PLoS One. 2024 Jul 26;19(7):e0307649. doi: 10.1371/journal.pone.0307649. eCollection 2024.

ABSTRACT

Cancer treatment has become one of the biggest challenges in the world today. Different treatments are used against cancer; drug-based treatments have shown better results. On the other hand, designing new drugs for cancer is costly and time-consuming. Some computational methods, such as machine learning and deep learning, have been suggested to solve these challenges using drug repurposing. Despite the promise of classical machine-learning methods in repurposing cancer drugs and predicting responses, deep-learning methods performed better. This study aims to develop a deep-learning model that predicts cancer drug response based on multi-omics data, drug descriptors, and drug fingerprints and facilitates the repurposing of drugs based on those responses. To reduce multi-omics data's dimensionality, we use autoencoders. As a multi-task learning model, autoencoders are connected to MLPs. We extensively tested our model using three primary datasets: GDSC, CTRP, and CCLE to determine its efficacy. In multiple experiments, our model consistently outperforms existing state-of-the-art methods. Compared to state-of-the-art models, our model achieves an impressive AUPRC of 0.99. Furthermore, in a cross-dataset evaluation, where the model is trained on GDSC and tested on CCLE, it surpasses the performance of three previous works, achieving an AUPRC of 0.72. In conclusion, we presented a deep learning model that outperforms the current state-of-the-art regarding generalization. Using this model, we could assess drug responses and explore drug repurposing, leading to the discovery of novel cancer drugs. Our study highlights the potential for advanced deep learning to advance cancer therapeutic precision.

PMID:39058696 | DOI:10.1371/journal.pone.0307649

Curr Issues Mol Biol. 2024 Jun 27;46(7):6566-6579. doi: 10.3390/cimb46070391.

ABSTRACT

Cervical cancer presents a significant challenge to the global health of women. Despite substantial advances in human papillomavirus (HPV)-related cervical cancer vaccines, non-HPV-related cervical cancer is still waiting novel therapeutic options. Drug repurposing has provided a promising approach to improve cancer therapy in recent years. Our study aimed to explore the potential in vitro antineoplastic effects of levosimendan on cervical cancer cells. The antiproliferative effects of levosimendan were investigated on cervical cancer cells using a standard MTT assay. Fluorescent double staining was performed to identify its ability to induce apoptosis and necrosis. The possible mechanism of action of levosimendan was explored using cell-cycle analysis. Furthermore, antimetastatic effects were investigated using a wound-healing assay and a Boyden chamber assay. Our results revealed that levosimendan exhibited the highest growth-inhibitory effect in the HPV-negative C33A cell line. However, the effects were modest compared to the standard agent, cisplatin. Cell-cycle analysis detected that levosimendan can induce cell-cycle arrest in C33A cells by increasing the G1 and G2/M phases, decreasing the S phase, and enhancing the hypodiploid subG1 population. Levosimendan inhibited cell migration and invasion in a concentration-dependent manner. As levosimendan showed antimetastatic efficacy, it could be considered for repurposing to contribute to overcoming resistance to therapy in cervical cancer.

PMID:39057033 | DOI:10.3390/cimb46070391

Cells. 2024 Jul 12;13(14):1186. doi: 10.3390/cells13141186.

ABSTRACT

Autophagy, an intrinsic catabolic mechanism that eliminates misfolded proteins, dysfunctional organelles, and lipid droplets, plays a vital function in energy balance and cytoplasmic quality control, in addition to maintaining cellular homeostasis. Liver cancer such as hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths globally and shows resistance to several anticancer drugs. Despite the rising incidence and poor prognosis of malignant HCC, the underlying molecular mechanisms driving this aggressive cancer remain unclear. Several natural compounds, such as phytochemicals of dietary and non-dietary origin, affect hepatocarcinogenesis signaling pathways in vitro and in vivo, which may help prevent and treat HCC cells. Current HCC cells treatments include chemotherapy, radiation, and surgery. However, these standard therapies have substantial side effects, and combination therapy enhances side effects for an acceptable therapeutic benefit. Therefore, there is a need to develop treatment strategies for HCC cells that are more efficacious and have fewer adverse effects. Multiple genetic and epigenetic factors are responsible for the HCC cells to become resistant to standard treatment. Autophagy contributes to maintain cellular homeostasis, which activates autophagy for biosynthesis and mitochondrial regulation and recycling. Therefore, modifying autophagic signaling would present a promising opportunity to identify novel therapies to treat HCC cells resistant to current standard treatments. This comprehensive review illustrates how natural compounds demonstrate their anti-hepatocellular carcinoma function through autophagy.

