J Cell Mol Med. 2024 Nov;28(22):e70188. doi: 10.1111/jcmm.70188.

ABSTRACT

New uses of old drugs hold great promise for clinical translation. Flubendazole, an FDA-approved antiparasitic drug, has been shown to target p53 and promote apoptosis in glioblastoma (GBM) cells. However, its damaging mechanism in GBM remains elusive. Herein, we explored the ferroptosis-inducing ability of flubendazole on GBM cells. After treating glioma cell lines U251 and LN229 with the flubendazole (DMSO <1‰), cell viability was inhibited in a concentration-dependent manner (IC50 for LN229 = 0.5331 μM, IC50 for U251 = 0.6809 μM), attributed to the induction of ferroptosis, as evidenced by increased MDA levels, accumulation of ROS and lipid peroxides, change in mitochondrial membrane potential and structure. Protein analysis related to ferroptosis showed upregulation of TFRC, DMT1 and p53, alongside downregulation of xCT, FHC and GPX4 (p < 0.05). All-atom docking studies demonstrated that flubendazole bound closely with xCT, and TFRC, validating its role in inducing glioma ferroptosis via modulation of these proteins. Notably, flubendazole could damage the glioblastoma stem cells (GSC) that are typically resistant to other therapies, thereby possessing advantages in stopping glioma recurrence. This study delved into the mechanisms of flubendazole-induced ferroptosis in glioma, broadening its application and providing new ideas for new uses of other old drugs.

PMID:39543084 | PMC:PMC11563996 | DOI:10.1111/jcmm.70188

Sci Rep. 2024 Nov 15;14(1):28097. doi: 10.1038/s41598-024-78330-5.

ABSTRACT

In the realm of epigenetic regulation, Protein arginine deiminase 2 (PAD2) stands out as a therapeutic target due to its significant role in neurological disorders, rheumatoid arthritis (RA), multiple sclerosis (MS), and various cancers. To date, no in silico studies have focused on PAD2 for lead compound identification. Therefore, we conducted structure-based pharmacophore modeling, virtual screening, molecular docking, molecular dynamics (MD) simulations, and essential dynamics studies using PCA and free energy landscape analyses to identify repurposed drugs and selective inhibitors against PAD2. The best pharmacophore model, 'Pharm_01,' had a selectivity score of 10.485 and an excellent ROC curve quality of 0.972. Pharm1 consisted of three hydrogen bond donors (HBD) and two hydrophobic (Hy) features (DDDHH). A virtual screening of about 9.2 million compounds yielded 2575 hits using a fit value threshold of 2.5 and drug-likeness criteria. Molecular docking identified the top ten molecules, which were verified using MD simulations. Stability was verified using MM-PBSA studies, whereas conformational differences were investigated using PCA and free energy landscape analyses. Two hits (Leads 1 and 2) from the DrugBank dataset showed promise for repurposing as PAD2 inhibitors, while one hit compound (Lead 8) from the ZINC database emerged as a novel PAD2 inhibitor. These findings indicate that the discovered compounds may be potent PAD2 inhibitors, necessitating additional preclinical and clinical research to produce viable treatments for cancer and neurological disorders.

PMID:39543332 | DOI:10.1038/s41598-024-78330-5

Trends Pharmacol Sci. 2024 Nov 13:S0165-6147(24)00223-2. doi: 10.1016/j.tips.2024.10.012. Online ahead of print.

ABSTRACT

Globalization and climate change have intensified the need to address the marginalization of R&D for neglected and zoonotic diseases. We propose that drug repurposing, using enabling technologies such as artificial intelligence, can address this need at a lower cost than de novo R&D processes.

PMID:39542782 | DOI:10.1016/j.tips.2024.10.012

Proc Natl Acad Sci U S A. 2024 Nov 19;121(47):e2421475121. doi: 10.1073/pnas.2421475121. Epub 2024 Nov 14.

NO ABSTRACT

PMID:39541358 | DOI:10.1073/pnas.2421475121

Mol Oncol. 2024 Nov 14. doi: 10.1002/1878-0261.13738. Online ahead of print.

ABSTRACT

Anaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy.

