Sci Rep. 2024 Nov 11;14(1):27545. doi: 10.1038/s41598-024-79391-2.

ABSTRACT

Glioblastoma (GBM) is the most malignant brain cancer and one of the leading causes of cancer-related death globally. So, identifying potential molecular signatures and associated drug molecules are crucial for diagnosis and therapies of GBM. This study suggested GBM-causing ten key genes (ASPM, CCNB2, CDK1, AURKA, TOP2A, CHEK1, CDCA8, SMC4, MCM10, and RAD51AP1) from nine transcriptomics datasets by combining supervised and unsupervised learning results. Differential expression patterns of key genes (KGs) between GBM and control samples were verified by different independent databases. Gene regulatory network (GRN) detected some important transcriptional and post-transcriptional regulators for KGs. The KGs-set enrichment analysis unveiled some crucial GBM-causing molecular functions, biological processes, cellular components, and pathways. The DNA methylation analysis detected some hypo-methylated CpG sites that might stimulate the GBM development. From the immune infiltration analysis, we found that almost all KGs are associated with different immune cell infiltration levels. Finally, we recommended KGs-guided four repurposable drug molecules (Fluoxetine, Vatalanib, TGX221 and RO3306) against GBM through molecular docking, drug likeness, ADMET analyses and molecular dynamics simulation studies. Thus, the discoveries of this study could serve as valuable resources for wet-lab experiments in order to take a proper treatment plan against GBM.

PMID:39528802 | DOI:10.1038/s41598-024-79391-2

Cancers (Basel). 2024 Oct 25;16(21):3607. doi: 10.3390/cancers16213607.

ABSTRACT

BACKGROUND/OBJECTIVES: Acute myeloid leukemia (AML) is characterized by therapeutic failure and long-term risk for disease relapses. As several therapeutic targets participate in networks, they can rewire to eventually evade single-target drugs. Hence, multi-targeting approaches are considered on the expectation that interference with many different components could synergistically hinder activation of alternative pathways and demolish the network one-off, leading to complete disease remission.

METHODS: Herein, we established a network-based, computer-aided approach for the rational design of drug combinations and de novo agents that interact with many AML network components simultaneously.

RESULTS: A reconstructed AML network guided the selection of suitable protein hubs and corresponding multi-targeting strategies. For proteins responsive to existing drugs, a greedy algorithm identified the minimum amount of compounds targeting the maximum number of hubs. We predicted permissible combinations of amiodarone, artenimol, fostamatinib, ponatinib, procaine, and vismodegib that interfere with 3-8 hubs, and we elucidated the pharmacological mode of action of procaine on DNMT3A. For proteins that do not respond to any approved drugs, namely cyclins A1, D2, and E1, we used structure-based de novo drug design to generate a novel triple-targeting compound of the chemical formula C15H15NO5, with favorable pharmacological and drug-like properties.

CONCLUSIONS: Overall, by integrating network and structural pharmacology with molecular modeling, we determined two complementary strategies with the potential to annihilate the AML network, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. These target-drug interactions could be prioritized for preclinical and clinical testing toward precision medicine for AML.

PMID:39518047 | DOI:10.3390/cancers16213607

Mol Psychiatry. 2024 Nov 8. doi: 10.1038/s41380-024-02820-1. Online ahead of print.

ABSTRACT

Working memory (WM), a key component of cognitive functions, is often impaired in psychiatric disorders such as schizophrenia. Through a genome-guided drug repurposing approach, we identified fampridine, a potassium channel blocker used to improve walking in multiple sclerosis, as a candidate for modulating WM. In a subsequent double-blind, randomized, placebo-controlled, crossover trial in 43 healthy young adults (ClinicalTrials.gov, NCT04652557), we assessed fampridine's impact on WM (3-back d-prime, primary outcome) after 3.5 days of repeated administration (10 mg twice daily). Independently of baseline cognitive performance, no significant main effect was observed (Wilcoxon P = 0.87, r = 0.026). However, lower baseline performance was associated with higher working memory performance after repeated intake of fampridine compared to placebo (rs = -0.37, P = 0.014, n = 43). Additionally, repeated intake of fampridine lowered resting motor threshold (F(1,37) = 5.31, P = 0.027, R2β = 0.01), the non-behavioral secondary outcome, indicating increased cortical excitability linked to cognitive function. Fampridine's capacity to enhance WM in low-performing individuals and to increase brain excitability points to its potential value for treating WM deficits.