PMID:39056768 | DOI:10.3390/cells13141186

Cells. 2024 Jul 10;13(14):1175. doi: 10.3390/cells13141175.

ABSTRACT

Lorlatinib is a pharmaceutical ALK kinase inhibitor used to treat ALK driven non-small cell lung cancers. This paper analyses the intersection of past published data on the physiological consequences of two unrelated drugs from general medical practice-itraconazole and cilostazol-with the pathophysiology of ALK positive non-small cell lung cancer. A conclusion from that data analysis is that adding itraconazole and cilostazol may make lorlatinib more effective. Itraconazole, although marketed worldwide as a generic antifungal drug, also inhibits Hedgehog signaling, Wnt signaling, hepatic CYP3A4, and the p-gp efflux pump. Cilostazol, marketed worldwide as a generic thrombosis preventative drug, acts by inhibiting phosphodiesterase 3, and, by so doing, lowers platelets' adhesion, thereby partially depriving malignant cells of the many tumor trophic growth factors supplied by platelets. Itraconazole may enhance lorlatinib effectiveness by (i) reducing or stopping a Hedgehog-ALK amplifying feedback loop, by (ii) increasing lorlatinib's brain levels by p-gp inhibition, and by (iii) inhibiting growth drive from Wnt signaling. Cilostazol, surprisingly, carries minimal bleeding risk, lower than that of aspirin. Risk/benefit assessment of the combination of metastatic ALK positive lung cancer being a low-survival disease with the predicted safety of itraconazole-cilostazol augmentation of lorlatinib favors a trial of this drug trio in ALK positive lung cancer.

PMID:39056757 | DOI:10.3390/cells13141175

Biomed Pharmacother. 2024 Jul 24;178:117202. doi: 10.1016/j.biopha.2024.117202. Online ahead of print.

ABSTRACT

GLP-1 receptor agonists (GLP-1RAs) are an innovative class of drugs with significant therapeutic value for type 2 diabetes mellitus (T2DM). The GLP-1RAs currently available on the market are biologic macromolecular peptide agents that are expensive to treat and not easy to take orally. Therefore, the development of small molecule GLP-1RAs is becoming one of the most sought-after research targets for hypoglycemic drugs. In this study, we sought to find a potential oral small molecule GLP-1RA and to evaluate its effect on insulin secretion in rat pancreatic β cells and on blood glucose in mice. We downloaded the mRNA expression profiles of GSE102194 and GSE37936 from the Gene Expression Omnibus database. Subsequently, the small molecule compound idebenone was screened through the connectivity map database. The results of molecular docking, biolayer interferometry, and cellular thermal shift assay indicated that idebenone could bind potently with GLP-1R. Furthermore, ibebenone elevated intracellular cAMP levels. The radioimmunoassay data showed that idebenone enhanced glucose-stimulated insulin secretion via agonism of GLP-1R. Moreover, the results of oral glucose tolerance tests in C57BL/6, Glp-1r-/-, and hGlp-1r mice demonstrated that the glucose-lowering effects of idebenone were mediated by GLP-1R and that there were no species differences in the agonistic effect of idebenone on GLP-1R. In summary, idebenone reduces blood glucose in mice by promoting insulin release through agonism of GLP-1R, suggesting that idebenone is probably a potential GLP-1RA, which is expected to provide a new therapeutic strategy for the prevention and treatment of metabolic diseases such as T2DM.

PMID:39053424 | DOI:10.1016/j.biopha.2024.117202

J Infect Dis. 2024 Jul 25;230(1):e149-e158. doi: 10.1093/infdis/jiad540.

ABSTRACT

BACKGROUND: Cytochrome bd complexes are respiratory oxidases found exclusively in prokaryotes that are important during infection for numerous bacterial pathogens.