PMID:39540457 | DOI:10.1002/1878-0261.13738

Int J Mol Med. 2025 Jan;55(1):17. doi: 10.3892/ijmm.2024.5458. Epub 2024 Nov 14.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited therapeutic options. Cisplatin is a primary chemotherapeutic agent utilized in combination with other drugs or radiotherapy for PDAC treatment. However, the severe side effects of cisplatin often necessitate discontinuation of therapy and drug resistance in tumor cells poses significant clinical challenges. Therefore, the development of effective therapeutic strategies is imperative. The present study investigated whether repositioning of the antipsychotic drug aripiprazole could sensitize the anticancer activity of cisplatin in pancreatic cancer at doses calculated by the combination index. The findings indicated that aripiprazole combined with cisplatin to suppress pancreatic cancer cell growth. Notably, the combination notably increased the expression of apoptosis markers, including cleaved caspase‑3, compared with cisplatin alone. Additionally, this combination effectively decreased XIAP and MCL‑1 expression via mitochondrial membrane potential change as revealed by JC‑1 assay, thereby inducing apoptosis. Furthermore, in fluid shear stress assay, the combination of aripiprazole and cisplatin notably inhibited cell adhesion and tumor spheroid formation. Mechanistically, phospho‑kinase array profiles showed that the enhanced anticancer efficacy of the combination treatment could be attributed to the inhibition of STAT3 signaling, which led to a significant reduction in tumor growth in a pancreatic cancer animal model. The results showed that the repositioning of aripiprazole inhibits cancer cell growth by blocking the STAT3 signaling pathway and effectively enhancing cisplatin‑induced apoptosis, thereby suggesting that the combination of aripiprazole and cisplatin may be a potent chemotherapeutic strategy for the treatment of pancreatic cancer.

PMID:39540370 | DOI:10.3892/ijmm.2024.5458

Korean J Physiol Pharmacol. 2024 Nov 14. doi: 10.4196/kjpp.24.176. Online ahead of print.

ABSTRACT

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi-target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

PMID:39539176 | DOI:10.4196/kjpp.24.176

Hum Genomics. 2024 Nov 14;18(1):124. doi: 10.1186/s40246-024-00688-4.

ABSTRACT

BACKGROUND: Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing opportunities. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drugs, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drugs for repurposing, but also to highlight shared etiology explaining repurposing.

METHODS: We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics data to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways. Similarly, for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer.

RESULTS: We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 74 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing.

CONCLUSIONS: Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known predisposing diseases. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.

PMID:39538313 | DOI:10.1186/s40246-024-00688-4

Nat Commun. 2024 Nov 13;15(1):9837. doi: 10.1038/s41467-024-54003-9.

ABSTRACT

Oligodendrocytes are critical for CNS myelin formation and are involved in preterm-birth brain injury (PBI) and multiple sclerosis (MS), both of which lack effective treatments. We present a pharmacogenomic approach that identifies compounds with potent pro-oligodendrogenic activity, selected through a scoring strategy (OligoScore) based on their modulation of oligodendrogenic and (re)myelination-related transcriptional programs. Through in vitro neural and oligodendrocyte progenitor cell (OPC) cultures, ex vivo cerebellar explants, and in vivo mouse models of PBI and MS, we identify FDA-approved leucovorin and dyclonine as promising candidates. In a neonatal chronic hypoxia mouse model mimicking PBI, both compounds promote neural progenitor cell proliferation and oligodendroglial fate acquisition, with leucovorin further enhancing differentiation. In an adult MS model of focal de/remyelination, they improve lesion repair by promoting OPC differentiation while preserving the OPC pool. Additionally, they shift microglia from a pro-inflammatory to a pro-regenerative profile and enhance myelin debris clearance. These findings support the repurposing of leucovorin and dyclonine for clinical trials targeting myelin disorders, offering potential therapeutic avenues for PBI and MS.

