Curr Microbiol. 2024 Nov 28;82(1):17. doi: 10.1007/s00284-024-03986-1.

ABSTRACT

Bacterial antimicrobial resistance (AMR), particularly multidrug resistance (MDR) in gram-negative bacterial strains, has emerged as a formidable challenge of substantial consequence, necessitating an urgent pursuit of a sustainable and efficacious strategic response. Repurposing nonantibiotic drugs as potential antibiotics or antibiotic adjuvants is a valuable approach to targeting MDR bacteria. A total of 1,750 FDA-approved drugs (APExBIO, USA) were screened to test their antimicrobial activities against MDR bacteria using the broth microdilution method according to the standard of the Clinical and Laboratory Standards Institute (CLSI). Microscale thermophoresis (MST) analysis was performed to detect the Fty720-LPS interactions. Fty720-indcued lipid changes were measured by untargeted lipidomic analysis. Isothermal titration calorimetry (ITC) analysis was used to determine the Fty720-lipid binding affinities. DNA degradation was assessed via agarose gel electrophoresis with ethidium bromide (EB) staining and visualized using a gel imaging system. Galleria mellonella larvae infection model and Mouse peritonitis infection models were used to evaluated the antibacterial ability of Fty720 in vivo. In this study, we identified Fty720, a pharmaceutical agent for treating multiple sclerosis, as a potent inhibitor of carbapenem-resistant Acinetobacter baumannii (CRAB). We demonstrated that Fty720 exerts antibacterial effects through multiple strategies, including disruption of the structural integrity of the membranes by interacting with LPS and glycerophospholipids, as well as degradation of bacterial DNA. Furthermore, through judicious structural modification, the pivotal role of the positively charged moiety (NH2) in Fty720's antibacterial activity was substantiated. Intriguingly, the translation of Fty720's antibacterial efficacy was demonstrated in vivo, substantiating its pronounced influence on elevating survival rates among models afflicted with MDR gram-negative bacterial infections. Fty720 targets CRAB via multiple pathways, including disruption of outer and inner membrane integrity and DNA degradation. This investigation unveils the multifaceted antibacterial mechanisms of Fty720 while concurrently delineating a prospective therapeutic avenue to counteract MDR gram-negative bacterial strains.

PMID:39607538 | DOI:10.1007/s00284-024-03986-1

Front Pharmacol. 2024 Nov 13;15:1423502. doi: 10.3389/fphar.2024.1423502. eCollection 2024.

ABSTRACT

Despite advances in cancer treatment, current cancer incidence and prevalence still demand multimodal treatments to enhance survival and clinical outcomes. Drugs used in cardiology, such as β-blockers and statins have gained attention for their potential roles in oncology. This review focused on their possible complementary use in solid tumors, including breast, colorectal, lung, and prostate cancers. The involvement of the autonomic nervous system in promoting tumor growth can be disrupted by β-blockers, potentially hindering cancer progression. Statins, known for their pleiotropic effects, may also inhibit cancer growth by reducing cholesterol availability, a key factor in cell proliferation. We will provide an update on the impact of these therapies on cancer treatment and surveillance, discuss the underlying mechanisms, and explore their effects on the heart, contributing to the growing field of cardio-oncology.

PMID:39605917 | PMC:PMC11598443 | DOI:10.3389/fphar.2024.1423502

Sci Rep. 2024 Nov 27;14(1):29436. doi: 10.1038/s41598-024-79897-9.