METHODS: In silico docking was employed to screen approved drugs for their ability to bind to the quinol site of Escherichia coli cytochrome bd-I. Respiratory inhibition was assessed with oxygen electrodes using membranes isolated from E. coli and methicillin-resistant Staphylococcus aureus strains expressing single respiratory oxidases (ie, cytochromes bd, bo', or aa3). Growth/viability assays were used to measure bacteriostatic and bactericidal effects.

RESULTS: The steroid drugs ethinylestradiol and quinestrol inhibited E. coli bd-I activity with median inhibitory concentration (IC50) values of 47 ± 28.9 µg/mL (158 ± 97.2 µM) and 0.2 ± 0.04 µg/mL (0.5 ± 0.1 µM), respectively. Quinestrol inhibited growth of an E. coli "bd-I only" strain with an IC50 of 0.06 ± 0.02 µg/mL (0.2 ± 0.07 µM). Growth of an S. aureus "bd only" strain was inhibited by quinestrol with an IC50 of 2.2 ± 0.43 µg/mL (6.0 ± 1.2 µM). Quinestrol exhibited potent bactericidal effects against S. aureus but not E. coli.

CONCLUSIONS: Quinestrol inhibits cytochrome bd in E. coli and S. aureus membranes and inhibits the growth of both species, yet is only bactericidal toward S. aureus.

PMID:39052707 | DOI:10.1093/infdis/jiad540

Turk J Biol. 2024 Apr 3;48(2):112-132. doi: 10.55730/1300-0152.2687. eCollection 2024.

ABSTRACT

Drug repurposing is the strategy of drug utilization for a treatment option other than the intended indications. This strategy has witnessed increased adoption over the past decades, especially within cancer nanomedicine. Cancer nanomedicine has been facilitated through nanoparticle-based (NP-based) delivery systems which can combat nonsmall-cell lung cancer (NSCLC) via recent advances in nanotechnology and apply its benefits to existing drugs. The repurposing of drugs, coupled with NP-based drug delivery systems, presents a promising avenue for achieving effective therapeutic solutions with accelerated outcomes. This review aims to present an overview of NSCLC treatments, with a specific focus on drug repurposing. It seeks to elucidate the latest advances in clinical studies and the utilization of NP-based drug delivery systems tailored for NSCLC treatment. First, the molecular mechanisms of Food and Drug Administration (FDA)-approved drugs for NSCLC, including ROS1 tyrosine kinase inhibitors (TKI) like repotrectinib, approved in November 2023, are detailed. Further, in vitro studies employing a combination strategy of drug repurposing and NP-based drug delivery systems as a treatment approach against NSCLC are listed. It includes the latest study on nanoparticle-based drug delivery systems loaded with repurposed drugs.

PMID:39051063 | PMC:PMC11265851 | DOI:10.55730/1300-0152.2687

Turk J Chem. 2024 Jan 4;48(2):402-421. doi: 10.55730/1300-0527.3667. eCollection 2024.

ABSTRACT

This research aimed to identify potential drug compounds from the ZINC15 molecule database that could effectively treat GnRH1R-related diseases. The study utilized molecular docking and molecular dynamics methods to achieve this goal, which is crucial in drug repurposing research. The virtual screening process involved analyzing known drug compounds using molecular docking. Additionally, molecular dynamics simulations and MM-GBSA were employed to evaluate the stability of the complexes and determine the interactions between the compounds and protein structure. As a result, this study provides significant insights for treating diseases such as endometriosis, uterine fibroids, and prostate cancer related to GnRH1R. The study also involved designing new drugs and identifying necessary molecular scaffolds.

PMID:39050495 | PMC:PMC11265929 | DOI:10.55730/1300-0527.3667

Eur Thyroid J. 2024 Jul 1:ETJ-24-0153. doi: 10.1530/ETJ-24-0153. Online ahead of print.

ABSTRACT

OBJECTIVES: Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a poor prognosis. Strategies for restoring the ability to take up iodine, so called redifferentiation, are promising but not suitable for all patients. Preclinical studies have shown that the cardiac glycoside digoxin restored RAI uptake, both in human cell lines as in a murine model. This prospective single-center open-label study aimed to investigate whether treatment with digoxin could reinduce clinically relevant RAI uptake in patients with metastasized RAI refractory NMTC.