PMID:39537633 | DOI:10.1038/s41467-024-54003-9

Arch Pharm (Weinheim). 2024 Nov 13:e2400628. doi: 10.1002/ardp.202400628. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) continues to be a significant health challenge, necessitating the development of efficient therapeutic strategies. Drug repurposing, which involves the use of existing medications for new purposes, presents a promising opportunity. Metformin, a widely used antidiabetic drug, has demonstrated potential anticancer effects. To enhance its efficacy, we formulated nano-metformin, metformin encapsulated within pectin nanoparticles. Our study aimed to evaluate the superiority of nano-metformin over free metformin in treating CRC. The cytotoxicity of both metformin and nano-metformin on Caco-2 CRC cells was assessed using the MTT assay, revealing a significant dose-dependent inhibition of cell growth using nano-metformin. The anti-inflammatory potential was evaluated by measuring the levels of nitric oxide and the pro-inflammatory cytokines IL-2 and IL-6 following lipopolysaccharide (LPS) induction, and the results revealed that treating LPS-induced cells with nano-metformin significantly reduced the production of these inflammatory mediators. To elucidate the mechanism of cell death, we employed an acridine orange/ethidium bromide staining assay, which revealed the enhancement of apoptotic cell death following treatment with nano-metformin. Additionally, we examined the expression of key apoptotic regulators using real-time qPCR. Nano-metformin, in particular, significantly downregulated the expression of the antiapoptotic markers Bcl-2 and Survivin while upregulating the proapoptotic caspases 3, 7, and 9. The comet assay revealed significant DNA damage induced by treatment with the nano-metformin compared with that in the free form. Moreover, nano-metformin significantly reduced the migration ability of cells. In conclusion, our work revealed the superior efficacy of our formulated nanoform over free metformin, highlighting its potential as a promising therapeutic agent for CRC treatment.

PMID:39535448 | DOI:10.1002/ardp.202400628

J Biomol Struct Dyn. 2024 Nov 13:1-15. doi: 10.1080/07391102.2024.2425840. Online ahead of print.

ABSTRACT

Non-small-cell lung cancer (NSCLC) is one of the most deadly tumors characterized by poor survival rates. Advances in therapeutics and precise identification of biomarkers can potentially reduce the mortality rate. Thus, this study aimed to identify a set of common and stable gene biomarkers through integrated bioinformatics approaches that might be effective for NSCLC early diagnosis, prognosis, and therapies. Four gene expression profiles (GSE19804, GSE19188, GSE10072, and GSE32863) downloaded from the Gene Expression Omnibus database to identify common differential expressed genes (DEGs). A total of 213 overlapping DEGs (oDEGs) between NSCLC and healthy samples were identified by using statistical LIMMA method. Then 6 common top-ranked key genes (KGs) (CENPF, CAV1, ASPM, CCNB2, PRC1, and KIAA0101) were selected by using four network-measurer methods in the protein- protein interaction network. The GO functional and KEGG pathway enrichment analysis were performed to reveal some significant functions and pathways associated with NSCLC progression. Transcriptional and post-transcriptional factors of KGs were identified through the regulatory interaction network. The prognostic power and expression level of KGs were validated by using the independent data through the Kaplan-Meier and Box plots, respectively. Finally, 4 KGs-guided repositioning candidate drugs (ZSTK474, GSK2126458, Masitinib, and Trametinib) were proposed. The stability of three top-ranked drug-target interactions (CAV1 vs. ZSTK474, CAV1 vs. GSK2126458, and ASPM vs. Trametinib) were investigated by computing their binding free energies for 140 ns MD-simulation based on MM-PBSA approach. Therefore, the findings of this computational study may be useful for early prognosis, diagnosis and therapies of NSCLC.

PMID:39535278 | DOI:10.1080/07391102.2024.2425840

J Biomol Struct Dyn. 2024 Nov 13:1-21. doi: 10.1080/07391102.2024.2427370. Online ahead of print.

