iScience. 2024 Oct 28;27(12):111277. doi: 10.1016/j.isci.2024.111277. eCollection 2024 Dec 20.

ABSTRACT

Septic management presented a tremendous challenge due to heterogeneous host responses. We aimed to develop a risk model for early septic stratification based on transcriptomic signature. Here, we combined genes OLAH, LY96, HPGD, and ABLIM1 into a prognostic risk score model, which demonstrated exceptional performance in septic diagnosis (AUC = 0.99-1.00) and prognosis (AUC = 0.61-0.70), outperforming that of Mars and SRS endotypes. Also, the model unveiled immunosuppressive status in high-risk patients and a poor response to hydrocortisone in low-risk individuals. Single-cell transcriptome analysis further elucidated expression patterns and effects of the four genes across immune cell types, illustrating integrated host responses reflected by this model. Upon distinct transcriptional profiles of risk subgroups, we identified fenretinide and meloxicam as therapeutic agents, which significantly improved survival in septic mice models. Our study introduced a risk model that optimized risk stratification and drug repurposing of sepsis, thereby offering a comprehensive management approach.

PMID:39628572 | PMC:PMC11613189 | DOI:10.1016/j.isci.2024.111277

J Transl Med. 2024 Dec 4;22(1):1100. doi: 10.1186/s12967-024-05851-y.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide, with highly variable prognosis and response to treatment. A large subset of patients does not respond to standard treatments or develops resistance. As an alternative, adoptive immunotherapy based on chimeric antigen receptor (CAR)-transduced immune cells has been proposed, however with significant adverse events. We therefore evaluated alternative CAR targets already tested in other tumour types and employed the natural killer cell line NK-92 for CAR transduction because of its more favourable toxicity profile.

METHODS: As an alternative antigen, we considered mesothelin (MSLN), the most represented target in CAR-based clinical studies for solid tumours. MSLN RNA expression was analysed in large series of CRC tumours (n = 640) and cell lines (n = 150), to evaluate its distribution and to identify MSLN-overexpressing models. NK-92 cells were transduced with anti-MSLN CAR, and subsequently sorted and cloned. Activity of CAR-NK-92 cells against target-expressing ovarian and CRC cells was assessed in vitro and in vivo. Statistical significance of efficacy was evaluated by t-test and log-rank test.

RESULTS: Large-scale expression analysis highlighted that about 10% of CRCs overexpress MSLN at levels comparable to those of ovarian cancer, a typical target of MSLN-CAR-based therapy. Intriguingly, MSLN overexpression is more frequent in poor prognosis and KRAS/BRAF-mutant CRC. Lentiviral transduction of NK-92 cells with the MSLN-CAR, followed by sorting and cloning, led to the identification of one clone, MSLN.CAR.NK-92.cl45, stably expressing the CAR and retaining the NK phenotype. As expected, the clone demonstrated significant in vitro and in vivo activity against ovarian cancer cells. When repurposed against models of CRC expressing high MSLN levels, it displayed comparable efficacy, both in vitro and in vivo. Specificity of the clone was confirmed by the absence of activity on control models with low or absent MSLN.

CONCLUSIONS: Our results provide preclinical evidence that a subset of colorectal cancers expressing high mesothelin levels can be effectively targeted by MSLN-CAR-based immunotherapy. The potential therapeutic impact of these findings is enhanced by the fact that frequently MSLN-overexpressing CRCs display worse prognosis and resistance to standard care.

PMID:39627822 | DOI:10.1186/s12967-024-05851-y

Anticancer Res. 2024 Dec;44(12):5271-5282. doi: 10.21873/anticanres.17355.