ABSTRACT

Monkeypox (Mpox) is a growing public health concern, with complex interactions within host systems contributing to its impact. This study employs multi-omics approaches to uncover therapeutic targets and potential drug repurposing opportunities to better understand Mpox's molecular pathogenesis. We developed an in silico host-pathogen interaction (HPI) network and applied weighted gene co-expression network analysis (WGCNA) to explore interactions between Mpox and host proteins. Subtype-specific host-pathogen protein-protein interaction networks were constructed, and key modules from the HPI and WGCNA were integrated to identify significant host proteins. To predict upstream signaling pathways and transcription factors, we used eXpression2Kinases and ChIP-X Enrichment Analysis. The multi-Steiner trees method was applied to compare our findings with those from FDA-approved antiviral drugs. Analysis of 55 differentially expressed genes in Mpox infection revealed 11 kinases and 15 transcription factors as key regulators. We identified 16 potential drug targets, categorized into 8 proviral genes (ESR2, ERK1, ERK2, P38, JNK1, CDK4, GSK3B, STAT3) designated for inhibition, and 8 antiviral genes (IKKA, HDAC1, HIPK2, TF65, CSK21, HIPK2, ESR2, GSK3B) designated for activation. Proviral genes are involved in the AKT, Wnt, and STAT3 pathways, while antiviral genes impact the AP-1, NF-κB, apoptosis, and IFN pathways. Promising FDA-approved candidates were identified, including kinase inhibitors, steroid hormone receptor agonists, STAT3 inhibitors, and notably Niclosamide. This study enhances our understanding of Mpox by identifying key therapeutic targets and potential repurposable drugs, providing a valuable framework for developing new treatments.

PMID:39604570 | DOI:10.1038/s41598-024-79897-9

J Biomol Struct Dyn. 2024 Nov 27:1-23. doi: 10.1080/07391102.2024.2428829. Online ahead of print.

ABSTRACT

HDAC8 and HDAC2 are recently reported to be overexpressed in cervical cancer. To date, studies related to the use of dual targeted HDAC inhibitor to treat cervical cancer are not well explored. Again, majority of the selective HDAC inhibitors discovered so far are hydroxamic acids, which have multiple adverse side-effects due to their strong zinc chelating ability. In this study, we repurposed DrugBank molecules to identify novel non hydroxamate compounds as potential HDAC8/2 dual inhibitors that can be effective for cervical cancer management. Therefore, a comprehensive integrated in silico approach, involving two-tier virtual screening, has been adopted. An initial e-pharmacophore model generation based on the co-ligands associated with HDAC8 and HDAC2 and subsequent PBVS of 12223 drug molecules were performed which eventually yielded 658 hits having fitness scores ≥ 1.0 for both the proteins. Then, SBVS for these hits was done using Glide XP method into the HDAC8 and HDAC2 crystal structures which resulted in 52 hits having XPGS ≤ -9.0 kcal/mol against both the proteins. Following this, they were re-docked into other HDAC isoforms to confirm isoform selectivity. DB11747, DB03973, DB03812, DB07890, and DB03448 were identified as top hits and were finally subjected to molecular dynamics simulation for stability of the complexes and MM-GBSA studies to calculate binding free energies. These hits have stable interactions with both HDAC8 and HDAC2 protein binding sites. In silico ADMET studies brought to limelight the promising pharmacokinetics and safety profiles of the hits. In silico cytotoxicity prediction studies also revealed potent anticancer activity.

PMID:39604351 | DOI:10.1080/07391102.2024.2428829

Diabetes Obes Metab. 2024 Nov 27. doi: 10.1111/dom.16105. Online ahead of print.

ABSTRACT

The term 'clinical cemetery' is frequently used to characterize ischaemic stroke, one of the leading causes of mortality and long-term morbidity globally. Over the past two decades, a number of novel therapies have been investigated for ischaemic stroke. However, aside from mechanical thrombectomy, the only FDA-approved prescription for treating ischaemic stroke is tissue plasminogen activator, which has a limited therapeutic period. Although post-stroke rehabilitation therapies are helpful in improving functional recovery, their benefits cannot be yielded promptly. Nowadays, drug repurposing might be an appealing approach to expanding therapeutic options for ischaemic stroke. During the last decade, metformin has been extensively researched as a potential repurposing medicine for ischaemic stroke, with a focus on both preventive and therapeutic approaches. With regard to the idea of repurposing metformin in ischaemic stroke, this review aims to compile the available data from pre-clinical and clinical trials, address and clarify any discrepancies, and offer solutions.