ABSTRACT

Lassa fever, caused by the zoonotic Lassa virus (LASV), poses a significant health threat in Africa, leading to thousands of infections and deaths annually and has the potential to spread to other parts of the world. Despite the urgency for effective treatments, there are currently no approved drugs or vaccines for Lassa fever. LASV possesses a unique negative-sense RNA genome, and NP plays a crucial role in viral assembly and infection. Crystallographic analysis reveals distinct domains in NP, with the N-terminal domain involved in RNA binding and the C-terminal domain exhibiting exoribonuclease activity, suppressing type I interferon-mediated immune responses. This study explores the potential of repurposing existing FDA-approved drugs by targeting the N-terminal domain of LASV's nucleoprotein (NP). Docking simulations and molecular dynamics experiments were conducted, revealing promising interactions between NP and widely used and well tolerated drugs such as metacycline, eltrombopag, glimepiride, lurasidone, paliperidone, prednisone, doxazosin, flavin mononucleotide, and pimozide. These drugs exhibited stable binding throughout 100 ns simulations, with interactions resembling those observed with the natural ligand, dTTP. Binding free energy calculations identified key amino acids, particularly Phe176 and Arg300, as crucial for drug-NP interactions. Notably, drugs like FMN, prednisone, metacycline, pimozide, and glimepiride displayed binding affinities comparable to dTTP, suggesting their potential as LASV inhibitors. The study underscores the importance of further experimental and clinical validation of these in silico findings. The identified drugs present promising candidates for potential treatments for Lassa fever, addressing the current gap in approved therapeutics for this life-threatening infectious disease.

PMID:39533921 | DOI:10.1080/07391102.2024.2427370

Curr Microbiol. 2024 Nov 12;82(1):1. doi: 10.1007/s00284-024-03971-8.

ABSTRACT

The rapid emergence of drug-resistant fungal strains necessitates the development of novel therapeutic approaches for battling biofilm-related infections. Biofilms, efflux pumps, and suppression of virulence traits in pathogenic yeasts are governed by epigenetic enzymes, namely, histone acetyltransferases (HATs) and histone deacetylases (HDACs). The review article is focused on the use of histone acetyltransferase inhibitors (HATi), a mechanism-based epidrug that inactivates the regular function of HATs. With an emphasis on specific plant-based HATi and their Structure-Activity Relationship (SAR), the review enumerates the extensive list of anticancer HATi that can be screened for antifungal activities. By repurposing these anticancer HATi, this approach may help generate broad-spectrum antifungal medications that highlight common biological pathways between fungus and cancer, possibly revolutionizing both treatment domains.

PMID:39532708 | DOI:10.1007/s00284-024-03971-8

J Biomol Struct Dyn. 2024 Nov 12:1-14. doi: 10.1080/07391102.2024.2425831. Online ahead of print.

ABSTRACT

Drug repurposing for cancer treatment is a valuable strategy to identify existing drugs with known safety profiles that could combat the neoplasm, by reducing costs. Oral squamous cell carcinoma, an ulcer-proliferative lesion on the mucosal epithelium, is the most common oral malignancy. About 10% of cancer patients within the Indian subcontinent suffer from OSCC, primarily due to chewing of betel plant derivatives. Concomitant administration of the chemotherapeutic agent (Cisplatin/Paclitaxel) is the treatment of choice. Analysis of the oral mycobiome of OSCC patients has projected the role of Candida albicans in potentiating OSCC. Hence, repurposing antifungal drugs emerges as a promising approach, as these drugs could target both the cancer cells and the infection. Cancer cells often have heightened energy requirements, and targeting mitochondrial proteins to disrupt mitochondrial division and induce dysfunction contributing to cell death, offers a method for treating OSCC. We identified 18 mitochondrial targets playing a crucial role in the maintenance of mitochondrial homeostasis. They were docked against 125 antifungal ligand molecules sourced from PUBCHEM. Ligand profiling was performed using Lipinski's rule of 5, SwissADME and ProTox. Also, molecular dynamics and MM-PBSA were performed to validate our results. Among all protein ligand interactions, we observed that targeting DRP1 with itraconazole yielded superior binding and stability. Overall, lower toxicity and thumping ADME properties solidified the choice of ligand. We hope this experimental approach will enable us to provide a basis for selecting a lead molecule for a possible novel nano-formulation and validate our finding through in-vitro cell line-based testing.

PMID:39530920 | DOI:10.1080/07391102.2024.2425831

Microbiol Spectr. 2024 Nov 12:e0180524. doi: 10.1128/spectrum.01805-24. Online ahead of print.

