Mol Neurobiol. 2023 Jul 17. doi: 10.1007/s12035-023-03502-9. Online ahead of print.

ABSTRACT

Neurodegenerative diseases (NDDs) and neuropsychiatric disorders (NPDs) are two common causes of death in elderly people, which includes progressive neuronal cell death and behavioral changes. NDDs include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and motor neuron disease, characterized by cognitive defects and memory impairment, whereas NPDs include depression, seizures, migraine headaches, eating disorders, addictions, palsies, major depressive disorders, anxiety, and schizophrenia, characterized by behavioral changes. Mounting evidence demonstrated that NDDs and NPDs share an overlapping mechanism, which includes post-translational modifications, the microbiota-gut-brain axis, and signaling events. Mounting evidence demonstrated that various drug molecules, namely, natural compounds, repurposed drugs, multitarget directed ligands, and RNAs, have been potentially implemented as therapeutic agents against NDDs and NPDs. Herein, we highlighted the overlapping mechanism, the role of anxiety/stress-releasing factors, cytosol-to-nucleus signaling, and the microbiota-gut-brain axis in the pathophysiology of NDDs and NPDs. We summarize the therapeutic application of natural compounds, repurposed drugs, and multitarget-directed ligands as therapeutic agents. Lastly, we briefly described the application of RNA interferences as therapeutic agents in the pathogenesis of NDDs and NPDs. Neurodegenerative diseases and neuropsychiatric diseases both share a common signaling molecule and molecular phenomenon, namely, pro-inflammatory cytokines, γCaMKII and MAPK/ERK, chemokine receptors, BBB permeability, and the gut-microbiota-brain axis. Studies have demonstrated that any alterations in the signaling mentioned above molecules and molecular phenomena lead to the pathophysiology of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and neuropsychiatric disorders, such as bipolar disorder, schizophrenia, depression, anxiety, autism spectrum disorder, and post-traumatic stress disorder.

PMID:37458987 | DOI:10.1007/s12035-023-03502-9

Microbiol Spectr. 2023 Jul 17:e0267922. doi: 10.1128/spectrum.02679-22. Online ahead of print.

ABSTRACT

Control and management of life-threatening bacterial and fungal infections are a global health challenge. Despite advances in antimicrobial therapies, treatment failures for resistant bacterial and fungal infections continue to increase. We aimed to repurpose the anthelmintic drug rafoxanide for use with existing therapeutic drugs to increase the possibility of better managing infection and decrease treatment failures. For this purpose, we evaluated the antibacterial and antifungal potential of rafoxanide. Notably, 70% (70/100) of bacterial isolates showed multidrug resistance (MDR) patterns, with higher prevalence among human isolates (73.5% [50/68]) than animal ones (62.5% [20/32]). Moreover, 22 fungal isolates (88%) were MDR and were more prevalent among animal (88.9%) than human (87.5%) sources. We observed alarming MDR patterns among bacterial isolates, i.e., Klebsiella pneumoniae (75% [30/40; 8 animal and 22 human]) and Escherichia coli (66% [40/60; 12 animal and 28 human]), and fungal isolates, i.e., Candida albicans (86.7% [13/15; 4 animal and 9 human]) and Aspergillus fumigatus (90% [9/10; 4 animal and 5 human]), that were resistant to at least one agent in three or more different antimicrobial classes. Rafoxanide had antibacterial and antifungal activities, with minimal inhibitory concentration (MICs) ranging from 2 to 128 μg/mL. Rafoxanide at sub-MICs downregulated the mRNA expression of resistance genes, including E. coli and K. pneumoniae blaCTX-M-1, blaTEM-1, blaSHV, MOX, and DHA, C. albicans ERG11, and A. fumigatus cyp51A. We noted the improvement in the activity of β-lactam and antifungal drugs upon combination with rafoxanide. This was apparent in the reduction in the MICs of cefotaxime and fluconazole when these drugs were combined with sub-MIC levels of rafoxanide. There was obvious synergism between rafoxanide and cefotaxime against all E. coli and K. pneumoniae isolates (fractional inhibitory concentration index [FICI] values ≤ 0.5). Accordingly, there was a shift in the patterns of resistance of 16.7% of E. coli and 22.5% of K. pneumoniae isolates to cefotaxime and those of 63.2% of C. albicans and A. fumigatus isolates to fluconazole when the isolates were treated with sub-MICs of rafoxanide. These results were confirmed by in silico and mouse protection assays. Based on the in silico study, one possible explanation for how rafoxanide reduced bacterial resistance is through its inhibitory effects on bacterial and fungal histidine kinase enzymes. In short, rafoxanide exhibited promising results in overcoming bacterial and fungal drug resistance. IMPORTANCE The drug repurposing strategy is an alternative approach to reducing drug development timelines with low cost, especially during outbreaks of disease caused by drug-resistant pathogens. Rafoxanide can disrupt the abilities of bacterial and fungal cells to adapt to stress conditions. The coadministration of antibiotics with rafoxanide can prevent the failure of treatment of both resistant bacteria and fungi, as the resistant pathogens could be made sensitive upon treatment with rafoxanide. From our findings, we anticipate that pharmaceutical companies will be able to utilize new combinations against resistant pathogens.