PMID:39604047 | DOI:10.1111/dom.16105

Curr Opin Lipidol. 2024 Nov 28. doi: 10.1097/MOL.0000000000000966. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: This review highlights contributions of the Global Lipids Genetics Consortium (GLGC) in advancing the understanding of the genetic etiology of blood lipid traits, including total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and non-HDL cholesterol. We emphasize the consortium's collaborative efforts, discoveries related to lipid and lipoprotein biology, methodological advancements, and utilization in areas extending beyond lipid research.

RECENT FINDINGS: The GLGC has identified over 923 genomic loci associated with lipid traits through genome-wide association studies (GWASs), involving more than 1.65 million individuals from globally diverse populations. Many loci have been functionally validated by individuals inside and outside the GLGC community. Recent GLGC studies show increased population diversity enhances variant discovery, fine-mapping of causal loci, and polygenic score prediction for blood lipid levels. Moreover, publicly available GWAS summary statistics have facilitated the exploration of lipid-related genetic influences on cardiovascular and noncardiovascular diseases, with implications for therapeutic development and drug repurposing.

SUMMARY: The GLGC has significantly advanced the understanding of the genetic basis of lipid levels and serves as the leading resource of GWAS summary statistics for these traits. Continued collaboration will be critical to further understand lipid and lipoprotein biology through large-scale genetic assessments in diverse populations.

PMID:39602359 | DOI:10.1097/MOL.0000000000000966

Pharmaceuticals (Basel). 2024 Nov 15;17(11):1536. doi: 10.3390/ph17111536.

ABSTRACT

BACKGROUND: Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved.

METHODS: This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide.

RESULTS: The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein-ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6-ligand complexes, confirming the stability of their interactions.

CONCLUSIONS: The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems.

PMID:39598445 | DOI:10.3390/ph17111536

Int J Mol Sci. 2024 Nov 19;25(22):12441. doi: 10.3390/ijms252212441.

ABSTRACT

Cancer ranks among the primary contributors to global mortality. In 2022, the global incidence of new cancer cases reached about 20 million, while the number of cancer-related fatalities reached 9.7 million. In Saudi Arabia, there were 13,399 deaths caused by cancer and 28,113 newly diagnosed cases of cancer. Drug repurposing is a drug discovery strategy that has gained special attention and implementation to enhance the process of drug development due to its time- and money-saving effect. It involves repositioning existing medications to new clinical applications. Cancer treatment is a therapeutic area where drug repurposing has shown the most prominent impact. This review presents a compilation of medications that have been repurposed for the treatment of various types of cancers. It describes the initial therapeutic and pharmacological classes of the repurposed drugs and their new applications and mechanisms of action in cancer treatment. The review reports on drugs from various pharmacological classes that have been successfully repurposed for cancer treatment, including approved ones and those in clinical trials and preclinical development. It stratifies drugs based on their anticancer repurpose as multi-type, type-specific, and mechanism-directed, and according to their pharmacological classes. The review also reflects on the future potential that drug repurposing has in the clinical development of novel anticancer therapies.

PMID:39596504 | DOI:10.3390/ijms252212441

Int J Mol Sci. 2024 Nov 14;25(22):12236. doi: 10.3390/ijms252212236.

