Invest Ophthalmol Vis Sci. 2024 Dec 2;65(14):14. doi: 10.1167/iovs.65.14.14.

ABSTRACT

PURPOSE: Refractory or recurrent retinoblastoma results from acquired chemoresistance and the management of these eyes often requires surgical removal. Our objective was to develop retinoblastoma models resistant to chemotherapy by exposing cancer cells to repeated chemotherapy mimicking the clinical scenario. These newly resistant cells were used to evaluate potential novel therapies.

METHODS: Chemoresistant cells were obtained by exposing two primary retinoblastoma cell cultures to three weekly doses of melphalan or topotecan. The sensitivity of these resistant cells to each chemotherapy was evaluated, and cross-resistance to topotecan, melphalan, and carboplatin was assessed. Genomic alterations and differential expression of efflux/influx transporters between chemoresistant and parental cells were analyzed. Subsequently, sensitivity of both resistant and parental cells to the repurposed agents digoxin, methylene blue, and gemcitabine was assessed.

RESULTS: Four chemoresistant models were successfully established, showing significantly higher half-maximal inhibitory concentration (IC50) values for melphalan and topotecan compared to their corresponding parental cells (P < 0.05). Cross-resistance between melphalan and topotecan was demonstrated, with a 3-fold increase in the IC50. Chemoresistant cells also showed reduced sensitivity to carboplatin (P < 0.05) compared to parental cells, whereas sensitivity to the evaluated repurposed agents remained unchanged. Genomic analysis revealed no selective alterations in the resistant cells, although differential expression of influx/efflux transporters was observed across all chemoresistant models.

CONCLUSIONS: In vitro simulation of patient treatment was useful to establish chemoresistant retinoblastomas and to identify strategies to overcome resistance to topotecan or melphalan through drug repurposed. Our results warrant further investigation to support the clinical translation.

PMID:39636723 | DOI:10.1167/iovs.65.14.14

Front Immunol. 2024 Nov 20;15:1443940. doi: 10.3389/fimmu.2024.1443940. eCollection 2024.

ABSTRACT

BACKGROUND: Traumatic brain injury (TBI) induces an acute reactive state of microglia, which contribute to secondary injury processes through phagocytic activity and release of cytokines. Several receptor tyrosine kinases (RTK) are activated in microglia upon TBI, and their blockade may reduce the acute inflammation and decrease the secondary loss of neurons; thus, RTKs are potential therapeutic targets. We have previously demonstrated that several members of the Fibroblast Growth Factor Receptor (FGFR) family are transiently phosporylated upon TBI; the availability for drug repurposing of FGFR inhibitors makes worthwhile the elucidation of the role of FGFR in the acute phases of the response to TBI and the effect of FGFR inhibition.

METHODS: A closed, blunt, weight-drop mild TBI protocol was employed. The pan-FGFR inhibitor Rogaratinib was administered to mice 30min after the TBI and daily up to 7 days post injury. Phosphor-RTK Arrays and proteomic antibody arrays were used to determine target engagement and large-scale impact of the FGFR inhibitor. pFGFR1 and pFGFR3 immunostaining were employed for validation. As outcome parameters of the TBI injury immunostainings for NeuN, VGLUT1, VGAT at 7dpi were considered.

RESULTS: Inhibition of FGFR during TBI restricted phosphorylation of FGFR1, FGFR3, FGFR4 and ErbB4. Phosphorylation of FGFR1 and FGFR3 during TBI was traced back to Iba1+ microglia. Rogaratinib substantially dowregulated the proteomic signature of the neuroimmunological response to trauma, including the expression of CD40L, CXCR3, CCL4, CCR4, ILR6, MMP3 and OPG. Prolonged Rogaratinib treatment reduced neuronal loss upon TBI and prevented the loss of excitatory (vGLUT+) synapses.

CONCLUSION: The FGFR family is involved in the early induction of reactive microglia in TBI. FGFR inhibition selectively prevented FGFR phosphorylation in the microglia, dampened the overall neuroimmunological response and enhanced the preservation of neuronal and synaptic integrity. Thus, FGFR inhibitors may be relevant targets for drug repurposing aimed at modulating microglial reactivity in TBI.

PMID:39635532 | PMC:PMC11614719 | DOI:10.3389/fimmu.2024.1443940

J Cell Mol Med. 2024 Dec;28(23):e70222. doi: 10.1111/jcmm.70222.