PMID:39516710 | DOI:10.1038/s41380-024-02820-1

Brain Res. 2024 Nov 6;1847:149313. doi: 10.1016/j.brainres.2024.149313. Online ahead of print.

ABSTRACT

Over the past century, significant shifts in daily living have led to an increased prevalence of mental disorders, often linked to hormonal imbalances. Among these, anxiety and depression stand out as prevalent diagnoses, particularly in industrialized nations. Depression, according to the DSM-5, is a heterogeneous condition that affects emotional, cognitive, and physical functioning, with symptoms including insomnia, sexual dysfunction, and weight changes. Cognitive theories of depression highlight its impact on judgment, decision-making, thinking, and focus. Depression's multifaceted nature means that no two patients experience identical symptoms, risk factors, or treatment responses. The COVID-19 pandemic has exacerbated mental health issues, with social isolation, restricted contact, and altered daily routines contributing to increased anxiety and depression, especially among adolescents and young adults. The pandemic's psychological toll underscores the need for effective treatment strategies for mental disorders. The physical manifestations of major depressive disorder (MDD) are associated with a heightened risk of developing various medical conditions, including metabolic disorders, cardiovascular disease, stroke, epilepsy, and dementia. This review provides a comprehensive exploration of depression and anxiety, covering their different types, epidemiology, potential causes, diagnostic criteria, and available treatment options. It delves into the role of pharmacological interventions and examines recent advancements to enhance therapeutic outcomes. Additionally, the review assesses the therapeutic potential of drugs, offering insights into their efficacy in treating these complex mental health disorders. By targeting the multifactorial etiology of depression through drug repurposing and new drug development, researchers aim to enhance treatment efficacy and achieve better outcomes for patients with depression.

PMID:39515744 | DOI:10.1016/j.brainres.2024.149313

J Bone Miner Metab. 2024 Nov 8. doi: 10.1007/s00774-024-01563-x. Online ahead of print.

ABSTRACT

INTRODUCTION: Achondroplasia (ACH) is a common skeletal dysplasia associated with short-limbed short stature caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Meclozine was found to inhibit FGFR3 signaling using a drug repositioning strategy. In some countries, growth hormone (GH) has been employed to ameliorate short stature in children with ACH. This study aims to investigate the effects of meclozine and GH on bone growth and quality using an experimental model of ACH.

MATERIALS AND METHODS: Meclozine (2 mg/kg/day) and/or GH (0.35 mg/kg/day) were administered to a mouse model of ACH from the age of 7 to 56 days. Body length and body weight of each mouse were measured during these treatments. At the end of treatments, these mice were subjected to micro-computed tomography scans to measure the lengths of long bones and bone mineral density (BMD). The width of the growth plate was quantified by histological analysis.

RESULTS: The body and bone length of transgenic mice significantly increased after treatment with meclozine and GH, although there was no additive effect of the combination therapy on promoting bone growth. In contrast, BMD was additively increased by the combination therapy. The width of the growth plate in transgenic mice was significantly increased by both treatments, although the hypertrophic zone was enlarged by meclozine but not by GH.

CONCLUSION: Meclozine or GH may be an option for treating children with ACH to ameliorate bone length and quality, but the additive effect would be limited.

PMID:39514089 | DOI:10.1007/s00774-024-01563-x

Cell Mol Neurobiol. 2024 Nov 8;44(1):75. doi: 10.1007/s10571-024-01511-3.

ABSTRACT

Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder that is characterized by gradual muscle weakness and atrophy due to the degeneration of alpha motor neurons that are present on the anterior horn of the spinal cord. Despite the comprehensive investigations conducted by global scientists, effective treatments or interventions remain elusive. The time- and resource-intensive nature of the initial stages of drug research underscores the need for alternate strategies like drug repurposing. This review explores the repurposed drugs that have shown some improvement in treating SMA, including branaplam, riluzole, olesoxime, harmine, and prednisolone. The current strategy for medication repurposing, however, lacks systematicity and frequently depends more on serendipitous discoveries than on organized approaches. To speed up the development of successful therapeutic interventions, it is apparent that a methodical approach targeting the molecular origins of SMA is strictly required.