ABSTRACT

BACKGROUND/AIM: Chemoresistance to paclitaxel (PTX) significantly ameliorates therapeutic efficacy in patients with non-small cell lung cancer (NSCLC), especially in advanced stages, deteriorating the progression free and overall survival rates. One of the critical mechanisms contributing to drug resistance is the excretion of PTX from target cells via efflux pumps. Ivermectin was developed as a bactericidal agent against parasites; however, it has recently been shown to inhibit the proliferation of human cancer cells. Hence, we aimed to evaluate the therapeutic potential of ivermectin in combination with PTX and investigate the molecular mechanisms by which ivermectin overcomes PTX resistance.

MATERIALS AND METHODS: We assessed the antitumor effects of ivermectin in A549 cells treated with or without PTX. We also established PTX-resistant cells using this cell line and explored the underlying mechanisms. Additionally, we evaluated whether ivermectin attenuates PTX-resistance with the retrieval of drug sensitivity.

RESULTS: Combined treatment of A549 cells with PTX and ivermectin inhibited cell growth. These cells acquired chemoresistance upon long-term exposure to gradually increasing PTX concentrations, which was accompanied by ABCB1 mRNA up-regulation, and subsequent overproduction of P-glycoprotein (P-gp). Consistent with this, P-gp over-expression resulted in a PTX-resistant phenotype. Notably, the simultaneous ivermectin treatment during the gradual exposure completely abolished P-gp expression, leading to an increased intracellular PTX concentration and sustained PTX sensitivity. Ivermectin was found to regulate P-gp expression via the EGFR/ERK/Akt/NF-[Formula: see text]B pathway.

CONCLUSION: Combined treatment of PTX-resistant A549 cells with ivermectin and PTX may circumvent PTX resistance caused by P-gp induction, highlighting a novel therapeutic avenue for drug repurposing.

PMID:39626921 | DOI:10.21873/anticanres.17355

Anticancer Res. 2024 Dec;44(12):5313-5322. doi: 10.21873/anticanres.17359.

ABSTRACT

BACKGROUND/AIM: Desmoid tumors (DTs), also referred to as aggressive fibromatosis, originate from connective tissues and typically manifest with a propensity for local invasion. Despite extensive research efforts aimed at exploring novel anti-tumor agents for DTs, the development of effective clinical management strategies remains an ongoing challenge due to the limited success of current treatments, which frequently lead to inconsistent outcomes and a high recurrence rate of DTs. To overcome these limitations, we focused our research aim on a drug repositioning approach to identify existing medications that could be effective against DTs.

MATERIALS AND METHODS: Mouse models with Apc mutations, specifically Apc1638N/+ and Apc1638N/+/Trp53-/-, were generated to study DTs. Primary desmoid cells were isolated from these models for experimental analysis. Idarubicin hydrochloride (IDH), a topoisomerase II (TOPO II) inhibitor, was tested on these primary cells, colorectal cancer (CRC) cell lines, and tumor organoids derived from Apc1638N/+ mice. Cell viability was determined with the WST reagent and colony formation assay was evaluated. The anti-tumor efficacy of IDH was tested in an in vivo CRC xenograft model using HCT-116 cells.

RESULTS: The TOPO II inhibitor IDH showed significant growth inhibition effects on Apc1638N/+ and Apc1638N/+/Trp53-/- cells. IDH also showed remarkable anti-tumor effects on CRC cell lines and tumor organoids derived from intestinal tumor cells of the Apc1638N/+ mouse model. Furthermore, IDH exerted dramatic anti-tumor effects on an HCT-116 cell line xenograft mouse model.

CONCLUSION: IDH could be a promising therapeutic agent for inhibiting DTs and CRC by targeting TOPO II.

PMID:39626909 | DOI:10.21873/anticanres.17359

Eur J Pharmacol. 2024 Dec 1:177162. doi: 10.1016/j.ejphar.2024.177162. Online ahead of print.