PMID:37458598 | DOI:10.1128/spectrum.02679-22

Fundam Clin Pharmacol. 2023 Jul 17. doi: 10.1111/fcp.12932. Online ahead of print.

ABSTRACT

BACKGROUND: Glioblastomas arise from multistep tumorigenesis of the glial cells. Despite the current state-of-art treatment, tumor recurrence is inevitable. Among the innovations blooming up against glioblastoma, drug repurposing could provide profound premises for treatment enhancement. While considering this strategy, the efficacy of the repurposed drugs as monotherapies were not up to par; hence, the focus has now shifted to investigate the multidrug combinations.

AIM: To investigate the efficacy of a quadruple-combinatorial treatment comprising temozolomide along with chloroquine, naringenin, and phloroglucinol in an orthotopic glioma-induced xenograft model.

METHODS: Antiproliferative effect of the drugs was assessed by immunostaining. The expression profiles of WNT/β-catenin and apoptotic markers were evaluated by qRT-PCR, immunoblotting, and ELISA. Patterns of mitochondrial depolarization was determined by flow cytometry. TUNEL assay was performed to affirm apoptosis induction. In vivo drug detection study was carried out by ESI-Q-TOF MS analysis.

RESULTS: The quadruple-drug treatment had significantly hampered glioma proliferation and had induced apoptosis by modulating the WNT/β-catenin signaling. Interestingly, the induction of apoptosis was associated with mitochondrial depolarization. The quadruple-drug cocktail had breached the blood-brain barrier and was detected in the brain tissue and plasma samples.

CONCLUSION: The quadruple-drug combination served as a promising adjuvant therapy to combat glioblastoma lethality in vivo and can be probed for translation from bench to bedside.

PMID:37458120 | DOI:10.1111/fcp.12932

Drug Des Devel Ther. 2023 Jul 11;17:2051-2061. doi: 10.2147/DDDT.S416325. eCollection 2023.

ABSTRACT

PURPOSE: Suramin is a multifunctional molecule with a wide range of potential applications, including parasitic and viral diseases, as well as cancer.

METHODS: A double-blinded, randomized, placebo-controlled single ascending dose study was conducted to investigate the safety, tolerability, and pharmacokinetics of suramin in healthy Chinese volunteers. A total of 36 healthy subjects were enrolled. All doses of suramin sodium and placebo were administered as a 30-minute infusion. Blood and urine samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events.

RESULTS: After a single dose, suramin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUClast) increased in a dose-proportional manner. The plasma half-life (t1/2) was dose-independent, average 48 days (range 28-105 days). The cumulative percentages of the dose excreted in urine over 7 days were less than 4%. Suramin can be detected in urine samples for longer periods (more than 140 days following infusion). Suramin was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild in severity.

CONCLUSION: The PK and safety profiles of suramin in Chinese subjects indicated that 10 mg/kg or 15 mg/kg could be an appropriate dose in a future multiple-dose study.

PMID:37457890 | PMC:PMC10349579 | DOI:10.2147/DDDT.S416325

PeerJ. 2023 Jul 10;11:e15624. doi: 10.7717/peerj.15624. eCollection 2023.