PMID:39514016 | DOI:10.1007/s10571-024-01511-3

Parasitology. 2024 Nov 7:1-8. doi: 10.1017/S0031182024001124. Online ahead of print.

ABSTRACT

Human alveolar echinococcosis is a hard-to-treat and largely untreated parasitic disease with high associated health care costs. The current antiparasitic treatment for alveolar echinococcosis relies exclusively on albendazole, which does not act parasiticidally and can induce severe adverse effects. Alternative, and most importantly, improved treatment options are urgently required. A drug repurposing strategy identified the approved antimalarial pyronaridine as a promising candidate against Echinococcus multilocularis infections. Following a 30-day oral regimen (80 mg kg−1 day−1), pyronaridine achieved an excellent therapeutic outcome in a clinically relevant hepatic alveolar echinococcosis murine model, showing a significant reduction in both metacestode size (72.0%) and counts (85.2%) compared to unmedicated infected mice, which revealed significantly more potent anti-echinococcal potency than albendazole treatment at an equal dose (metacestode size: 42.3%; counts: 4.1%). The strong parasiticidal activity of pyronaridine was further confirmed by the destructive damage to metacestode tissues observed morphologically. In addition, a screening campaign combined with computational similarity searching against an approved drug library led to the identification of pirenzepine, a gastric acid-inhibiting drug, exhibiting potent parasiticidal activity against protoscoleces and in vitro cultured small cysts, which warranted further in vivo investigation as a promising anti-echinococcal lead compound. Pyronaridine has a known drug profile and a long track record of safety, and its repurposing could translate rapidly to clinical use for human patients with alveolar echinococcosis as an alternative or salvage treatment.

PMID:39508157 | DOI:10.1017/S0031182024001124

Front Med (Lausanne). 2024 Oct 23;11:1489094. doi: 10.3389/fmed.2024.1489094. eCollection 2024.

NO ABSTRACT

PMID:39507708 | PMC:PMC11537879 | DOI:10.3389/fmed.2024.1489094

Sci Rep. 2024 Nov 7;14(1):27034. doi: 10.1038/s41598-024-76947-0.

ABSTRACT

This study aims to repurpose sericin in combating non-small lung cancer cells (A549 and H460) by combining it with dactolisib or vitamin D to reduce the dose of dactolisib and boost the anticancer effectiveness of dactolisib and vitamin D. Therefore, the binding affinities of individual and combined drugs were examined using in silico and protein-protein interaction studies, targeting NF-κB, Cyclin D1, p-AKT, and VEGF1 proteins. The findings manifested remarkable affinities for combinatorial drugs compared to individual compounds. To substantiate these findings, the combined IC50 for each combination (sericin + dactolisib and sericin + vitamin D) were determined, reporting 31.9 and 41.8 µg/ml, respectively, against A549 cells and 47.9 and 55.3 µg/ml, respectively, against H460 cells. Furthermore, combination indices were assessed to lower the doses of each drug. Interestingly, in vitro results exhibited marked diminutions in NF-κB, Cyclin D1, p-AKT, and VEGF1 after treatment with sericin + dactolisib and sericin + vitamin D compared to control lung cancer cells and those treated with a single drug. Moreover, A549 and H460 cells treated with both combinations demonstrated augmented caspase-3 levels, implying substantial apoptotic activity. Altogether, these results accentuated the prospective implementation of sericin in combination with dactolisib and vitamin D at low doses to preclude lung cancer cell proliferation.

PMID:39505930 | DOI:10.1038/s41598-024-76947-0

Biol Pharm Bull. 2024;47(11):1804-1812. doi: 10.1248/bpb.b24-00538.