ABSTRACT

The circadian clock protein reverse erythroblastosis virus (REV)-ERBα is implicated in the pathogenesis of various diseases, including cancer and myocardial infarction. Emerging evidence suggests that SR9009, an agonist of REV-ERBα, regulates multiple signaling molecules independent or dependent of REV-ERBα. However, the impact of SR9009 on renal fibrosis remains largely unevaluated. In this study, we investigated the effects of SR9009 on transforming growth factor (TGF)-β1-induced fibrotic responses and elucidated the mechanisms involved. Masson's trichome staining revealed that in the unilateral ureteral obstruction groups, there was a decrease in REV-ERBα expression, accompanied by increased levels of the profibrotic factor TGF-β1 and the fibrosis marker α-smooth muscle actin (α-SMA). REV-ERBα knockdown significantly increased α-SMA expression in NRK-49F cells. SR9009 significantly attenuated unilateral ureteral obstruction-induced fibrosis and TGF-β1-induced fibrotic responses in normal rat kidney fibroblasts (NRK-49F cells). Conversely, the REV-ERBα antagonist SR8278 did not affect TGF-β1-induced fibrotic responses. Mechanistic studies revealed that SR9009 significantly inhibited the phosphorylation of ERK and p38, concomitant with reduced α-SMA levels, suppressing TGF-β1-induced NADPH oxidase 4 (NOX4) mRNA expression in NRK-49F cells. Notably, SR9009 did not influence the expression of dual specificity phosphatase 4, which dephosphorylates MAPKs, including p38. Furthermore, REV-ERBα knockdown did not affect the ability of SR9009 to inhibit TGF-β1-induced fibrotic responses and NOX4 expression in NRK-49F cells. In conclusion, SR9009 exerts a protective role against renal fibrosis independent of REV-ERBα. Therefore, SR9009 is a promising therapeutic agent for the prevention and treatment of renal fibrosis associated with renal failure.

PMID:39626804 | DOI:10.1016/j.ejphar.2024.177162

Rev Prat. 2024 Nov;74(9):942-946.

ABSTRACT

DRUG REPOSITIONING. Developing new therapeutic agents ("de novo") for human diseases is an increasingly lengthy and costly process, aimed at ensuring patient safety and drug efficacy. An alternative approach, drug repurposing or repositioning, involves using already commercialized or advanced molecules. This strategy offers several advantages, including the availability of extensive data on their safety, efficacy, and potential side effects. Drug repurposing speeds up the early drug development phases and prioritizes molecules for which the outcome on humans is documented. Drug repurposing currently benefits from methodological developments, such as better-annotated databases, the application of advanced algorithms and architectures in the field of AI, and novel physics-based modeling approaches. How is drug repurposing defined, and how much does it impact current drug development pipelines?

PMID:39625015

J Steroid Biochem Mol Biol. 2024 Nov 30:106652. doi: 10.1016/j.jsbmb.2024.106652. Online ahead of print.

ABSTRACT

Breast cancer is a substantial global health problem, and drug repurposing provides novel opportunities to address the urgent need for therapeutics. According to significant Mendelian randomization (MR) results, we identified 26 genes for overall breast cancer, 25 genes for ER+ breast cancer and 4 genes (CASP8, KCNN4, MYLK4, TNNT3) for ER- breast cancer. In order to explore the differences between 5 intrinsic subtypes, we found 29 actionable druggable genes for Luminal A breast cancer, 2 genes (IGF2 and TNNT3) for Luminal B breast cancer, 1 gene (FAAH) for Luminal B HER2 negative breast cancer, and 3 genes (CASP8, KCNN4, and TP53) for triple-negative breast cancer. After colocalization analysis, we determined OPRL1 as a prioritized target in both overall and Luminal A breast cancer. Additionally, FES and FAAH were considered prioritized targets for ER+ breast cancer. Through molecular docking, crizotinib stand out as a prioritized FES target drug repurposing opportunity with the lowest binding energy (-10.13kJ·mol-1) and CCK-8 assay showed ER+ cell groups were more sensitive to crizotinib than ER- cell groups. In conclusion, OPRL1 was identified as a prioritized target for both overall and Luminal A breast cancer. Moreover, FES and FAAH were recognized as prioritized targets for ER+ breast cancer.