ABSTRACT

Computational drug repositioning approaches are important, as they cost less compared to the traditional drug development processes. This study proposes a novel network-based drug repositioning approach, which computes similarities between disease-causing genes and drug-affected genes in a network topology to suggest candidate drugs with highest similarity scores. This new method aims to identify better treatment options by integrating systems biology approaches. It uses a protein-protein interaction network that is the main topology to compute a similarity score between candidate drugs and disease-causing genes. The disease-causing genes were mapped on this network structure. Transcriptome profiles of drug candidates were taken from the LINCS project and mapped individually on the network structure. The similarity of these two networks was calculated by different network neighborhood metrics, including Adamic-Adar, PageRank and neighborhood scoring. The proposed approach identifies the best candidates by choosing the drugs with significant similarity scores. The method was experimented on melanoma, colorectal, and prostate cancers. Several candidate drugs were predicted by applying AUC values of 0.6 or higher. Some of the predictions were approved by clinical phase trials or other in-vivo studies found in literature. The proposed drug repositioning approach would suggest better treatment options with integration of functional information between genes and transcriptome level effects of drug perturbations and diseases.

PMID:37456868 | PMC:PMC10340098 | DOI:10.7717/peerj.15624

J Zhejiang Univ Sci B. 2023 Jul 15;24(7):554-573. doi: 10.1631/jzus.B2300168.

ABSTRACT

Over the past few decades, complementary and alternative treatments have become increasingly popular worldwide. The purported therapeutic characteristics of natural products have come under increased scrutiny both in vitro and in vivo as part of efforts to legitimize their usage. One such product is tea tree oil (TTO), a volatile essential oil primarily obtained from the native Australian plant, Melaleuca alternifolia, which has diverse traditional and industrial applications such as topical preparations for the treatment of skin infections. Its anti-inflammatory-linked immunomodulatory actions have also been reported. This systematic review focuses on the anti-inflammatory effects of TTO and its main components that have shown strong immunomodulatory potential. An extensive literature search was performed electronically for data curation on worldwide accepted scientific databases, such as Web of Science, Google Scholar, PubMed, ScienceDirect, Scopus, and esteemed publishers such as Elsevier, Springer, Frontiers, and Taylor & Francis. Considering that the majority of pharmacological studies were conducted on crude oils only, the extracted data were critically analyzed to gain further insight into the prospects of TTO being used as a neuroprotective agent by drug formulation or dietary supplement. In addition, the active constituents contributing to the activity of TTO have not been well justified, and the core mechanisms need to be unveiled especially for anti-inflammatory and immunomodulatory effects leading to neuroprotection. Therefore, this review attempts to correlate the anti-inflammatory and immunomodulatory activity of TTO with its neuroprotective mechanisms.

PMID:37455134 | PMC:PMC10350368 | DOI:10.1631/jzus.B2300168

NPJ Syst Biol Appl. 2023 Jul 15;9(1):33. doi: 10.1038/s41540-023-00294-5.

ABSTRACT

Rheumatoid arthritis (RA) is a complex autoimmune disease with an unknown aetiology. However, rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) play a significant role in initiating and perpetuating destructive joint inflammation by expressing immuno-modulating cytokines, adhesion molecules, and matrix remodelling enzymes. In addition, RA-FLS are primary drivers of inflammation, displaying high proliferative rates and an apoptosis-resistant phenotype. Thus, RA-FLS-directed therapies could become a complementary approach to immune-directed therapies by predicting the optimal conditions that would favour RA-FLS apoptosis, limit inflammation, slow the proliferation rate and minimise bone erosion and cartilage destruction. In this paper, we present a large-scale Boolean model for RA-FLS that consists of five submodels focusing on apoptosis, cell proliferation, matrix degradation, bone erosion and inflammation. The five-phenotype-specific submodels can be simulated independently or as a global model. In silico simulations and perturbations reproduced the expected biological behaviour of the system under defined initial conditions and input values. The model was then used to mimic the effect of mono or combined therapeutic treatments and predict novel targets and drug candidates through drug repurposing analysis.

PMID:37454172 | DOI:10.1038/s41540-023-00294-5

Exp Biol Med (Maywood). 2023 Jul 15:15353702231181188. doi: 10.1177/15353702231181188. Online ahead of print.