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality globally, often exacerbated by infections such as methicillin-resistant Staphylococcus aureus (MRSA). The rise in antibiotic-resistant strains complicates treatment and underscores the need for novel therapeutic drugs. In this paper, we further investigated the antimicrobial potential of a fluoropyrimidine anticancer drug doxifluridine against multidrug-resistant S. aureus. Determination of minimum inhibitory concentration (MIC) or minimum bactericidal concentration (MBC), monitoring of growth curve, time-kill assays, biofilm bactericidal assays, and chequerboard studies were conducted to evaluate the antibacterial efficacy of doxifluridine. Safety was assessed via hemolysis and cytotoxicity assays, and an in vivo Galleria mellonella larvae model was employed to test protective effects. Doxifluridine demonstrated significant antibacterial activity against clinical multidrug resistance (MDR) S. aureus isolates, with MIC and MBC values ranging from 0.5 to 2 µg/mL and 1 to 4 µg/mL, respectively. The results revealed doxifluridine's potent bactericidal effects within 8 hours. Moreover, doxifluridine-treated bacteria showed a substantial reduction in biofilm mass and viability. Furthermore, chequerboard assays indicated synergistic interactions between doxifluridine and other antibiotics, reducing MIC values by two- to eightfold. More importantly, safety evaluations confirmed that doxifluridine did not exhibit hemolytic toxicity or cytotoxicity. Finally, doxifluridine significantly increased the survival rate of MRSA-infected G. mellonella larvae in vivo. In brief, doxifluridine exhibited promising in vitro and in vivo antibacterial activity against MRSA, suggesting its potential as a repurposed drug for treating resistant bacterial infections in COPD patients.IMPORTANCEThe study provides robust evidence for the antibacterial efficacy of doxifluridine against Methicillin-resistant Staphylococcus aureus in chronic obstructive pulmonary disease (COPD) patients. Its rapid action, ability to disrupt biofilms, and synergistic effects with other antibiotics, combined with a favorable safety profile, highlight its potential as a repurposed therapeutic agent. Future clinical trials will be essential to confirm these findings and pave the way for its integration into clinical practice. This work not only provides candidate for tackling the management of bacterial infections in COPD but also exemplifies the potential of drug repurposing in combating antibiotic-resistant infections.

PMID:39530670 | DOI:10.1128/spectrum.01805-24

Eur J Haematol. 2024 Nov 12. doi: 10.1111/ejh.14312. Online ahead of print.

ABSTRACT

Notch1 and Notch2, transmembrane receptors belonging to the Notch family, are pivotal mediators of intercellular communication and have profound implications including cell fate determination, embryonic development, and tissue homeostasis in various cellular processes. Despite their structural homology, Notch1 and Notch2 exhibit discrete phenotypic characteristics and functional nuances that necessitate their individualized targeting in specific medical scenarios. Aberrant Notch signaling, often driven by the dysregulated activity of one receptor over the other, is implicated under various pathological conditions. Notch1 dysregulation is frequently associated with T-cell acute lymphoblastic leukemia, whereas Notch2 perturbations are linked to B-cell malignancies and solid tumors, including breast cancer. Hence, tailored therapeutic interventions that selectively inhibit the relevant Notch receptor need to be devised to disrupt the signaling pathways driving the specific disease phenotype. In this review, we emphasize the importance of distinct tissue-specific expression patterns, functional divergence, disease-specific considerations, and the necessity to minimize off-target effects that collectively underscore the significance of "individualized" targeting for Notch1 and Notch2. This comprehensive review sheds light on the receptor-specific characteristics of Notch1 and Notch2, providing insights into their roles in cellular processes and offering opportunities for developing tailored therapeutic interventions in the fields of biomedical research and clinical practice.

PMID:39530322 | DOI:10.1111/ejh.14312

Front Pharmacol. 2024 Oct 28;15:1512783. doi: 10.3389/fphar.2024.1512783. eCollection 2024.

ABSTRACT

[This corrects the article DOI: 10.3389/fphar.2024.1466351.].