ABSTRACT

Bacterial blight (BB) of rice caused by Xanthomonas oryzae pathovar oryzae (Xoo) is a serious global rice disease. Due to increasing bactericide resistance, developing new inhibitors is urgent. Drug repositioning offers a potential strategy to address this issue. In this study, we integrated transcriptional data into a genome-scale metabolic model (GSMM) to screen novel anti-Xoo targets. Two RNA-seq datasets (before and after bismerthiazol treatment) were used to constrain the GSMM and simulate metabolic processes. Metabolic fluxes were calculated using parsimonious flux balance analysis (pFBA) identifying reactions with significant changes for target screening. Glutathione oxidoreductase (GSR) was selected as a potential anti-Xoo target and validated through antibacterial experiments. Virtual screening based on the target identified DB12411 as a lead compound with the potential for new antibacterial agents. This approach demonstrates that integrating metabolic networks and transcriptional data can aid in both understanding antibacterial mechanisms and discovering novel drug targets.

PMID:39596301 | DOI:10.3390/ijms252212236

Biomolecules. 2024 Oct 29;14(11):1376. doi: 10.3390/biom14111376.

ABSTRACT

Collagen VI-related dystrophies (COL6RD) are a group of rare muscle disorders caused by mutations in specific genes responsible for type VI collagen production. It affects muscles, joints, and connective tissues, leading to weakness, joint problems, and structural issues. Currently, there is no effective treatment for COL6RD; its management typically addresses symptoms and complications. Therefore, it is essential to decipher the disease's molecular mechanisms, identify drug targets, and develop effective treatment strategies to treat COL6RD. In this study, we employed differential gene expression analysis, weighted gene co-expression network analysis, and genome-scale metabolic modeling to investigate gene expression patterns in COL6RD patients, uncovering key genes, significant metabolites, and disease-related pathophysiological pathways. First, we performed differential gene expression and weighted gene co-expression network analyses, which led to the identification of 12 genes (CHCHD10, MRPS24, TRIP10, RNF123, MRPS15, NDUFB4, COX10, FUNDC2, MDH2, RPL3L, NDUFB11, PARVB) as potential hub genes involved in the disease. Second, we utilized a drug repurposing strategy to identify pharmaceutical candidates that could potentially modulate these genes and be effective in the treatment. Next, we utilized context-specific genome-scale metabolic models to compare metabolic variations between healthy individuals and COL6RD patients. Finally, we conducted reporter metabolite analysis to identify reporter metabolites (e.g., phosphatidates, nicotinate ribonucleotide, ubiquinol, ferricytochrome C). In summary, our analysis revealed critical genes and pathways associated with COL6RD and identified potential targets, reporter metabolites, and candidate drugs for therapeutic interventions.

PMID:39595553 | DOI:10.3390/biom14111376

Biomedicines. 2024 Nov 19;12(11):2645. doi: 10.3390/biomedicines12112645.

ABSTRACT

Autophagy is an intrinsic breakdown system that recycles organelles and macromolecules, which influences metabolic pathways, differentiation, and thereby cell survival. Oral health is an essential component of integrated well-being, and it is critical for developing therapeutic interventions to understand the molecular mechanisms underlying the maintenance of oral homeostasis. However, because of the complex dynamic relationship between autophagy and oral health, associated treatment modalities have not yet been well elucidated. Determining how autophagy affects oral health at the molecular level may enhance the understanding of prevention and treatment of targeted oral diseases. At the molecular level, hard and soft oral tissues develop because of complex interactions between epithelial and mesenchymal cells. Aging contributes to the progression of various oral disorders including periodontitis, oral cancer, and periapical lesions during aging. Autophagy levels decrease with age, thus indicating a possible association between autophagy and oral disorders with aging. In this review, we critically review various aspects of autophagy and their significance in the context of various oral diseases including oral cancer, periapical lesions, periodontal conditions, and candidiasis. A better understanding of autophagy and its underlying mechanisms can guide us to develop new preventative and therapeutic strategies for the management of oral diseases.

PMID:39595208 | DOI:10.3390/biomedicines12112645

Biomedicines. 2024 Nov 7;12(11):2543. doi: 10.3390/biomedicines12112543.