ABSTRACT

The economic and visual burdens associated with age-related macular degeneration (AMD) are expected to significantly increase in the coming years. As of now, interventions to delay or prevent AMD are limited. Hence, there is an urgent and unmet need to expand our therapeutic tools for AMD in a manner, that is, both efficient and cost-effective. In this review, we consider the idea of drug repurposing, in which existing medications with other indications can be re-imagined for treating AMD. We detail the results of several population-level studies that have shown associations between several candidates and decreased risk of AMD development or progression. Such candidates include the more extensively studied metformin and statins, in addition to recently identified candidates fluoxetine and l-DOPA (levodopa) that show promise. We then briefly explore results from an advanced bioinformatics study, which provides further evidence that existing medications are associated with AMD risk genes. Many of these candidates warrant further study in prospective, clinical trials, where their potential causal relationships with AMD can be thoroughly assessed.

PMID:37452694 | DOI:10.1177/15353702231181188

J Neural Transm (Vienna). 2023 Jul 15. doi: 10.1007/s00702-023-02671-0. Online ahead of print.

NO ABSTRACT

PMID:37452192 | DOI:10.1007/s00702-023-02671-0

Heliyon. 2023 Jun 27;9(7):e17603. doi: 10.1016/j.heliyon.2023.e17603. eCollection 2023 Jul.

ABSTRACT

AIMS: To explore the new indications and key mechanism of Bazi Bushen capsule (BZBS) by network pharmacology and in vitro experiment.

METHODS: The ingredients library of BZBS was constructed by retrieving multiple TCM databases. The potential target profiles of the components were predicted by target prediction algorithms based on different principles, and validated by using known activity data. The target spectrum of BZBS with high reliability was screened by considering the source of the targets and the node degree in compound-target (C-T) network. Subsequently, new indications for BZBS were predicted by disease ontology (DO) enrichment analysis and initially validated by GO and KEGG pathway enrichment analysis. Furthermore, the target sets of BZBS acting on AD signaling pathway were identified by intersection analysis. Based on STRING database, the PPI network of target was constructed and their node degree was calculated. Two Alzheimer's disease (AD) cell models, BV-2 and SH-SY5Y, were used to preliminarily verify the anti-AD efficacy and mechanism of BZBS in vitro.

RESULTS: In total, 1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula, and 1320 BZBS targets with high confidence were predicted. Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treatment of AD. GO and KEGG enrichment results provide a preliminary verification of this point. Among them, 113 functional targets of BZBS belong to AD pathway. A PPI network containing 113 functional targets and 1051 edges for the treatment of AD was constructed. In vitro experiments showed that BZBS could significantly reduce the release of TNF-α and IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells, which may be related to the regulation of ERK1/2/NF-κB signaling pathway. BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells, significantly increased mitochondrial membrane potential, reduced the expression of Caspase3 active fragment and PSEN1, and increased the expression of IDE. This may be related to the regulation of GSK-3β/β-catenin signaling pathway.

CONCLUSIONS: BZBS formula has a potential use in the treatment of AD, which is achieved through regulation of ERK1/2, NF-κB signaling pathways, and GSK-3β/β-catenin signaling pathway. Furthermore, the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action. The study lays a foundation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.

PMID:37449101 | PMC:PMC10336525 | DOI:10.1016/j.heliyon.2023.e17603

Nanomaterials (Basel). 2023 Jun 25;13(13):1933. doi: 10.3390/nano13131933.

ABSTRACT

Due to the increase in new types of cancer cells and resistance to drugs, conventional cancer treatments are sometimes insufficient. Therefore, an alternative is to apply nanotechnology to biomedical areas, minimizing side effects and drug resistance and improving treatment efficacy. This work aims to find a promising cancer treatment in the human colorectal adenocarcinoma cell line (HT-29) to minimize the viability of cells (IC50) by using carbon nanotubes (CNTs) combined with different drugs (5-fluorouracil (5-FU) and two repurposing drugs-tacrine (TAC) and ethionamide (ETA). Several CNT samples with different functional groups (-O, -N, -S) and textural properties were prepared and characterized by elemental and thermogravimetry analysis, size distribution, and textural and temperature programmed desorption. The samples that interacted most with the drugs and contributed to improving HT-29 cell treatment were samples doped with nitrogen and sulfur groups (CNT-BM-N and CNT-H2SO4-BM) with IC50 1.98 and 2.50 µmol∙dm-3 from 5-FU and 15.32 and 15.81 µmol∙dm-3 from TAC. On the other hand, ETA had no activity, even combined with the CNTs. These results allow us to conclude that the activity was improved for both 5-FU and TAC when combined with CNTs.