METHODS: Eight patients with metastasized RAI refractory NMTC were included between November 2022 and June 2023. Before treatment a baseline [123I]NaI-scintigraphy was performed. Thereafter, patients were treated with digoxin for three weeks. Starting doses depended on age and weight. For safety reasons, the usual therapeutic range was aimed for. After one week, the digoxin plasma concentration as measured and digoxin dose was adjusted if necessary. After three weeks of digoxin treatment, a second [123I]NaI-scintigraphy was performed. RAI uptake was compared between the two scintigraphies.

RESULTS: Seven patients completed the digoxin treatment and were evaluable. None of the seven patients showed clinically relevant RAI uptake after digoxin treatment. No digoxin-related serious adverse events occurred during this trial.

CONCLUSION: Contrary to results from preclinical trials, in this trial, three weeks of digoxin treatment did not reinduce RAI uptake in patients with NMTC. This highlights essential challenges regarding the approach towards optimization of studies aimed to restore the RAI uptake and its therapeutic efficacy through drug repurposing.

PMID:39047141 | DOI:10.1530/ETJ-24-0153

Bioorg Med Chem Lett. 2024 Jul 21:129894. doi: 10.1016/j.bmcl.2024.129894. Online ahead of print.

ABSTRACT

Drug repurposing and rescuing have been widely explored as cost-effective approaches to expand the portfolio of chemotherapeutic agents. Based on the reported antitumor properties of both trans-cinnamic acids and quinacrine, an antimalarial aminoacridine, we explored the antiproliferative properties of two series of N-cinnamoyl-aminoacridines recently identified as multi-stage antiplasmodial leads. The compounds were evaluated in vitro against three cancer cell lines (MKN-28, Huh-7, and HepG2), and human primary dermal fibroblasts. One of the series displayed highly selective antiproliferative activity in the micromolar range against the three cancer cell lines tested, without any toxicity to non-carcinogenic cells.

PMID:39043264 | DOI:10.1016/j.bmcl.2024.129894

Heliyon. 2024 Jun 26;10(13):e33751. doi: 10.1016/j.heliyon.2024.e33751. eCollection 2024 Jul 15.

ABSTRACT

The interplay of onco-immunology and kidney transplantation heralds a transformative era in medical science. This integration, while promising, presents significant challenges. Chief among these is the dichotomy of immunosuppression-boosting immunity against malignancies while suppressing it for graft survival. Additionally, limited clinical data on novel therapies, genetic variations influencing responses, economic concerns, and the narrow therapeutic window for post-transplant malignancies necessitate strategic addressal. Conversely, opportunities abound, including personalized immune monitoring, targeted therapies, minimized immunosuppression, and improved patient quality of life. Emphasizing collaborative research and interdisciplinary cooperation, the merging of these fields offers the potential for enhanced graft survival and reduced post-transplant malignancy risks. As we harness modern technology and promote patient-centric care, the vision for the future of kidney transplantation becomes increasingly hopeful, paving the way for more personalized and effective treatments. The article aims to elucidate the critical challenge of balancing immunosuppression to simultaneously combat malignancies and ensure graft survival. It addresses the scarcity of clinical data on novel therapies, the impact of genetic variations on treatment responses, and the economic and therapeutic concerns in managing post-transplant malignancies. Furthermore, it explores the opportunities precision medicine offers, such as personalized immune monitoring, targeted therapies, and reduced immunosuppression, which could significantly improve patient outcomes. Highlighting the importance of collaborative research and interdisciplinary efforts, the article seeks to demonstrate the potential for enhanced graft survival and reduced post-transplant malignancy risks. By leveraging modern technology and prioritizing patient-centric care, it envisions a future where kidney transplantation is more personalized and effective, offering hope for advancements in this field.

PMID:39040404 | PMC:PMC11261886 | DOI:10.1016/j.heliyon.2024.e33751

Curr Pharm Des. 2024 Jul 19. doi: 10.2174/0113816128318032240702045822. Online ahead of print.