ABSTRACT

Objective: Previous drug repositioning studies have suggested that parthenolide may be a differentiation-inducing agent for glioma cells. This study aimed to experimentally verify the neuronal differentiation-inducing effects and proliferative impact of parthenolide on human glioma cells and explore its potential mechanisms. Methods: HE staining was used to observe the morphological changes in human glioma cell lines U87 and A172 induced by parthenolide. Immunocytochemistry was conducted to detect the expression of differentiation markers. The Ki-67 detection and CCK-8 assay were used to assess the effects of parthenolide on cell proliferation. The sphere formation assay was conducted to evaluate the self-renewal. Glioma stem cells (GSCs) derived from U87 cells were utilized to assess the ability of parthenolide to induce differentiation in GSCs. Western blot was used to detect the expression of histone deacetylase 1 (HDAC1). Bioinformatics analysis based on the CGGA database was conducted to evaluate the role of HDAC1 in glioma. Results: Parthenolide (4 μM) altered the morphology of U87 and A172 cells, as elongated cell projections were observed. Parthenolide induced glioma cells to express neuronal markers NeuN, MAP2, SYP, and NEFL, but not astrocyte or oligodendrocyte markers. Parthenolide significantly inhibited proliferation and self-renewal in glioma cells. Similar effects were observed in U87 GSCs. Furthermore, parthenolide downregulated HDAC1 expression in glioma cells, and the bioinformatics analysis revealed a potential relationship between neuronal characteristics and low expression of HDAC1 in glioma. Conclusion: Parthenolide induced neuronal differentiation and inhibited the cell proliferation in human glioma cells, which might be associated with the inhibition of HDAC1.

PMID:39595109 | DOI:10.3390/biomedicines12112543

Cells. 2024 Nov 13;13(22):1876. doi: 10.3390/cells13221876.

ABSTRACT

Glucose metabolism is essential for the maintenance and function of the central nervous system. Although the brain constitutes only 2% of the body weight, it consumes approximately 20% of the body's total energy, predominantly derived from glucose. This high energy demand of the brain underscores its reliance on glucose to fuel various functions, including neuronal activity, synaptic transmission, and the maintenance of ion gradients necessary for nerve impulse transmission. Increasing evidence shows that many neurodegenerative diseases, including Parkinson's disease (PD), are associated with abnormalities in glucose metabolism. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the accumulation of α-synuclein protein aggregates. These pathological features are exacerbated by mitochondrial dysfunction, oxidative stress, and neuroinflammation, all of which are influenced by glucose metabolism disruptions. Emerging evidence suggests that targeting glucose metabolism could offer therapeutic benefits for PD. Several antidiabetic drugs have shown promise in animal models and clinical trials for mitigating the symptoms and progression of PD. This review explores the current understanding of the association between PD and glucose metabolism, emphasizing the potential of antidiabetic medications as a novel therapeutic approach. By improving glucose uptake and utilization, enhancing mitochondrial function, and reducing neuroinflammation, these drugs could address key pathophysiological mechanisms in PD, offering hope for more effective management of this debilitating disease.

PMID:39594624 | DOI:10.3390/cells13221876

Diagnostics (Basel). 2024 Nov 14;14(22):2560. doi: 10.3390/diagnostics14222560.