PMID:37446448 | DOI:10.3390/nano13131933

Int J Mol Sci. 2023 Jul 1;24(13):11000. doi: 10.3390/ijms241311000.

ABSTRACT

Because there are a limited number of animal models for psychiatric diseases that can be extrapolated to humans, drug repurposing has been actively pursued. This study was aimed at uncovering recent trends in drug repurposing approaches and new technologies that can predict efficacy on humans based on animal models used in psychiatric drug development. Psychiatric drugs that were approved by the FDA between 2002 and 2022 were listed, and the method of how the drug repurposing has been applied was analyzed. Drug repurposing has been increasingly applied to recently approved psychiatric drugs. The development concepts of psychiatric drugs that have been developed through drug repurposing over the past 20 years were found to be divided into six categories: new application exploration, reduction of side effects, improvement of symptom control, improvement of medication compliance, enhancement of drug efficacy, and reduction of drug-drug interactions. All repurposed drugs approved before 2016 used either prodrugs or active metabolites, while all drugs approved in 2021 and beyond used fixed-dose combinations with sophisticated ideas. SmartCube®, which uses artificial intelligence to predict human drug efficacy from animal phenotypes, was developed and produced novel drugs that show clinical efficacy. Well-designed drug repurposing approaches and new technologies for predicting human drug efficacy based off of animal models would contribute to novel psychiatric drug development.

PMID:37446178 | DOI:10.3390/ijms241311000

Int J Mol Sci. 2023 Jun 28;24(13):10817. doi: 10.3390/ijms241310817.

ABSTRACT

The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of ovarian cancer, but there has been no clinically tested FOXM1 inhibitor to date. We investigated in this study the effects of domatinostat, a class I-selective HDAC inhibitor currently in the clinical stage of development as a cancer therapeutic, on the expression of FOXM1 and viability of ovarian cancer cells. Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. The effect of FOXM1 knockdown on survivin expression and those of genetic and pharmacological inhibition of survivin alone or in combination with the chemotherapeutic agents on cell viability were also examined. Domatinostat reduced the protein and mRNA expression of FOXM1 and survivin and also the viability of ovarian cancer cells alone and in combination with cisplatin or paclitaxel at clinically relevant concentrations. Knockdown experiments showed survivin expression was dependent on FOXM1 in ovarian cancer cells. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1-survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer.

PMID:37445993 | DOI:10.3390/ijms241310817

Int J Mol Sci. 2023 Jun 27;24(13):10696. doi: 10.3390/ijms241310696.

ABSTRACT

Mitochondrial diseases (MDs) refer to a group of clinically and genetically heterogeneous pathologies characterized by defective mitochondrial function and energy production. Unfortunately, there is no effective treatment for most MDs, and current therapeutic management is limited to relieving symptoms. The yeast Saccharomyces cerevisiae has been efficiently used as a model organism to study mitochondria-related disorders thanks to its easy manipulation and well-known mitochondrial biogenesis and metabolism. It has been successfully exploited both to validate alleged pathogenic variants identified in patients and to discover potential beneficial molecules for their treatment. The so-called "drug drop test", a phenotype-based high-throughput screening, especially if coupled with a drug repurposing approach, allows the identification of molecules with high translational potential in a cost-effective and time-saving manner. In addition to drug identification, S. cerevisiae can be used to point out the drug's target or pathway. To date, drug drop tests have been successfully carried out for a variety of disease models, leading to very promising results. The most relevant aspect is that studies on more complex model organisms confirmed the effectiveness of the drugs, strengthening the results obtained in yeast and demonstrating the usefulness of this screening as a novel approach to revealing new therapeutic molecules for MDs.

PMID:37445873 | DOI:10.3390/ijms241310696

Cells. 2023 Jun 23;12(13):1697. doi: 10.3390/cells12131697.