ABSTRACT

Pancreatic cancer is an intractable disease with the worst prognosis of all common cancers. The treatment regimens currently used for pancreatic cancer do not significantly impact patient survival, and therefore, effective treatment strategies are urgently needed. Drug repurposing, which identifies new indications for existing and approved drugs, has proven to be a desirable approach to anti-cancer drug discovery. Indeed, the antihelminthic drug, pyrvinium pamoate, has shown promise as an anti-pancreatic cancer drug. However, the only mechanism of action ascribed to this has been its ability to inhibit mitochondrial function. This study showed, using pancreatic cancer 2D cell cultures and 3D spheroids, that pyrvinium pamoate exhibited short- and long-term cytotoxicity, inhibited epithelial-to-mesenchymal transition and cell invasion and migration. Mechanistically, pyrvinium pamoate induced DNA damage, inhibited stemness markers and the PI3K/AKT cell survival pathway, triggered an S-phase cell cycle arrest and induced apoptotic and autophagic cell death. Importantly, pyrvinium pamoate acted synergistically with the first-line drug, gemcitabine, in 2D and 3D pancreatic cancer cell culture models. This study provides evidence that pyrvinium pamoate is effective as a single agent and in combination with gemcitabine for the treatment of pancreatic cancer.

PMID:39632282 | DOI:10.1111/jcmm.70222

Interdiscip Sci. 2024 Dec 4. doi: 10.1007/s12539-024-00672-5. Online ahead of print.

ABSTRACT

Computational systems biology employs computational algorithms and integrates diverse data sources, such as gene expression profiles, molecular interactions, and network modeling, to identify promising drug candidates through repurposing existing compounds in response to urgent healthcare needs. This study tackles the urgent need for rapid therapeutic development against emerging infectious diseases. We introduce a novel analytic expression for sensitivity analysis based on the Kronecker product and enhance model prediction performance using Graph Convolutional Networks (GCNs) with sensitivity-based graph reduction. Our algorithm refines prediction performance by leveraging sensitivity-based graph reduction. By integrating RNA-seq data, molecular interactions, and GCNs, we identify disease-related genes and pathways, construct heterogeneous graph models, and predict potential drugs. This approach involves novel analytical expressions that assess sensitivity to model loss, employing the Kronecker product approach. Subgraph analysis identifies nodes for removal, leading to a refined graph used for model retraining. This cost-effective pipeline focuses on computational methods for drug repurposing, targeting infectious diseases such as Zika virus and COVID-19 infection. Applied to these infections, our methodology integrates 659 proteins and 703 drugs for Zika virus, and 495 proteins and 468 drugs for COVID-19, along with their interactions derived from gene expression profiles. Top candidate drugs, such as Betamethasone phosphate and Bizelesin for Zika virus, and Chloroquine, Heparin Disaccharide, and Resveratrol for COVID-19, were validated through literature review or docking analysis. This scalable approach demonstrates promise in repurposing drugs for urgent healthcare challenges.

PMID:39630350 | DOI:10.1007/s12539-024-00672-5

Int J Cancer. 2024 Dec 4. doi: 10.1002/ijc.35276. Online ahead of print.

ABSTRACT

Non-small cell lung cancer (NSCLC) shows limited therapeutic response to vinorelbine and carboplatin. Combining these drugs with an antifibrotic drug may enhance their antitumor effect. Pirfenidone is an antifibrotic drug whose antitumor activity has been described in different types of cancer. This work aimed to perform preclinical studies on the combination of pirfenidone with vinorelbine, or with vinorelbine plus carboplatin, in NSCLC. Our data revealed that pirfenidone sensitized three NSCLC cell lines to vinorelbine by reducing cell growth, viability and proliferation, inducing alterations in the cell cycle profile, and increasing cell death (%). Importantly, pirfenidone increased the sensitivity of the three NSCLC cell lines to the combined treatment of vinorelbine plus carboplatin. This combined drug treatment (triplet) did not induce cytotoxicity against non-tumorigenic cells. Notably, the triplet drug combination significantly reduced the growth and proliferation of A-549 xenografts in nude mice, as also reduced vimentin and collagen expression. Most interestingly, the triplet treatment exhibited a safer toxicological profile than the doublet (vinorelbine plus carboplatin) currently applied in the clinical practice. Altogether, these preclinical data support the possibility of repurposing pirfenidone in combination with vinorelbine or with vinorelbine plus carboplatin for NSCLC perioperative treatment, improving therapeutic efficacy while reducing toxicity.