ABSTRACT

Disulfiram (DSF), an irreversible aldehyde dehydrogenase 2 (ALDH2) inhibitor, is an U.S. Food and Drug Administration (FDA)-approved drug for the treatment of chronic alcoholism. Recent studies have reported an interesting antitumor activity of DSF against a wide range of human malignancies, while a growing number of ongoing and completed clinical trials have provided evidence supporting the repurposing of DSF as an anticancer treatment. Nevertheless, despite its current clinical indications and potential future therapeutic applications for treating various diseases, DSF is associated with serious side effects attributed to the inhibition of ALDH2. We have recently synthesized DSF analogs (2a-v) with limited inhibition of ALDH2. Here, we report the anticancer activity of these molecules by highlighting their effects on cell signaling in Jurkat cells. DSF and two DSF analogs, 2g and 2r, all stimulated apoptotic signaling pathways, although the 2g analog activated more apoptosis-related genes and induced higher levels of apoptosis in vitro. Differential gene expression data suggested that compounds 2g and 2r specifically reprogram target cells to downregulate pathways related to cell growth and division, while upregulating pathways related to apoptosis or differentiation. Interestingly, both compounds 2g and 2r had more differentially expressed genes related to DNA damage pathways (including those related to apoptosis) when compared to DSF, which may offer insights into their mechanisms of action.

PMID:39505546 | DOI:10.1248/bpb.b24-00538

Acta Crystallogr F Struct Biol Commun. 2024 Dec 1. doi: 10.1107/S2053230X24010550. Online ahead of print.

ABSTRACT

Onchocerca volvulus causes blindness, onchocerciasis, skin infections and devastating neurological diseases such as nodding syndrome. New treatments are needed because the currently used drug, ivermectin, is contraindicated in pregnant women and those co-infected with Loa loa. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) produced, crystallized and determined the apo structure of N-terminally hexahistidine-tagged O. volvulus macrophage migration inhibitory factor-1 (His-OvMIF-1). OvMIF-1 is a possible drug target. His-OvMIF-1 has a unique jellyfish-like structure with a prototypical macrophage migration inhibitory factor (MIF) trimer as the `head' and a unique C-terminal `tail'. Deleting the N-terminal tag reveals an OvMIF-1 structure with a larger cavity than that observed in human MIF that can be targeted for drug repurposing and discovery. Removal of the tag will be necessary to determine the actual biological oligomer of OvMIF-1 because size-exclusion chomatographic analysis of His-OvMIF-1 suggests a monomer, while PISA analysis suggests a hexamer stabilized by the unique C-terminal tails.

PMID:39503735 | DOI:10.1107/S2053230X24010550

Comput Struct Biotechnol J. 2024 Oct 17;24:639-660. doi: 10.1016/j.csbj.2024.10.017. eCollection 2024 Dec.

ABSTRACT

Background The growth of biomedical literature presents challenges in extracting and structuring knowledge. Knowledge Graphs (KGs) offer a solution by representing relationships between biomedical entities. However, manual construction of KGs is labor-intensive and time-consuming, highlighting the need for automated methods. This work introduces BioKGrapher, a tool for automatic KG construction using large-scale publication data, with a focus on biomedical concepts related to specific medical conditions. BioKGrapher allows researchers to construct KGs from PubMed IDs. Methods The BioKGrapher pipeline begins with Named Entity Recognition and Linking (NER+NEL) to extract and normalize biomedical concepts from PubMed, mapping them to the Unified Medical Language System (UMLS). Extracted concepts are weighted and re-ranked using Kullback-Leibler divergence and local frequency balancing. These concepts are then integrated into hierarchical KGs, with relationships formed using terminologies like SNOMED CT and NCIt. Downstream applications include multi-label document classification using Adapter-infused Transformer models. Results BioKGrapher effectively aligns generated concepts with clinical practice guidelines from the German Guideline Program in Oncology (GGPO), achieving F 1 -Scores of up to 0.6. In multi-label classification, Adapter-infused models using a BioKGrapher cancer-specific KG improved micro F 1 -Scores by up to 0.89 percentage points over a non-specific KG and 2.16 points over base models across three BERT variants. The drug-disease extraction case study identified indications for Nivolumab and Rituximab. Conclusion BioKGrapher is a tool for automatic KG construction, aligning with the GGPO and enhancing downstream task performance. It offers a scalable solution for managing biomedical knowledge, with potential applications in literature recommendation, decision support, and drug repurposing.