PMID:39622444 | DOI:10.1016/j.jsbmb.2024.106652

Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec 2. doi: 10.1007/s00210-024-03625-3. Online ahead of print.

ABSTRACT

Traditional drug discovery approach is based on one drug-one target, that is associated with very lengthy timelines, high costs and very low success rates. Network pharmacology (NP) is a novel method of drug designing, that is based on a multiple-target approach. NP integrates systems such as biology, pharmacology and computational techniques to address the limitations of traditional methods of drug discovery. With help of mapping biological networks, it provides deep insights into biological molecules' interactions and enhances our understanding to the mechanism of drugs, polypharmacology and disease etiology. This review explores the theoretical framework of network pharmacology, discussing the principles and methodologies that enable the construction of drug-target and disease-gene networks. It highlights how data mining, bioinformatics tools and computational models are utilised to predict drug behaviour, repurpose existing drugs and identify novel therapeutic targets. Applications of network pharmacology in the treatment of complex diseases-such as cancer, neurodegenerative disorders, cardiovascular diseases and infectious diseases-are extensively covered, demonstrating its potential to identify multi-target drugs for multifaceted disease mechanisms. Despite the promising results, NP faces challenges due to incomplete and quality of biological data, computational complexities and biological system redundancy. It also faces regulatory challenges in drug approval, demanding revision in regulatory guidelines towards multi-target therapies. Advancements in AI and machine learning, dynamic network modelling and global collaboration can further enhance the efficacy of network pharmacology. This integrative approach has the potential to revolutionise drug discovery, offering new solutions for personalised medicine, drug repurposing and tackling the complexities of modern diseases.

PMID:39621088 | DOI:10.1007/s00210-024-03625-3

J Tissue Eng. 2024 Nov 29;15:20417314241295332. doi: 10.1177/20417314241295332. eCollection 2024 Jan-Dec.

ABSTRACT

Non-healing bone defects are a pressing public health concern accounting for one main cause for decreased life expectancy and quality. An aging population accompanied with increasing incidence of comorbidities, foreshadows a worsening of this socio-economic problem. Conventional treatments for non-healing bone defects prove ineffective for 5%-10% of fractures. Those challenges not only increase the patient's burden but also complicate medical intervention, underscoring the need for more effective treatment strategies and identification of patients at risk before treatment selection. To address this, our proteomic meta-analysis aims to identify universally affected proteins and functions in the context of bone regeneration that can be utilized as novel bioactive biomaterial functionalizations, drug targets or therapeutics as well as analytical endpoints, or biomarkers in implant design and testing, respectively. We compiled 29 proteomic studies covering cellular models, extracellular vesicles, extracellular matrix, bone tissue, and liquid-biopsies to address different tissue hierarchies and species. An innovative, integrated framework consisting of data harmonization, candidate protein selection, network construction, and functional enrichment as well as drug repurposing and protein scoring metrics was developed. To make this framework widely applicable to other research questions, we have published a detailed tutorial of our meta-analysis process. We identified 51 proteins that are potentially important for bone healing. This includes well-known ECM components such as collagens, fibronectin and periostin, and proteins less explored in bone biology like YWHAE, HSPG2, CCN1, HTRA1, IGFBP7, LGALS1, TGFBI, C3, SERPINA1, and ANXA1 that might be utilized in future bone biomaterial development. Furthermore, we discovered the compounds trifluoperazine, phenethyl isothiocyanate, quercetin, and artenimol, which target key proteins such as S100A4, YWHAZ, MMP2, and TPM4 providing the option to manipulate undesired processes in bone regeneration. This may open new ways for treatment options to face the increasing socio-economic pressure of non-healing bone defects.