ABSTRACT

Acute myeloid leukemia (AML) is a complex clonal disorder characterized by clinical, genetic, metabolomic, and epigenetic heterogeneity resulting in the uncontrolled proliferation of aberrant blood-forming precursor cells. Despite advancements in the understanding of the genetic, metabolic, and epigenetic landscape of AML, it remains a significant therapeutic challenge. Functional profiling techniques, such as BH3 profiling (BP), gene expression profiling (GEP), proteomics, metabolomics, drug sensitivity/resistance testing (DSRT), CRISPR/Cas9, and RNAi screens offer valuable insights into the functional behavior of leukemia cells. BP evaluates the mitochondrial response to pro-apoptotic BH3 peptides, determining a cell's apoptotic threshold and its reliance on specific anti-apoptotic proteins. This knowledge can pinpoint vulnerabilities in the mitochondria-mediated apoptotic pathway in leukemia cells, potentially informing treatment strategies and predicting therapeutic responses. GEP, particularly RNA sequencing, evaluates the transcriptomic landscape and identifies gene expression alterations specific to AML subtypes. Proteomics and metabolomics, utilizing mass spectrometry and nuclear magnetic resonance (NMR), provide a detailed view of the active proteins and metabolic pathways in leukemia cells. DSRT involves exposing leukemia cells to a panel of chemotherapeutic and targeted agents to assess their sensitivity or resistance profiles and potentially guide personalized treatment strategies. CRISPR/Cas9 and RNAi screens enable systematic disruption of genes to ascertain their roles in leukemia cell survival and proliferation. These techniques facilitate precise disease subtyping, uncover novel biomarkers and therapeutic targets, and provide a deeper understanding of drug-resistance mechanisms. Recent studies utilizing functional profiling have identified specific mutations and gene signatures associated with aggressive AML subtypes, aberrant signaling pathways, and potential opportunities for drug repurposing. The integration of multi-omics approaches, advances in single-cell sequencing, and artificial intelligence is expected to refine the precision of functional profiling and ultimately improve patient outcomes in AML. This review highlights the diverse landscape of functional profiling methods and emphasizes their respective advantages and limitations. It highlights select successes in how these methods have further advanced our understanding of AML biology, identifies druggable targets that have improved outcomes, delineates challenges associated with these techniques, and provides a prospective view of the future where these techniques are likely to be increasingly incorporated into the routine care of patients with AML.

PMID:39594226 | DOI:10.3390/diagnostics14222560

Anticancer Drugs. 2024 Nov 25. doi: 10.1097/CAD.0000000000001667. Online ahead of print.

ABSTRACT

Neuron conversion leads to proliferation inhibition of glioma cells and may be an effective strategy to combat glioma and prevent recurrence. In this study, drug repositioning based on Connectivity Map (CMap) was conducted to discover drugs that could induce the differentiation of glioma cells into neuron-like cells, complemented by in vitro experimental validation. Downregulated neuronal genes in glioma were identified by the Human Protein Atlas database and the GeneCards database, and enrichment analysis and Gene Expression Profiling Interactive Analysis (GEPIA) were performed to ensure their reliability before they were uploaded to CMap for drug screening. The potential drug targets were screened through GEPIA and validated by the Chinese Glioma Genome Atlas database. Cell morphology, proliferation, and neuronal marker expression were detected to evaluate the differentiation-inducing effect of the selected drugs. The bioinformatics analysis identified histone deacetylase (HDAC) inhibitors as potential drugs. HDAC1/3/7 showed the relationship with neuronal genes, and HDAC1 showed the highest level of inverse correlation with neuronal gene expression and had the highest hazard ratio. In vitro study showed that both the pan-HDAC inhibitor belinostat, class I and class IIa HDAC inhibitor valproic acid, and selective HDAC1 inhibitor parthenolide induce morphology alteration, proliferation inhibition, expression of neuronal markers including microtubule-associated protein 2, neuronal nuclei antigen, and synaptophysin in U87 cells. This study suggests that the HDAC inhibitors belinostat, valproic acid, and parthenolide can induce glioma cells to differentiate into neuron-like cells, with HDAC1/3/7 being the likely drug targets and HDAC1 potentially playing an important role in this.

PMID:39589225 | DOI:10.1097/CAD.0000000000001667

Urolithiasis. 2024 Nov 25;52(1):167. doi: 10.1007/s00240-024-01669-x.