PMID:39502384 | PMC:PMC11536026 | DOI:10.1016/j.csbj.2024.10.017

NPJ Syst Biol Appl. 2024 Nov 5;10(1):128. doi: 10.1038/s41540-024-00449-y.

ABSTRACT

Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. We leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on human brain expression quantitative trait loci (QTL) (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Using a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in known ALS pathobiological pathways. Applying network proximity analysis of predicted ALS-associated genes and drug-target networks under the human protein-protein interactome (PPI) model, we identified potential repurposable drugs (i.e., Diazoxide and Gefitinib) for ALS. Subsequent validation established preclinical evidence for top-prioritized drugs. In summary, we presented a network-based multi-omics framework to identify drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.

PMID:39500920 | DOI:10.1038/s41540-024-00449-y

Adv Sci (Weinh). 2024 Nov 5:e2410285. doi: 10.1002/advs.202410285. Online ahead of print.

ABSTRACT

Immune checkpoint inhibitors (ICIs) are drugs that inhibit immune checkpoint (ICP) molecules to restore the antitumor activity of immune cells and eliminate tumor cells. Due to the limitations and certain side effects of current ICIs, such as programmed death protein-1, programmed cell death-ligand 1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibodies, there is an urgent need to find new drugs with ICP inhibitory effects. In this study, a network-based computational framework called multi-network algorithm-driven drug repositioning targeting ICP (Mnet-DRI) is developed to accurately repurpose novel ICIs from ≈3000 Food and Drug Administration-approved or investigational drugs. By applying Mnet-DRI to PD-L1, maprotiline (MAP), an antidepressant drug is repurposed, as a potential PD-L1 modifier for colorectal and lung cancers. Experimental validation revealed that MAP reduced PD-L1 expression by targeting E3 ubiquitin ligase speckle-type zinc finger structural protein (SPOP), and the combination of MAP and anti-CTLA4 in vivo significantly enhanced the antitumor effect, providing a new alternative for the clinical treatment of colorectal and lung cancer.

PMID:39499771 | DOI:10.1002/advs.202410285

Sci Prog. 2024 Oct-Dec;107(4):368504241296304. doi: 10.1177/00368504241296304.

ABSTRACT

OBJECTIVE: This study aimed to repurpose pimozide (PMZ) by incorporating it into nanostructured lipid carriers (NLC) using a modified melting emulsion ultrasonication method.

METHODS: We employed stearic and oleic acids in a 1:1 ratio as lipids, with Tween 80 and PEG 4000 as surfactants. The formulation was analyzed for particle size, zeta potential, and encapsulation efficiency. Transmission electron microscopy (TEM) was used to confirm the spherical shape of the particles. The release profile of PMZ-NLC was evaluated under different pH conditions, and anticancer activity was tested on A549 cell lines.

RESULTS: The PMZ-NLC exhibited an average particle size of 136 ± 2.9 nm, a zeta potential of -25.1 ± 0.9 mV, and an encapsulation efficiency of 86% ± 11. TEM confirmed the spherical shape of the NLCs. PMZ release from PMZ-NLC was pH-sensitive, enhancing tumor targeting. IC50 values were 16.5 μM for free PMZ and 12.9 μM for PMZ-NLC after 72 h.

DISCUSSION: PMZ-NLC demonstrated improved anticancer activity compared to free PMZ, suggesting that encapsulation enhances the drug's effectiveness. The pH-sensitive release profile supports its potential for targeted therapy in lung cancer.

CONCLUSIONS: PMZ-NLC showed potential as a safe and effective strategy for lung cancer treatment. Further investigation is warranted to evaluate its in vivo efficacy, long-term safety, and clinical application.

PMID:39497512 | DOI:10.1177/00368504241296304

NPJ Syst Biol Appl. 2024 Nov 4;10(1):127. doi: 10.1038/s41540-024-00455-0.