PMID:39620099 | PMC:PMC11605762 | DOI:10.1177/20417314241295332

Cancer Discov. 2024 Dec 2;14(12):2332-2345. doi: 10.1158/2159-8290.CD-24-1476.

ABSTRACT

This article discusses the specific advances made in precision oncology in 2024. We comment on the evolving nature of predictive molecular events used to select patients who will most benefit clinically from treatment. We also discuss advances in the development of strategic treatment regimens for combination therapies, rational drug design of small-molecule inhibitors, and structurally informed drug repurposing.

PMID:39618285 | DOI:10.1158/2159-8290.CD-24-1476

Biol Psychiatry. 2024 Nov 28:S0006-3223(24)01781-5. doi: 10.1016/j.biopsych.2024.11.013. Online ahead of print.

ABSTRACT

BACKGROUND: Opioid addiction is a worldwide public health crisis. In the United States, for example, opioids cause more drug overdose deaths than any other substance. Yet, opioid addiction treatments have limited efficacy, meaning that additional treatments are needed.

METHODS: To help address this problem, we used network-based machine learning techniques to integrate results from genome-wide association studies (GWAS) of opioid use disorder (OUD) and problematic prescription opioid misuse with transcriptomic, proteomic, and epigenetic data from the dorsolateral prefrontal cortex (dlPFC) of opioid overdose victims and controls.

RESULTS: We identified 211 highly interrelated genes identified by GWAS or dysregulation in the dlPFC of opioid overdose victims that implicated the Akt, BDNF, and ERK pathways, identifying 414 drugs targeting 48 of these opioid addiction-associated genes. Some of the identified drugs are approved to treat other substance use disorders (SUDs) or depression.

CONCLUSIONS: Our synthesis of multi-omics using a systems biology approach revealed key gene targets that could contribute to drug repurposing, genetics-informed addiction treatment, and future discovery.

PMID:39615775 | DOI:10.1016/j.biopsych.2024.11.013

Parasitol Res. 2024 Nov 30;123(12):402. doi: 10.1007/s00436-024-08418-4.

ABSTRACT

Despite the long history of experimental trials to combat schistosomiasis, it remains a significant burden due to drug resistance and the effectiveness of the standard treatment only against the mature stage, while skipping other early developmental stages thus leading to severe permanent pathological sequelae. Therefore, repurposing a commonly used well-known safe drug would be a wise alternative. We investigated the potential anti-schistosomal drug activity of Daflon® (DAF) against different schistosomal developmental stages. DAF was administrated at a dose of 100 mg/kg/mouse on days zero, 21, and 42 post-infection towards the invasive, immature, and mature stages of Schistosoma mansoni respectively in comparison to the standard anti-schistosomal drug (Praziquantel). All mice were sacrificed on day 49 post-infection. DAF induced a significant reduction in the total and female worm count, hepatic granuloma size, and number, the extent of liver parenchymal injury and fibrosis as well as intestinal and hepatic egg count compared to the infected untreated control. Liver malondialdehyde (MDA) levels significantly decreased in all DAF-treated groups. Scanning electron microscope findings revealed edema, tegumental blebs, cracks, and fissures in male tegument in all DAF-treated groups with distortion of the ventral suckers and disarrangement of the spines of the oral sucker. The female worm from DAF-treated groups showed tegumental edema with loss of the spines at the posterior end. Compared to the documented reduction of testosterone levels and distortion of testicular architecture in the S. mansoni-infected untreated group, DAF significantly restored testosterone levels and testicular architecture.

PMID:39614882 | DOI:10.1007/s00436-024-08418-4

BMC Microbiol. 2024 Nov 29;24(1):507. doi: 10.1186/s12866-024-03666-x.