PMID:39630019 | DOI:10.1002/ijc.35276

Curr Med Chem. 2024 Dec 3. doi: 10.2174/0109298673322888240718104833. Online ahead of print.

ABSTRACT

<p> Background and objective: Colorectal Cancer (CRC) affects the colon and rectum part of the digestive system and is a significant global health concern, with approximately 1.1 million new cases annually. It ranks second in cancer-related deaths. Studies have shown future projections of CRC cases to enhance at a worrisome rate, estimating 3.2 million new cases and 1.6 million deaths worldwide by 2040. Studies have shown the downregulation of TMEM236 in CRC, and this study aimed to find the agonist to restore the function of TMEM236 via the drug repurposing method. </p><p> Methods: The different molecular and structural level analyses were performed to understand how the TMEM236 expression can be restored. To obtain the molecular level data, the following analyses were employed to understand the binding affinity and agonistic behaviour of the screened drugs: molecular docking, oral toxicity prediction, Molecular Dynamics (MD) simulation, Free Energy Landscape (FEL) analysis, and g_mmpbsa. </p><p> Results: The molecular docking, oral toxicity, and molecular interaction analyses have identified db06435, db05423, and db15197 drugs from the DrugBank database to either belong to an approved or investigational class of drugs as a potential agonist for TMEM236. The MD simulation and PCA analysis had shown db05423 (ORG-317) to exhibit stable interaction with TMEM236 protein. Similar results were obtained through FEL analysis. </p><p> Conclusion: The downregulation of TMEM236 expression and its constant binding affinity with db05423 during MD simulation suggest that this drug may restore the diminished function and expression of TMEM236. Additionally, it could function as an agonist and can be used for CRC treatment.</p>.

PMID:39629582 | DOI:10.2174/0109298673322888240718104833

Cancer Sci. 2024 Dec 4. doi: 10.1111/cas.16422. Online ahead of print.

ABSTRACT

Pancreatic cancer is among the deadliest cancers, with a grim prognosis despite advances in treatment. We conducted a population-based case-control study from Taiwan, linking Health and Welfare Data Science Center data to the Taiwan Cancer Registry, which offers a promising strategy for its treatment through drug repurposing. The study aims to identify the association of anti-parkinsonian drugs with pancreatic cancer risk across different age groups. The analysis encompassed 18,921 pancreatic cancer cases and 75,684 matched controls, employing conditional logistic regression to assess the impact of anti-parkinsonian drugs on the risk of pancreatic cancer. Key findings revealed a statistically significant association of the administration with specific anti-parkinsonian medications, including anticholinergic agents, tertiary amines, dopa derivatives, and dopamine receptor agonists, with a reduction in pancreatic cancer risk. These associations were represented as adjusted odds ratios (aORs), ranging from 0.620 (95% CI 0.470-0.810) to 0.764 (95% CI 0.655-0.891). Further, age-stratified analysis revealed variations in efficacy across different age groups. Anticholinergic agents and tertiary amines exhibited greater effectiveness in the 40-64-year age group (aOR, 0.653; 95% CI, 0.489-0.872), whereas dopa derivatives and dopamine receptor agonists were particularly efficacious in the cohort aged ≥65 years (aOR, 0.728; 95% CI, 0.624-0.850 and aOR, 0.665; 95% CI, 0.494-0.894, respectively). Notably, specific drugs such as trihexyphenidyl, levodopa/dopa decarboxylase inhibitor (DDCI), and pramipexole demonstrated a significant decrease in cancer risk, especially in the elderly population. These preliminary findings can contribute to the possible therapeutic role of anti-parkinsonian drugs in the treatment of pancreatic cancer.

PMID:39629516 | DOI:10.1111/cas.16422

Lancet Reg Health Am. 2024 Nov 14;41:100939. doi: 10.1016/j.lana.2024.100939. eCollection 2025 Jan.

NO ABSTRACT

PMID:39628989 | PMC:PMC11613157 | DOI:10.1016/j.lana.2024.100939

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