ABSTRACT

Kidney stone disease (KSD) is facing rising global prevalence and recurrence rates. Mendelian randomization aids in drug repurposing and the discovery of therapeutic targets. This study utilized Mendelian randomization (MR) to identify protein targets for KSD treatment and assess potential adverse drug reactions. A proteome-wide MR study assessed plasma proteins' causal relationship with KSD risk. Data from UK Biobank Proteomics Profiling Project (2940 proteins) and FinnGen R10 for KSD (10,556 cases, 400,681 controls) were analyzed. Colocalization analysis identified shared causal variants. Additionally, a Phenome-wide association study (PheWAS) used the FinnGen to explore adverse reactions of druggable proteins. MR study found ITIH4, F12, FKBPL positively correlated with KSD risk, while DAG1, ITIH1, LTB, CACYBP negatively correlated (Pfdr < 0.05). Colocalization analysis and PheWAS identified CACYBP as the most promising druggable protein for the prevention or treatment of nephrolithiasis recurrence. This study identified genetic protein biomarkers for KSD risk and explored potential drug side effects, offering new insights and targets for prevention and treatment.

PMID:39585470 | DOI:10.1007/s00240-024-01669-x

Curr Microbiol. 2024 Nov 25;82(1):8. doi: 10.1007/s00284-024-04001-3.

ABSTRACT

Infections and antimicrobial resistance are becoming serious global public health crises. Multidrug-resistant Staphylococcus aureus (S. aureus) infections necessitate novel antimicrobial development. In this study, we demonstrated TAK-285, a novel dual HER2/EGFR inhibitor, exerted antibacterial activity against 17 clinical methicillin-resistant S. aureus (MRSA) and 15 methicillin sensitive S. aureus (MSSA) isolates in vitro, with a minimum inhibitory concentration (MIC) of 13.7 μg/mL. At 1 × MIC, TAK-285 completely inhibited the growth of S. aureus bacterial planktonic cells, and at 2 × MIC, it exhibited a superior inhibitory effect on intracellular S. aureus SA113-GFP compared to linezolid. Moreover, TAK-285 effectively inhibited biofilm formation at sub-MIC, eradicated mature biofilm and eliminated bacteria within biofilms, as confirmed by CLSM. Furthermore, the disruption of cell membrane permeability and potential was found by TAK-285 on S. aureus, suggesting its targeting of cell membrane integrity. Global proteomic analysis demonstrated that TAK-285 disturbed the metabolic processes of S. aureus, interfered with biofilm-related gene expression, and disrupted membrane-associated proteins. Conclusively, we repurposed TAK-285 as an antimicrobial with anti-biofilm properties against S. aureus by targeting cell membrane. This study provided strong evidence for the potential of TAK-285 as a promising antimicrobial agent against S. aureus.

PMID:39585416 | DOI:10.1007/s00284-024-04001-3

Int J Pharm. 2024 Nov 22:124989. doi: 10.1016/j.ijpharm.2024.124989. Online ahead of print.

ABSTRACT

The backbone of induction therapy in acute myeloid leukaemia (AML) is to use an anthracycline in combination with cytarabine. Despite recent advances in AML therapy, this treatment remains the standard, and it has remained unchanged for decades. There are few curative options for patients unfit for this treatment. The anti-protozoal agent emetine improves efficacy of anthracycline treatment towards AML in vitro and in vivo but the effect is more potent when emetine is administered 30 min after anthracyclines. To delay the onset of protein synthesis inhibition we produced a novel inactive emetine prodrug and co-encapsulated this with the anthracycline daunorubicin (DNR) in liposomes. Nanoencapsulation protects the prodrug from degradation in the blood and ensure simultaneous delivery of both drugs to cancer cells. The prodrug concept will delay the onset of action of emetine relative to DNR. In AML cells, the combination of DNR and the emetine-prodrug in liposomes increased cytotoxicity compared to liposomes with DNR and native emetine. Liposomes loaded with the emetine prodrug did not show increased toxicity towards non-cancerous cell lines and zebrafish larvae. In patients, a liposomal formulation such as that presented herein could allow for a reduced DNR dose without compromising efficacy, thereby reducing toxic side effects and enabling improved therapy for patients not fit for current treatment options.