ABSTRACT

It is critical to find novel therapeutic approaches owing to the dissemination of multidrug resistance (MDR) in pathogenic bacteria, particularly Staphylococcus aureus. FDA-drug repurposing is an important therapeutic tactic to fight MDR bacteria. Here, we inspected the antibacterial activity of ambroxol against clinical MDR S. aureus isolates. Using the broth microdilution method, ambroxol revealed minimum inhibitory concentrations (MICs) of 0.75 to 1.5 mg/mL. Also, it revealed antibiofilm action on 42.17% of the isolates by crystal violet assay. A scanning electron microscope was employed to study the antibiofilm action of ambroxol. It revealed that the association between the cells was interrupted by ambroxol, and the biofilm construction was devastated. Moreover, qRT-PCR was utilized to elucidate the consequence of ambroxol on the gene expression of efflux and biofilm. Remarkably, ambroxol has downregulated the expression of cna, fnb A, ica, nor A, nor B genes. Ambroxol's in vivo antibacterial action was investigated using S. aureus infected burn infection. Interestingly, ambroxol has improved the histological features of the skin tissues, significantly diminished the bacterial burden, and increased the wound healing percentage. Also, it revealed a significant reduction in the immunohistochemical staining of tumor necrosis factor-alpha. Finally, the in silico investigations were performed to elucidate the potential of ambroxol on five possible targets of S. aureus. Ambroxol showed good affinities on the five investigated targets in S. aureus, with CrtM being the highest, proposing its probable role in the mechanisms for ambroxol's action on S. aureus.

PMID:39614163 | DOI:10.1186/s12866-024-03666-x

Sci Rep. 2024 Nov 29;14(1):29672. doi: 10.1038/s41598-024-78022-0.

ABSTRACT

The pyruvate dehydrogenase kinase-3 (PDK3) plays an important role in the regulation of a variety of cancers, including lung, by inhibiting the pyruvate dehydrogenase complex (PDC), shifting energy production towards glycolysis necessary for cancer metabolism. In this study, we aimed to identify potential PDK3 inhibitors using a computer-based drug design approach. Virtual screening of the FDA-approved library of 3839 compounds was carried out, from which Bagrosin and Dehydrocholic acid appeared best due to their strong binding affinity, specific interactions, and potential biological characteristics, and thus were selected for further investigations. Both compounds show strong interactions with functionally important residues of the PDK3 with a binding affinity of - 10.6 and - 10.5 kcal/mol for Bagrosin and Dehydrocholic acid, respectively. MD simulation studies for 100 ns suggest the formation of stable complexes, which is evident from RMSD, RMSF, Rg, and SASA parameters. The PCA and FEL analysis suggested admirable global energy minima for the bagrosin-PDK3 and dehydrocholic acid-PDK3 complexes. Finally, we identified FDA-approved drugs, Bagrosin and Dehydrocholic acid, that offer valuable resources and potential therapeutic molecules for targeting lung cancer. Further clinical investigations are required to validate the clinical utility of selected molecules.

PMID:39613779 | DOI:10.1038/s41598-024-78022-0

Assay Drug Dev Technol. 2024 Nov 29. doi: 10.1089/adt.2024.126. Online ahead of print.

NO ABSTRACT

PMID:39611655 | DOI:10.1089/adt.2024.126

J Biomol Struct Dyn. 2024 Nov 29:1-10. doi: 10.1080/07391102.2024.2434026. Online ahead of print.