ABSTRACT

Neural tube defects (NTDs), including anencephaly and spina bifida, are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or severe lifelong complications (spina bifida). Despite hundreds of genetic mouse models of neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals, such as antiseizure medications, have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette cortical organoid (SOSR-COs) system, we have developed a high-throughput image analysis pipeline for evaluating the SOSR-CO structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. GSK3β and HDAC inhibitors caused similar lumen expansion; however, RNA sequencing suggests VPA does not inhibit GSK3β at these concentrations. The knockout of SHROOM3, a well-known NTD-related gene, also caused expansion of the lumen, as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction, suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity.

PMID:37443734 | DOI:10.3390/cells12131697

Nat Commun. 2023 Jul 13;14(1):4179. doi: 10.1038/s41467-023-39577-0.

ABSTRACT

Human nuclear receptors (NRs) are a superfamily of ligand-responsive transcription factors that have central roles in cellular function. Their malfunction is linked to numerous diseases, and the ability to modulate their activity with synthetic ligands has yielded 16% of all FDA-approved drugs. NRs regulate distinct gene networks, however they often function from genomic sites that lack known binding motifs. Here, to annotate genomic binding sites of known and unexamined NRs more accurately, we use high-throughput SELEX to comprehensively map DNA binding site preferences of all full-length human NRs, in complex with their ligands. Furthermore, to identify non-obvious binding sites buried in DNA-protein interactomes, we develop MinSeq Find, a search algorithm based on the MinTerm concept from electrical engineering and digital systems design. The resulting MinTerm sequence set (MinSeqs) reveal a constellation of binding sites that more effectively annotate NR-binding profiles in cells. MinSeqs also unmask binding sites created or disrupted by 52,106 single-nucleotide polymorphisms associated with human diseases. By implicating druggable NRs as hidden drivers of multiple human diseases, our results not only reveal new biological roles of NRs, but they also provide a resource for drug-repurposing and precision medicine.

PMID:37443151 | DOI:10.1038/s41467-023-39577-0

Biomed Pharmacother. 2023 Jul 11;165:115008. doi: 10.1016/j.biopha.2023.115008. Online ahead of print.

ABSTRACT

Raloxifene belongs to the family of Selective Estrogen Receptor Modulators (SERMs), which are drugs widely prescribed for Estrogen Receptor alpha (ERα)-related pathologies. Recently, SERMs are being tested in repurposing strategies for ERα-independent clinical indications, including a wide range of microbial infections. Macrophages are central in the fight against pathogen invasion. Despite estrogens have been shown to regulate macrophage phenotype, SERMs activity in these cells is still poorly defined. We investigated the activity of Raloxifene in comparison with another widely used SERM, Tamoxifen, on immune gene expression in macrophages obtained from mouse and human tissues, including mouse peritoneal macrophages, bone marrow-derived macrophages, microglia or human blood-derived macrophages, assaying for the involvement of the ERα, PI3K and NRF2 pathways also under inflammatory conditions. Our data demonstrate that Raloxifene acts by a dual mechanism, which entails ERα antagonism and off-target mediators. Moreover, micromolar concentrations of Raloxifene increase the expression of immune metabolic genes, such as Vegfa and Hmox1, through PI3K and NRF2 activation selectively in peritoneal macrophages. Conversely, Il1b mRNA down-regulation by SERMs is consistently observed in all macrophage subtypes and unrelated to the PI3K/NRF2 system. Importantly, the production of the inflammatory cytokine TNFα induced by the bacterial endotoxin, LPS, is potentiated by SERMs and paralleled by the cell subtype-specific increase in IL1β secretion. This work extends our knowledge on the biological and molecular mechanisms of SERMs immune activity and indicate macrophages as a pharmacological target for the exploitation of the antimicrobial potential of these drugs.

PMID:37442065 | DOI:10.1016/j.biopha.2023.115008

JAR Life. 2023 Jun 20;12:35-45. doi: 10.14283/jarlife.2023.8. eCollection 2023.

ABSTRACT

BACKGROUND: The criteria for use of Alzheimer's disease (AD) drug Leqembi recommended by the Department of Veterans Affairs (VA) include patients aged 65 years or older with mild cognitive impairment (MCI) or mild AD. Comorbidities that include hypertension, hyperlipidemia, and diabetes are common among these patients.

