcium, and lipid droplet accumulation were noted upon BPA exposure. BPA treatment upregulated the expression of epithelial to mesenchymal transition pathway members and enhanced the nuclear translocation of CTNNB1. We showed that the enhanced migration and nuclear translocation of CTNNB1 upon BPA exposure is a calcium-dependent process. The present study identified potential BPA-responsive genes and provided novel insights into the biological effects and mechanisms affected by BPA in CC. Our study raises concern over the use of BPA.

PMID:38555994 | DOI:10.1016/j.tox.2024.153791

Int Rev Neurobiol. 2024;175:153-185. doi: 10.1016/bs.irn.2024.02.002. Epub 2024 Mar 12.

ABSTRACT

Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.

PMID:38555115 | DOI:10.1016/bs.irn.2024.02.002

Artif Intell Med. 2024 Apr;150:102805. doi: 10.1016/j.artmed.2024.102805. Epub 2024 Feb 17.

ABSTRACT

Predicting drug-disease associations can contribute to discovering new therapeutic potentials of drugs, and providing important association information for new drug research and development. Many existing drug-disease association prediction methods have not distinguished relevant background information for the same drug targeted to different diseases. Therefore, this paper proposes a drug-disease association prediction model based on graph convolutional network and graph attention network (GCNGAT) to reposition marketed drugs under the distinguishment of background information. Firstly, in order to obtain initial drug-disease information, a drug-disease heterogeneous graph structure is constructed based on all known drug-disease associations. Secondly, based on the heterogeneous graph structure, the corresponding subgraphs of each group of drug-disease association pairs are extracted to distinguish different background information for the same drug from different diseases. Finally, a model combining Graph neural network with global Average pooling (GnnAp) is designed to predict potential drug-disease associations by learning drug-disease interaction feature representations. The experimental results show that adding subgraph extraction can effectively improve the prediction performance of the model, and the graph representation learning module can fully extract the deep features of drug-disease. Using the 5-fold cross-validation, the proposed model (GCNGAT) achieves AUC (Area Under the receiver operating characteristic Curve) values of 0.9182 and 0.9417 on the PREDICT dataset and CDataset dataset, respectively. Compared with other predictors on the same dataset (PREDICT dataset), GCNGAT outperforms the existing best-performing model (PSGCN), with a 1.58% increase in the AUC value. It is anticipated that this model can provide experimental reference for drug repositioning and further promote the drug research and development process.

PMID:38553169 | DOI:10.1016/j.artmed.2024.102805

Biomed Pharmacother. 2024 Mar 27;174:116497. doi: 10.1016/j.biopha.2024.116497. Online ahead of print.

ABSTRACT

The study of chemicals extracted from natural sources should be encouraged due to the significant number of cancer deaths each year and the financial burden imposed by this disease on society. The causes of almost all cancers involve a combination of lifestyle, environmental factors, and genetic and inherited factors. Modern medicine researchers are increasingly interested in traditional phytochemicals as they hold potential for new bioactive compounds with medical applications. Recent publications have provided evidence of the antitumor properties of phytochemicals, a key component of traditional Chinese medicine, thereby opening new avenues for their use in modern medicine. Various studies have demonstrated a strong correlation between apoptosis and autophagy, two critical mechanisms involved in cancer formation and regulation, indicating diverse forms of crosstalk between them. Phytochemicals have the ability to activate both pro-apoptotic and pro-autophagic pathways. Therefore, understanding how phytochemicals influence the relationship between apoptosis and autophagy is crucial for developing a new cancer treatment strategy that targets these molecular mechanisms. This review aims to explore natural phytochemicals that have demonstrated anticancer effects, focusing on their role in regulating the crosstalk between apoptosis and autophagy, which contributes to uncontrolled tumor cell growth. Additionally, the review highlights the limitations and challenges of current research methodologies while suggesting potential avenues for future research in this field.

PMID:38552443 | DOI:10.1016/j.biopha.2024.116497

IEEE J Biomed Health Inform. 2024 Mar 29;PP. doi: 10.1109/JBHI.2024.3383245. Online ahead of print.

ABSTRACT

Binding affinity prediction of three-dimensional (3D) protein-ligand complexes is critical for drug repositioning and virtual drug screening. Existing approaches usually transform a 3D protein-ligand complex to a two-dimensional (2D) graph, and then use graph neural networks (GNNs) to predict its binding affinity. However, the node and edge features of the 2D graph are extracted based on invariant local coordinate systems of the 3D complex. As a result, these approaches can not fully learn the global information of the complex, such as the physical symmetry and the topological information of bonds. To address these issues, we propose a novel Equivariant Line Graph Network (ELGN) for binding affinity prediction of 3D protein-ligand complexes. The proposed ELGN firstly adds a super node to the 3D complex, and then builds a line graph based on the 3D complex. After that, ELGN uses a new E(3)-equivariant network layer to pass the messages between nodes and edges based on the global coordinate system of the 3D complex. Experimental results on two real datasets demonstrate the effectiveness of ELGN over several state-of-the-art baselines.

PMID:38551822 | DOI:10.1109/JBHI.2024.3383245