ABSTRACT

Mycobacterium tuberculosis (M.tb) drug resistance is a major challenge in eradicating its infection globally. M.tb is continuously evolving to overcome the anti-TB drug stress and retain its survival inside the host cells. This continuous evolution of M.tb can only be tackled by the continuous search for novel drug targets as well as developing new therapeutics. Using computational-based approaches we analyzed the potential of 2449 different FDA-approved drugs to interact and bind with GidB (Rv3919c), a key methyltransferase responsible for rRNA methylation in M.tb. Using molecular docking technique, we analyzed the binding energy and the potential affinity of the compounds to the molecular target GidB. Molecular dynamics simulations were performed to investigate the stability of the top-docked compounds and their crucial interactions throughout the 100 ns simulation period. Medronic acid, Arbutin, Oxidronic acid, Pamidronic acid, Dipyrithione, and Zoledronic acid are the 6 top FDA-approved compounds recorded to have high binding affinity for GidB. However, only 4 of these namely, Medronic acid, Arbutin, Dipyrithione, and Zoledronic acid were found to make stable interactions. This initial study put forward the stable interactors of M.tb GidB that could be efficient inhibitors of this key enzyme. Future comprehensive in vitro and in vivo investigations of these identified compounds will aid in the discovery of potential repurposed anti-TB drugs. This study highlights the significance of targeting well known M.tb RNA methyltransferases to combat drug-resistant M.tb and proposes the mentioned drugs as promising inhibitors of GidB for future pre-clinical investigations. Through this multi-step structure-based drug repurposing workflow 4 promising inhibitors of GidB were identified. The identified compounds offer a promising avenue for developing new anti-TB drugs, potentially bolstering the arsenal against drug-resistant strains. Their discovery represents hope for those fighting against the relentless spread of tuberculosis, bringing us closer to more effective treatments for patients in need.

PMID:39611616 | DOI:10.1080/07391102.2024.2434026

Front Pharmacol. 2024 Nov 14;15:1488585. doi: 10.3389/fphar.2024.1488585. eCollection 2024.

ABSTRACT

Histone deacetylase 8 (HDAC8) is a member of class I histone deacetylases (HDACs) that catalyzes the deacetylation of both histone and non-histone proteins. Dysregulation and overexpression of HDAC8 are implicated in the development of various complex diseases, including cancer and neurodegenerative disorders. HDAC8 plays a significant role in cancer progression, contributing to cancer cell proliferation, metastasis, immune evasion, and drug resistance. The available HDAC8-targeting inhibitors suffer from poor target engagement and low tolerability, and demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients, and thus urging for the identification and development of new molecules. Drug repurposing is a useful strategy for identifying useful drugs for predefined targets which can be exploited here for identifying promising drug molecules against HDAC8. This study involved an integrated virtual screening against HDAC8 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC8 activity. The process started by selecting the top 10 drug molecules based on their binding affinity. The drug profiling and biological function of selected molecules were then evaluated, showing anti-cancer and anti-neurological properties with a high probability of being active. Interaction analysis revealed crucial binding of radotinib and sertindole molecules with the HDAC8 protein. Both molecules showed higher binding affinity than reference inhibitor droxinostat. The elucidated molecules were further evaluated for 500 ns long-run molecular dynamics (MD) simulation with HDAC8. Structural deviation, compactness, folding behavior, hydrogen bonds analysis, and secondary structure content profiling revealed complex stability formed by HDAC8 and the selected compounds. Principal component analysis and Gibbs free energy calculations strongly recommend that both complexes were highly stable during the simulation. Overall, the results indicate that radotinib and sertindole can be promising candidates as HDAC8-targeting repurposed drugs against cancer and neuropathological conditions.

PMID:39611171 | PMC:PMC11602702 | DOI:10.3389/fphar.2024.1488585

Knowl Based Syst. 2024 Dec 3;305:112638. doi: 10.1016/j.knosys.2024.112638. Epub 2024 Oct 19.