PMID:39581514 | DOI:10.1016/j.ijpharm.2024.124989

Tissue Cell. 2024 Nov 19;91:102624. doi: 10.1016/j.tice.2024.102624. Online ahead of print.

ABSTRACT

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population within the tumor that have recently come into the spotlight. By extracellular matrix (ECM) remodeling and robust cross-talk with cancer cells via different secretions such as cytokines, chemokines, and growth factors, CAFs contribute to cancer progression and poorer prognoses in patients. Novel candidates have been developed to inhibit CAFs; however, due to safety and efficacy issues, none have successfully passed clinical trials. Despite these shortcomings, one concept embraced by many researchers is to repurpose non-oncology drugs with potential anti-cancer properties for cancer treatment. One such example is pirfenidone (PFD), an oral anti-fibrotic medication, primarily administered for idiopathic pulmonary fibrosis. Emerging evidence suggests that PFD has promising anti-cancer effects, mainly manifesting through targeting CAFs. With inhibitory effects on CAFs, PFD restricts cancer proliferation, metastasis, immunosuppression, drug resistance, and tumor stiffness. To improve efficacy and minimize adverse effects, several innovative approaches have been proposed for targeting CAFs via PFD. Interestingly, combination therapy comprising PFD and chemotherapeutics e.g. doxorubicin has shown synergistic anti-cancer effects while protecting normal tissue. Furthermore, novel drug delivery systems, e.g. biomimetic liposomes and multilayer core-shell nanoparticles, have enhanced the pharmacokinetic properties of PFD and further increased its intratumoral delivery. Single-cell RNA sequencing (scRNA-seq) has also been suggested to characterize different subpopulations of CAFs and design precise PFD-based therapeutic strategies. Herein, we discuss the promising anti-cancer effects of PFD via inhibition of CAFs. We then provide findings on novel PFD-based approaches to target CAFs using combination therapy, nanocarrier-based drug delivery, and scRNA-seq.

PMID:39581071 | DOI:10.1016/j.tice.2024.102624

J Biomol Struct Dyn. 2024 Nov 24:1-16. doi: 10.1080/07391102.2024.2431666. Online ahead of print.

ABSTRACT

Antimicrobial resistance is recognized as a major worldwide public health dilemma in the current century. Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen, causes nosocomial infections like respiratory tract infections, urinary tract infections, dermatitis, and cystic fibrosis. It manifests antibiotic resistance via intrinsic, acquired, and adaptive pathways, where efflux pumps function in the extrusion of antibiotics from the cell. MexB protein, part of the tripartite efflux pumps MexAB-OprM present in P.aeruginosa, expels the penems and β-lactam antibiotics, thereby enhancing Pseudomonas resistance. The current study was intended to screen around 1602 clinically approved drugs to understand their ability to inhibit the MexB protein. Amongst them, the top 5 drug molecules were selected based on the binding energies for analyzing their physio-chemical and toxicity properties. Lomitapide was found to have the maximum negative binding energy followed by Nilotinib, whereas Nilotinib's number of hydrogen bonds was higher than that of Lomitapide. ADMET study revealed that all 5 drug molecules had limited solubility. Also, Lomitapide and Venetoclax showed low bioavailability scores, while Nilotinib, Eltrombopag, and Conivaptan demonstrated higher potential for therapeutic levels. A molecular dynamic simulation study of the 5 drugs against MexB was carried out for 200 nanoseconds. The RMSD, RMSF, Hydrogen bond formation, Radius of gyration, SASA, PCA, DCCM, DSSP and MM-PBSA binding energy calculation along with demonstrated high stability of the MexB-Nilotinib complex with lesser distortions. Our study concludes, that Nilotinib is a potential inhibitor and can be developed as a therapeutic agent against MexB protein for controlling P. aeruginosa infections.

PMID:39580714 | DOI:10.1080/07391102.2024.2431666