OBJECTIVES: Our objective is to investigate the comparative effectiveness of the administration of one, two, or three medications belonging to the categories of angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), Beta Blockers, Statins, and Metformin, for their potential to delay the clinical onset of AD and provide a window of opportunity for therapeutic intervention.

DESIGN: Retrospective matched case-control study.

SETTING: Data from the Department of Veterans Affairs national corporate data warehouse.

PARTICIPANTS: We conducted an analysis of 122,351 participants (13,611 with AD and 108,740 without AD), aged 65-89, who began at least one of the prescribed medication classes under investigation between October 1998 and April 2018.

MEASUREMENTS: We utilized Cox proportional hazard regressions, both with and without propensity score weighting, to estimate hazard ratios (HR) associated with the use of different medication combinations for the pre-symptomatic survival time of AD onset. Additionally, we employed a supervised machine learning algorithm (random forest) to assess the relative importance of various therapies in predicting the occurrence of AD.

RESULT: Adding Metformin to the combination of ACEI+Beta Blocker (HR = 0.56, 95% CI (0.41, 0.77)) reduced the risk of AD onset compared to ACEI monotherapy alone (HR = 0.91, (0.85, 0.98)), Beta Blocker monotherapy (HR = 0.86, 95% CI (0.80, 0.92)), or combined ACEI+Beta Blocker (HR=0.85, 95%CI (0.77, 0.94)), when statin prescribers were used as a reference. Prescriptions of ARB alone or the combination of ARB with Beta Blocker showed an association with a lower risk of AD onset.

CONCLUSION: Selected medications for the treatment of multiple chronic conditions among elderly individuals with hypertension, hyperlipidemia, and diabetes as monotherapy or combination therapies lengthen the pre-symptomatic period before the onset of AD.

PMID:37441415 | PMC:PMC10333644 | DOI:10.14283/jarlife.2023.8

Front Mol Biosci. 2023 Jun 27;10:1227371. doi: 10.3389/fmolb.2023.1227371. eCollection 2023.

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disease that primarily affects elderly individuals. Recent studies have found that sigma-1 receptor (S1R) agonists can maintain endoplasmic reticulum stress homeostasis, reduce neuronal apoptosis, and enhance mitochondrial function and autophagy, making S1R a target for AD therapy. Traditional experimental methods are costly and inefficient, and rapid and accurate prediction methods need to be developed, while drug repurposing provides new ways and options for AD treatment. In this paper, we propose HNNDTA, a hybrid neural network for drug-target affinity (DTA) prediction, to facilitate drug repurposing for AD treatment. The study combines protein-protein interaction (PPI) network analysis, the HNNDTA model, and molecular docking to identify potential leads for AD. The HNNDTA model was constructed using 13 drug encoding networks and 9 target encoding networks with 2506 FDA-approved drugs as the candidate drug library for S1R and related proteins. Seven potential drugs were identified using network pharmacology and DTA prediction results of the HNNDTA model. Molecular docking simulations were further performed using the AutoDock Vina tool to screen haloperidol and bromperidol as lead compounds for AD treatment. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation results indicated that both compounds had good pharmacokinetic properties and were virtually non-toxic. The study proposes a new approach to computer-aided drug design that is faster and more economical, and can improve hit rates for new drug compounds. The results of this study provide new lead compounds for AD treatment, which may be effective due to their multi-target action. HNNDTA is freely available at https://github.com/lizhj39/HNNDTA.

PMID:37441162 | PMC:PMC10334190 | DOI:10.3389/fmolb.2023.1227371

Adv Exp Med Biol. 2023;1415:73-77. doi: 10.1007/978-3-031-27681-1_12.

ABSTRACT

The need for new drugs to treat dry forms of age-related macular degeneration remains high. A promising approach is repurposing of FDA-approved medications to treat AMD. Databases containing medical and drug records allow for retroactive identification of drugs whose use correlates with reduced AMD diagnosis. This short review summarizes progress in several classes of drugs considered for repurposing: GPR-143 agonists (L-DOPA), anti-diabetic drugs (metformin, acarbose, empagliflozin, fenofibrate), mitochondrial activators (PU-91), and serotonin pathway drugs (fluoxetine, flibanserin, xaliproden, buspirone). The promises and caveats of repurposing are discussed herein.

PMID:37440017 | DOI:10.1007/978-3-031-27681-1_12