ABSTRACT

The process of developing new drugs is both time-consuming and costly, often taking over a decade and billions of dollars to obtain regulatory approval. Additionally, the complexity of patent protection for novel compounds presents challenges for pharmaceutical innovation. Drug repositioning offers an alternative strategy to uncover new therapeutic uses for existing medicines. Previous repositioning models have been limited by their reliance on homogeneous data sources, failing to leverage the rich information available in heterogeneous biomedical knowledge graphs. We propose HeteroKGRep, a novel drug repositioning model that utilizes heterogeneous graphs to address these limitations. HeteroKGRep is a multi-step framework that first generates a similarity graph from hierarchical concept relations. It then applies SMOTE over-sampling to address class imbalance before generating node sequences using a heterogeneous graph neural network. Drug and disease embeddings are extracted from the network and used for prediction. We evaluated HeteroKGRep on a graph containing biomedical concepts and relations from ontologies, pathways and literature. It achieved state-of-the-art performance with 99% accuracy, 95% AUC ROC and 94% average precision on predicting repurposing opportunities. Compared to existing homogeneous approaches, HeteroKGRep leverages diverse knowledge sources to enrich representation learning. Based on heterogeneous graphs, HeteroKGRep can discover new drug-desease associations, leveraging de novo drug development. This work establishes a promising new paradigm for knowledge-guided drug repositioning using multimodal biomedical data.

PMID:39610660 | PMC:PMC11600970 | DOI:10.1016/j.knosys.2024.112638

NPJ Genom Med. 2024 Nov 28;9(1):63. doi: 10.1038/s41525-024-00449-1.

ABSTRACT

The global burden of undiagnosed diseases, particularly in adults, is rising due to their significant socioeconomic impact. To address this, we enrolled 232 adult probands with undiagnosed conditions, utilizing bioinformatics tools for genetic analysis. Alongside exome and genome sequencing, repeat-primed PCR and Cas9-mediated nanopore sequencing were applied to suspected short tandem repeat disorders. Probands were classified into probable genetic (n = 128) or uncertain (n = 104) origins. The study found genetic causes in 66 individuals (28.4%) and non-genetic causes in 12 (5.2%), with a longer diagnostic journey for those in the probable genetic group or with pediatric symptom onset, emphasizing the need for increased efforts in these populations. Genetic diagnoses facilitated effective surveillance, cascade screening, drug repurposing, and pregnancy planning. This study demonstrates that integrating sequencing technologies improves diagnostic accuracy, may shorten the time to diagnosis, and enhances personalized management for adults with undiagnosed diseases.

PMID:39609445 | DOI:10.1038/s41525-024-00449-1

Phytother Res. 2024 Nov 28. doi: 10.1002/ptr.8393. Online ahead of print.

ABSTRACT

Non-alcoholic steatohepatitis (NASH) has no effective treatment drug. Our previous study initially found that artemether (Art) treatment significantly attenuates NSAH by regulating liver lipid metabolism. This study further elucidates new mechanisms of Art in improving liver inflammation and provides evidence for drug repurposing. Herein, we utilized HFHF diet-induced animal model and macrophage models to detect the mechanisms of Art in NASH. We confirmed that Art significantly reduced hepatic steatosis, injury, and fibrosis in a high-fat high-fructose (HFHF) diet-induced animal model. Art significantly suppressed the activation of inflammatory macrophages and secretion of pro-inflammatory cytokine (IL-1β) by reducing serum double-stranded DNA (dsDNA) levels and triggering the AIM2/Caspase-1/GSDMD signaling in vivo. dsDNA-induced Caspase-1 and PI-positive cells pyroptosis, AIM2 inflammasome activation, IL-1β, and IL-18 secretion increase were inhibited by Art in vitro. Furthermore, we found Art effectively suppressed mitochondrial DNA (mtDNA), a typical form of dsDNA, released from free fatty acid (FFA)-stressed hepatocytes, which further inhibited AIM2 inflammasome mediated-pyroptosis through decreasing the cleavage of Caspase-1/GSDMD/IL-1β. Moreover, inhibition of the AIM2 gene partly reversed the inhibitory effect of Art on macrophage pyroptosis. Impaired mitochondrial structure and function were confirmed in FFA-stressed hepatocytes and the HFHF-diet-induced NASH mouse model, which was reversed by Art treatment. The present study provides evidence for Art as a potential anti-pyroptosis therapeutic agent for NASH treatment.

PMID:39609107 | DOI:10.1002/ptr.8393