ABSTRACT

Chronic inflammation characterizes Inflammatory Bowel Disease (IBD), encompassing Crohn's Disease (CD) and Ulcerative Colitis (UC). Despite modest activity of disease in most UC patients, exacerbations occur, especially in those with severe symptoms, necessitating interventions, like colectomy. Current treatments for IBD, predominantly small molecule therapies, impose significant economic burdens. Drug repurposing offers a cost-effective alternative, leveraging existing drugs for novel therapeutic applications. This approach capitalizes on shared molecular pathways across diseases, accelerating therapeutic discovery while minimizing costs and risks. This article provides an overview of IBD and explores drug repurposing as a promising avenue for more effective and affordable treatments. Through computational and animal studies, potential drug candidates are categorized, offering insights into IBD pathogenesis and treatment strategies.

PMID:39039672 | DOI:10.2174/0113816128318032240702045822

Brief Bioinform. 2024 May 23;25(4):bbae353. doi: 10.1093/bib/bbae353.

ABSTRACT

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder for which current treatments are limited and drug development costs are prohibitive. Identifying drug targets for ASD is crucial for the development of targeted therapies. Summary-level data of expression quantitative trait loci obtained from GTEx, protein quantitative trait loci data from the ROSMAP project, and two ASD genome-wide association studies datasets were utilized for discovery and replication. We conducted a combined analysis using Mendelian randomization (MR), transcriptome-wide association studies, Bayesian colocalization, and summary-data-based MR to identify potential therapeutic targets associated with ASD and examine whether there are shared causal variants among them. Furthermore, pathway and drug enrichment analyses were performed to further explore the underlying mechanisms and summarize the current status of pharmacological targets for developing drugs to treat ASD. The protein-protein interaction (PPI) network and mouse knockout models were performed to estimate the effect of therapeutic targets. A total of 17 genes revealed causal associations with ASD and were identified as potential targets for ASD patients. Cathepsin B (CTSB) [odd ratio (OR) = 2.66 95, confidence interval (CI): 1.28-5.52, P = 8.84 × 10-3], gamma-aminobutyric acid type B receptor subunit 1 (GABBR1) (OR = 1.99, 95CI: 1.06-3.75, P = 3.24 × 10-2), and formin like 1 (FMNL1) (OR = 0.15, 95CI: 0.04-0.58, P = 5.59 × 10-3) were replicated in the proteome-wide MR analyses. In Drugbank, two potential therapeutic drugs, Acamprosate (GABBR1 inhibitor) and Bryostatin 1 (CASP8 inhibitor), were inferred as potential influencers of autism. Knockout mouse models suggested the involvement of the CASP8, GABBR1, and PLEKHM1 genes in neurological processes. Our findings suggest 17 candidate therapeutic targets for ASD and provide novel drug targets for therapy development and critical drug repurposing opportunities.

PMID:39038939 | DOI:10.1093/bib/bbae353

Brief Bioinform. 2024 May 23;25(4):bbae337. doi: 10.1093/bib/bbae337.

ABSTRACT

MOTIVATION: Drug repositioning, the identification of new therapeutic uses for existing drugs, is crucial for accelerating drug discovery and reducing development costs. Some methods rely on heterogeneous networks, which may not fully capture the complex relationships between drugs and diseases. However, integrating diverse biological data sources offers promise for discovering new drug-disease associations (DDAs). Previous evidence indicates that the combination of information would be conducive to the discovery of new DDAs. However, the challenge lies in effectively integrating different biological data sources to identify the most effective drugs for a certain disease based on drug-disease coupled mechanisms.

RESULTS: In response to this challenge, we present MiRAGE, a novel computational method for drug repositioning. MiRAGE leverages a three-step framework, comprising negative sampling using hard negative mining, classification employing random forest models, and feature selection based on feature importance. We evaluate MiRAGE on multiple benchmark datasets, demonstrating its superiority over state-of-the-art algorithms across various metrics. Notably, MiRAGE consistently outperforms other methods in uncovering novel DDAs. Case studies focusing on Parkinson's disease and schizophrenia showcase MiRAGE's ability to identify top candidate drugs supported by previous studies. Overall, our study underscores MiRAGE's efficacy and versatility as a computational tool for drug repositioning, offering valuable insights for therapeutic discoveries and addressing unmet medical needs.