ABSTRACT

Biomarkers associated with the progression from gastric intestinal metaplasia (GIM) to gastric adenocarcinoma (GA), i.e., GA-related GIM, could provide valuable insights into identifying patients with increased risk for GA. The aim of this study was to utilize multi-bioinformatics to reveal potential biomarkers for the GA-related GIM and predict potential drug repurposing for GA prevention in patients. The multi-bioinformatics included gene expression matrix (GEM) by microarray gene expression (MGE), ScType (a fully automated and ultra-fast cell-type identification based solely on a given scRNA-seq data), Ingenuity Pathway Analysis, PageRank centrality, GO and MSigDB enrichments, Cytoscape, Human Protein Atlas and molecular docking analysis in combination with immunohistochemistry. To identify GA-related GIM, paired surgical biopsies were collected from 16 GIM-GA patients who underwent gastrectomy, yielding 64 samples (4 biopsies per stomach x 16 patients) for MGE. Co-analysis was performed by including scRNAseq and immunohistochemistry datasets of endoscopic biopsies of 37 patients. The results of the present study showed potential biomarkers for GA-related GIM, including GEM of individual patients, individual genes (such as RBP2 and CD44), signaling pathways, network of molecules, and network of signaling pathways with key topological nodes. Accordingly, potential treatment targets with repurposed drugs were identified including epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase Src, paxillin, transcription factor Jun, breast cancer type 1 susceptibility protein, cellular tumor antigen p53, mouse double minute 2, and CD44.

PMID:39496635 | DOI:10.1038/s41540-024-00455-0

Nihon Yakurigaku Zasshi. 2024;159(6):374-380. doi: 10.1254/fpj.24041.

ABSTRACT

The mainstay of treatment for endometriosis is hormonal therapy, which suppresses ovulation; therefore, patients cannot conceive during treatment. There is a dilemma with ovarian-sparing surgery, known as laparoscopic cystectomy, as it can potentially damage the ovaries. Therefore, there is a need for non-hormonal drug therapies. We addressed these challenges in endometriosis treatment, aiming to maintain ovarian function while achieving effective treatment through basic research. Herein, we present two studies using different mouse models of endometriosis. The first study investigates the effects of a nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3 inhibitor in a mouse model of ovarian endometriotic cysts. We confirmed the increased expression of NLRP in ovarian endometriotic cysts compared with that in the uterine endometrium in both patient-derived samples and mouse model lesions. Administering an NLRP3 inhibitor to model mice resulted in lesion reduction. The second study used a peritoneal lesion mouse model to examine bacterial infection in the endometrium and its association with endometriosis development. Using existing databases and patient-derived samples, we identified that Fusobacterium was involved in the development of endometriosis and lesion enlargement when infecting the endometrium in the model. Furthermore, antibiotic treatment led to a reduction in the lesions. These studies highlight the potential of repositioning existing drugs with NLRP3 inhibitory effects or antibiotics as new non-hormonal treatments for endometriosis.

PMID:39496411 | DOI:10.1254/fpj.24041

Curr Microbiol. 2024 Nov 4;81(12):441. doi: 10.1007/s00284-024-03960-x.

ABSTRACT

The current global scenario presents us with a growing increase in infections caused by fungi, referred to by specialists in the field as a "silent epidemic", aggravated by the limited pharmacological arsenal and increasing resistance to this therapy. For this reason, drug repositioning and therapeutic compound combinations are promising strategies to mitigate this serious problem. In this context, this study investigates the antifungal activity of the non-toxic, low-cost and widely available cationic polyelectrolyte Poly(diallyldimethylammonium chloride) (PDDA), in combination with different antifungal drugs: systemic (amphotericin B, AMB), topical (clioquinol, CLIO) and oral (nitroxoline, NTX). For each combination, different drug:PDDA ratios were tested and, through the broth microdilution technique, the minimum inhibitory concentration (MIC) of these drugs in the different ratios against clinically important Candida species strains was determined. Overall, PDDA combinations with the studied drugs demonstrated a significant increase in drug activity against most strains, reaching MIC reductions of up to 512 fold for the fluconazole resistant Candida krusei (Pichia kudriavzevii). In particular, the AMB-PDDA combination 1:99 was highly effective against AMB-resistant strains, demonstrating the excellent profile of PDDA as an adjuvant/association in novel antifungal formulations with outdated conventional drugs.