PMID:39529881 | PMC:PMC11551026 | DOI:10.3389/fphar.2024.1512783

Front Cardiovasc Med. 2024 Oct 25;11:1419440. doi: 10.3389/fcvm.2024.1419440. eCollection 2024.

ABSTRACT

BACKGROUND: Coronary artery calcification (CAC) is associated with an increased risk of mortality and cardiovascular events. However, none therapeutic drugs have been proven effective for CAC treatment. The objective of this study was to identify potential therapeutic targets for CAC through the utilization of Mendelian randomization (MR) and colocalization analysis.

METHODS: The expression quantitative trait loci (eQTLs) of 16,943 genes from the eQTLGen consortium and protein quantitative trait loci (pQTLs) of 4,412 proteins from a plasma proteome were utilized as genetic instruments. Genetic associations with CAC were derived from a GWAS meta-analysis of 26,909 individuals. The MR and colocalization analysis were utilized to identify potential target genes.

RESULTS: A total of 671 genes were found to be significantly associated with the risk of CAC based on transcriptomic MR analysis at a false discovery rate <0.05, while proteomic MR analysis identified 15 genes with significant associations with CAC at the same threshold. With robust evidence from colocalization analysis, we observed positive associations between CWF19L2, JARID2, and MANBA and the risk of CAC, while KLB exhibited an inverse association. In summary, our study identified 23 potential therapeutic targets for CAC. Further downstream analysis revealed IGFBP3, ABCC6, ULK3, DOT1L, KLB and AMH as promising candidates for repurposing in the treatment of CAC.

CONCLUSION: The integrated MR analysis of transcriptomic and proteomic data identified multiple potential drug targets for the treatment of CAC. ULK3, DOT1L, and AMH were recognized as novel targets for drug repurposing for CAC and deserve further investigation.

PMID:39526184 | PMC:PMC11543530 | DOI:10.3389/fcvm.2024.1419440

Brain Behav Immun Health. 2024 Oct 25;42:100894. doi: 10.1016/j.bbih.2024.100894. eCollection 2024 Dec.

ABSTRACT

Drug repurposing, also known as drug repositioning, involves identifying new applications for drugs whose effects in a disease are already established. Doxycycline, a broad-spectrum antibiotic belonging to the tetracycline class, has demonstrated potential activity against neurodegenerative diseases like Alzheimer's and Parkinson's. However, despite its promise, the repurposed use of doxycycline encounters challenges in reaching the brain in adequate concentrations to exert its effects. To address this issue, nanostructured systems offer an innovative approach that can enhance brain targeting and the desired therapeutic outcomes. This review discusses the advances in doxycycline repurposing for Alzheimer's disease, presenting physicochemical and biological aspects that permeate doxycycline's repositioning and its application in nano-based delivery systems.

PMID:39525305 | PMC:PMC11550769 | DOI:10.1016/j.bbih.2024.100894

Bioinform Biol Insights. 2024 Nov 7;18:11779322241294130. doi: 10.1177/11779322241294130. eCollection 2024.

ABSTRACT

Scorpion envenomation, a grave public health concern, is primarily driven by the potent neurotoxins chlorotoxin and leiurotoxin present in Leiurus species venom. Developing effective treatments is crucial to mitigate its impact. Utilizing a drug-repositioning bioinformatics-based approach, potential inhibitors of these neurotoxins were identified from Food and Drug Administration (FDA)-approved drugs. Through virtual screening and subsequent molecular dynamics simulations, their ability to stabilize the peptides over time was evaluated. Among the compounds scrutinized, bolazine emerged as a promising candidate, demonstrating significant affinity for both neurotoxins, indicating potential dual inhibitory activity. Molecular dynamics simulations further corroborated the enhanced stability of bolazine complexes compared to neurotoxins alone. These findings suggest the feasibility of repurposing existing drugs to develop new therapeutic strategies to treat scorpion envenomation. Such interventions hold promise in alleviating the severe health repercussions of scorpion stings and meeting the urgent demand for effective remedies in affected communities.

PMID:39524146 | PMC:PMC11544650 | DOI:10.1177/11779322241294130