PMID:39038932 | DOI:10.1093/bib/bbae337

J Phys Chem Lett. 2024 Jul 22:7681-7693. doi: 10.1021/acs.jpclett.4c01509. Online ahead of print.

ABSTRACT

Accurate prediction of Drug-Target Interactions (DTI) is crucial for drug development. Current state-of-the-art deep learning methods have significantly advanced the field; however, these methods exhibit limitations in predictive performance and the propensity for false negatives. Therefore, we propose EADTN, a simple and efficient ensemble model. We have designed an innovative feature adaptation technique to automatically extract local weights of drugs and targets, and we utilize clustering-enhanced parameter fine-tuning to overcome the issue of false negatives, thereby enhancing its reliability in drug discovery. Based on EADTN, we also propose a Shapley value-based method for identifying key drug substructures, effectively enhancing the model's interpretability. Additionally, we utilized EADTN to reveal potential interactions between NQO1 targets and the drugs SIRT-IN-1 and LY2183240, which were subsequently validated through wet-lab experiments. Experimental evidence demonstrates that EADTN consistently outperforms existing best-performing models across various data sets, promising significant benefits in fields such as drug repositioning.

PMID:39038219 | DOI:10.1021/acs.jpclett.4c01509

Iran Biomed J. 2024 Jun 29. doi: 10.61186/ibj.4177. Online ahead of print.

ABSTRACT

BACKGROUND: Cutaneous leishmaniasis is a major health problem caused by an intracellular pathogen of the genus Leishmania. CL results in morphologically distinct skin injuries, ranging from nodules to plaques and ulcers, which persist as a recuperating incessant injury depending on the type of contaminating parasite. There is still no effective treatment to reduce the skin lesions in patients infected with CL. The aim of this study was to develop strategies to treat skin lesions in CL patients.

METHODS: We retrieved the transcriptomic data of skin lesions from patients with CL and normal skin from the GEO database. The PPIN was constructed using the STRING database and Cytoscape v3.10.1 software. Critical genes were identified by topological network analysis and cluster detection. Finally, gene ontology and repurposing drugs for critical genes were determined.

RESULTS: CD8A, IFNG, IL-6, PTPRC, CCR7, TLR2, GSTA5, CYBB, IL-12RB2, ITGB2, FCGR3A, CTLA4, and IFNG were identified as the critical genes in PPIN and subnetworks. Enrichment analysis revealed that T-cell receptor signaling, TLR signaling, cytokine-cytokine receptor interaction, graft-versus-host disease, leishmaniasis, chemokine signaling, primary immunodeficiency, and Th17 cell differentiation were the major pathways associated with critical genes. The drug repurposing results identified cyclosporine, rituximab, infliximab, blinatumomab, and methylprednisolone as candidates for treatment of CL.

CONCLUSION: After validating our model with available experimental data, we found that critical molecules and drug candidates play a crucial role in the treatment of skin lesions caused by Leishmania in prospective studies.

PMID:39036455 | DOI:10.61186/ibj.4177

Med Oncol. 2024 Jul 20;41(8):204. doi: 10.1007/s12032-024-02451-0.

ABSTRACT

The concept of drug repurposing is now widely utilized by biomedical scientists for drug discovery. An example of this is the use of selegiline (SEL), a monoamine oxidase inhibitor that was initially used for the management of depression but is now being considered for another purpose. This study compares the cytotoxic effects of SEL on different cancer cells. Further, the study explores the molecular mechanism of cell death, validating the possibility of its repurposing for cancer. Preliminary analysis of network pharmacological data was conducted in silico, followed by in vitro cytotoxicity tests on PC12, G361, MDA-MB231, MCF7, THP-1, and Hela cells under normoxic and hypoxic conditions, using the MTT assay. The mechanism of cell death was then confirmed by performing DAPI and FITC-conjugated Annexin V and Propidium Iodide (PI) staining assays. Additionally, ROS levels and PKC phosphorylation were also evaluated. In silico analysis has revealed that SEL is associated with ten genes linked to different cancer types. Specifically, SEL was most cytotoxic to neuronal pheochromocytoma, triple-negative human epithelial breast cancer cells, and ER+ and PR+ breast cancer cells. Furthermore, it was observed that this cell death occurred through ROS-independent apoptosis pathways. In addition, SEL was found to inhibit the phosphorylation of PKC, which may contribute to cell death. SEL induces apoptosis in breast cancer cells independently of reactive oxygen species and inhibits the phosphorylation of protein kinase C, which merits further exploration.