PMID:39495372 | DOI:10.1007/s00284-024-03960-x

Adv Sci (Weinh). 2024 Nov 3:e2402274. doi: 10.1002/advs.202402274. Online ahead of print.

ABSTRACT

Striatal cholinergic interneurons (ChIs) provide acetylcholine tone to the striatum and govern motor functions. Nicotine withdrawal elicits physical symptoms that dysregulate motor behavior. Here, the role of striatal ChIs in physical nicotine withdrawal is investigated. Mice under RNAi-dependent genetic inhibition of striatal ChIs (ChIGI) by suppressing the sodium channel subunit NaV1.1, lessening action potential generation and activity-dependent acetylcholine release is first generated. ChIGI markedly reduced the somatic signs of nicotine withdrawal without affecting other nicotine-dependent or striatum-associated behaviors. Multielectrode array (MEA) recording revealed that ChIGI reversed ex vivo nicotine-induced alterations in the number of neural population spikes in the dorsal striatum. Notably, the drug repurposing strategy revealed that a clinically-approved antimuscarinic drug, procyclidine, fully mimicked the therapeutic electrophysiological effects of ChIGI. Furthermore, both ChIGI and procyclidine prevented the nicotine withdrawal-induced reduction in striatal dopamine release in vivo. Lastly, therapeutic intervention with procyclidine dose-dependently diminished the physical signs of nicotine withdrawal. The data demonstrated that the striatal ChIs are a critical substrate of physical nicotine withdrawal and that muscarinic antagonism holds therapeutic potential against nicotine withdrawal.

PMID:39491887 | DOI:10.1002/advs.202402274

Spine J. 2024 Nov 2:S1529-9430(24)01103-3. doi: 10.1016/j.spinee.2024.10.014. Online ahead of print.

ABSTRACT

BACKGROUND CONTEXT: Degenerative cervical myelopathy (DCM) is a progressive spinal condition that can lead to severe neurological dysfunction. Despite its degenerative pathophysiology, family history has shown to be a largely important factor in incidence and progression, suggesting that inherent genetic predisposition may play a role in pathophysiology.

PURPOSE: To determine the tissue-specific, functional genetic basis of hereditary predisposition to cervical myelopathy.

STUDY DESIGN: Retrospective case-control study using patient genetics and matched EHR from the Mount Sinai BioMe Biobank.

METHODS: In a large, diverse, urban biobank of 32,031 individuals, with 558 individuals with cervical myopathy, we applied transcriptomic imputation to identify genetically regulated gene expression signatures associated with DCM. We performed drug-repurposing analysis using the CMAP database to identify candidate therapeutic interventions to reverse the cervical myelopathy-associated gene signature.

RESULTS: We identified 16 genes significantly associated with DCM across five different tissues, suggesting tissue-specific manifestations of inherited genetic risk (upregulated: HES6, PI16, TMEM183A, BDH2, LINC00937, CLEC4D, USP43, SPATA1; downregulated: TTC12, CDK5, PAFAH1B2, RCSD1, KLHL29, PTPRG, RP11-620J15.3, C1RL). Drug repurposing identified 22 compounds with the potential to reverse the DCM-associated signature, suggesting points of therapeutic intervention.

CONCLUSIONS: The inherited genetic risk for cervical myelopathy is functionally associated with genes involved in tissue-specific nociceptive and proliferative processes. These signatures may be reversed by candidate therapeutics with nociceptive, calcium channel modulating, and antiproliferative effects.

CLINICAL SIGNIFICANCE: Understanding the genetic basis of DCM provides critical insights into the hereditary factors contributing to the disease, allowing for more personalized and targeted therapeutic approaches. The identification of candidate drugs through transcriptomic imputation and drug repurposing analysis offers potential new treatments that could significantly improve patient outcomes and quality of life by addressing the underlying genetic mechanisms of DCM.

PMID:39491753 | DOI:10.1016/j.spinee.2024.10.014