PMID:39033171 | DOI:10.1007/s12032-024-02451-0

Med Microbiol Immunol. 2024 Jul 20;213(1):16. doi: 10.1007/s00430-024-00799-8.

ABSTRACT

Melioidosis is a severe infectious disease caused by Burkholderia pseudomallei, an intracellular pathogen with a high mortality rate and significant antibiotic resistance. The high mortality rate and resistance to antibiotics have drawn considerable attention from researchers studying melioidosis. This study evaluated the effects of various concentrations (75, 50, and 25 µg/mL) of promethazine hydrochloride (PTZ), a potent antihistamine, on biofilm formation and lipase activity after 24 h of exposure to B. thailandensis E264. A concentration-dependent decrease in both biofilm biomass and lipase activity was observed. RT-PCR analysis revealed that PTZ treatment not only made the biofilm structure loose but also reduced the expression of btaR1, btaR2, btaR3, and scmR. Single gene knockouts of quorum sensing (QS) receptor proteins (∆btaR1, ∆btaR2, and ∆btaR3) were successfully constructed. Deletion of btaR1 affected biofilm formation in B. thailandensis, while deletion of btaR2 and btaR3 led to reduced lipase activity. Molecular docking and biological performance results demonstrated that PTZ inhibits biofilm formation and lipase activity by suppressing the expression of QS-regulated genes. This study found that repositioning PTZ reduced biofilm formation in B. thailandensis E264, suggesting a potential new approach for combating melioidosis.

PMID:39033094 | DOI:10.1007/s00430-024-00799-8

Life Sci. 2024 Jul 18:122923. doi: 10.1016/j.lfs.2024.122923. Online ahead of print.

ABSTRACT

AIMS: Sepsis pathophysiology is complex and identifying effective treatments for sepsis remains challenging. The study aims to identify effective drugs and targets for sepsis through transcriptomic analysis of sepsis patients, repositioning analysis of compounds, and validation by animal models.

MAIN METHODS: GSE185263 obtained from the GEO database that includes gene expression profiles of 44 healthy controls and 348 sepsis patients categorized by severity. Bioinformatic algorithms revealed the molecular, function, and immune characteristics of the sepsis, and constructed sepsis-related protein-protein interaction networks. Subsequently, Random Walk with Restart analysis was applied to identify candidate drugs for sepsis, which were tested in animal models for survival, inflammation, coagulation, and multi-organ damage.

KEY FINDINGS: Our analysis found 1862 genes linked to sepsis development, enriched in functions like neutrophil extracellular trap formation (NETs) and complement/coagulation cascades. With disease progression, immune activation-associated cells were inhibited, while immune suppression-associated cells were activated. Next, the drug repositioning method identified candidate drugs, such as alpha-1 antitrypsin, that may play a therapeutic role by targeting neutrophil elastase (NE) to inhibit NETs. Animal experiments proved that alpha-1 antitrypsin treatment can improve the survival rate, reduce sepsis score, reduce the levels of inflammation markers in serum, and alleviate muti-organ morphological damage in mice with sepsis. The further results showed that α-1 antitrypsin can inhibit the NETs by suppressing the NE for the treatment of sepsis.

SIGNIFICANCE: Alpha-1 antitrypsin acted on the NE to inhibit NETs thereby protecting mice from sepsis-induced inflammation and coagulation.

PMID:39032690 | DOI:10.1016/j.lfs.2024.122923

Mol Inform. 2024 Jun 21:e202300336. doi: 10.1002/minf.202300336. Online ahead of print.

ABSTRACT

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC50 values of 3.3, 3.2 and 5.8 μM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6 μM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible.

PMID:39031899 | DOI:10.1002/minf.202300336