J Pak Med Assoc. 2024 Mar;74(3 (Supple-3)):S64-S81. doi: 10.47391/JPMA.S3.GNO-08.

ABSTRACT

Low- and middle-income countries (LMICs) have historically been under-represented in clinical trials, leading to a disparity in evidence-based recommendations for the management of neurooncological conditions. To address this knowledge gap, we conducted a scoping review to assess the current literature on clinical trials in neuro-oncology from LMICs. The eligibility criteria for inclusion in this review included clinical trials registered and conducted with human subjects, with available English language text or translation, and focussed on neuro-oncological cases. The literature search strategy captured 408 articles, of which 61 met these criteria, with a significant number of randomised controlled trials from specific LMICs. The review found that LMIC clinical trials have contributed significantly to understanding surgical, chemotherapeutic, and radiation therapy interventions for brain tumours, paediatric cancers, and the repurposing of drugs as new targets in neuro-oncology. These findings highlight the potential for expanding clinical trials research in neuro-oncology in LMICs, which may significantly impact global understanding and management of these conditions, particularly from diverse populations from the global south.

PMID:39262066 | DOI:10.47391/JPMA.S3.GNO-08

Chin Med. 2024 Sep 11;19(1):124. doi: 10.1186/s13020-024-00994-y.

ABSTRACT

BACKGROUND: Drug repositioning has the potential to reduce costs and accelerate the rate of drug development, with highly promising applications. Currently, the development of artificial intelligence has provided the field with fast and efficient computing power. Nevertheless, the repositioning of traditional Chinese medicine (TCM) is still in its infancy, and the establishment of a reasonable and effective research method is a pressing issue that requires urgent attention. The use of graph neural network (GNN) to compute the similarity between TCM prescriptions to develop a method for finding their new indications is an innovative attempt.

METHODS: This paper focused on traditional Chinese medicine prescriptions containing ephedra, with 20 prescriptions for treating external cough and asthma taken as target prescriptions. The remaining 67 prescriptions containing ephedra were taken as to-be-matched prescriptions. Furthermore, a multitude of data pertaining to the prescriptions, including diseases, disease targets, symptoms, and various types of information on herbs, was gathered from a diverse array of literature sources, such as Chinese medicine databases. Then, cosine similarity and Jaccard coefficient were calculated to characterize the similarity between prescriptions using graph convolutional network (GCN) with a self-supervised learning method, such as deep graph infomax (DGI).

RESULTS: A total of 1340 values were obtained for each of the two calculation indicators. A total of 68 prescription pairs were identified after screening with 0.77 as the threshold for cosine similarity. Following the removal of false positive results, 12 prescription pairs were deemed to have further research value. A total of 5 prescription pairs were screened using a threshold of 0.50 for the Jaccard coefficient. However, the specific results did not exhibit significant value for further use, which may be attributed to the excessive variety of information in the dataset.

CONCLUSIONS: The proposed method can provide reference for finding new indications of target prescriptions by quantifying the similarity between prescriptions. It is expected to offer new insights for developing a scientific and systematic research methodology for traditional Chinese medicine repositioning.

PMID:39261848 | DOI:10.1186/s13020-024-00994-y

Sci Rep. 2024 Sep 11;14(1):21282. doi: 10.1038/s41598-024-72136-1.

ABSTRACT

Visceral cestodiases, like cysticercoses and echinococcoses, are caused by cystic larvae from parasites of the Cestoda class and are endemic or hyperendemic in many areas of the world. Current therapeutic approaches for these diseases are complex and present limitations and risks. Therefore, new safer and more effective treatments are urgently needed. The Niemann-Pick C1 (NPC1) protein is a cholesterol transporter that, based on genomic data, would be the solely responsible for cholesterol uptake in cestodes. Considering that human NPC1L1 is a known target of ezetimibe, used in the treatment of hypercholesterolemia, it has the potential for repurposing for the treatment of visceral cestodiases. Here, phylogenetic, selective pressure and structural in silico analyses were carried out to assess NPC1 evolutive and structural conservation, especially between cestode and human orthologs. Two NPC1 orthologs were identified in cestode species (NPC1A and NPC1B), which likely underwent functional divergence, leading to the loss of cholesterol transport capacity in NPC1A. Comparative interaction analyses performed by molecular docking of ezetimibe with human NPC1L1 and cestode NPC1B pointed out to similarities that consolidate the idea of cestode NPC1B as a target for the repurposing of ezetimibe as a drug for the treatment of visceral cestodiases.

PMID:39261546 | DOI:10.1038/s41598-024-72136-1

Sci Rep. 2024 Sep 11;14(1):21258. doi: 10.1038/s41598-024-71922-1.

ABSTRACT

Parkinson's disease is the second most frequent neurodegenerative disease, and its severity is increasing with extended life expectancy. Most of current treatments provide symptomatic relief; however, disease progression is not inhibited. There are multiple trials for treatments that target the causes of the disease but they were flawed. The mechanisms underlying neurodegenerative diseases are intricate, and understanding the interplay among the biological elements involved is crucial. These relationships can be effectively analyzed through biological networks, and the application of network-based analyses in the context of neurodegenerative disease treatment has gained considerable attention. Moreover, considering the significance differences in interactions between biological elements within the network is important. Therefore, we introduce a novel biological pathway based edge-weighted network construction method for drug repurposing in Parkinson's disease. The interaction found in multiple Parkinson's disease-related pathways is more significant than other interactions, and this significance is reflected in the network edge weights. Using the edge-weighted network construction method, we found a significant difference in the efficacy between known and unknown Parkinson's disease drugs. The method predicts drug-disease interactions more accurately than approaches that do not consider the significance differences among interactions, and the paths between the drug and disease within the network correspond to the drug's mechanism of action. In summary, we propose a network-based drug repurposing method using the biological pathway based edge-weighted network. Using this methodology, researchers can find novel drug candidates for the parkinson's disease and their mechanism of actions.

PMID:39261542 | DOI:10.1038/s41598-024-71922-1

Sci Rep. 2024 Sep 11;14(1):21257. doi: 10.1038/s41598-024-71706-7.

ABSTRACT

The bacterium Clostridium botulinum, well-known for producing botulinum neurotoxins, which cause the severe paralytic illness known as botulism, produces C2 toxin, a binary AB-toxin with ADP-ribosyltranferase activity. C2 toxin possesses two separate protein components, an enzymatically active A-component C2I and the binding and translocation B-component C2II. After proteolytic activation of C2II to C2IIa, the heptameric structure binds C2I and is taken up via receptor-mediated endocytosis into the target cells. Due to acidification of endosomes, the C2IIa/C2I complex undergoes conformational changes and consequently C2IIa forms a pore into the endosomal membrane and C2I can translocate into the cytoplasm, where it ADP-ribosylates G-actin, a key component of the cytoskeleton. This modification disrupts the actin cytoskeleton, resulting in the collapse of cytoskeleton and ultimately cell death. Here, we show that the serine-protease inhibitor α1-antitrypsin (α1AT) which we identified previously from a hemofiltrate library screen for PT from Bordetella pertussis is a multitoxin inhibitor. α1AT inhibits intoxication of cells with C2 toxin via inhibition of binding to cells and inhibition of enzyme activity of C2I. Moreover, diphtheria toxin and an anthrax fusion toxin are inhibited by α1AT. Since α1AT is commercially available as a drug for treatment of the α1AT deficiency, it could be repurposed for treatment of toxin-mediated diseases.

PMID:39261531 | DOI:10.1038/s41598-024-71706-7

Expert Opin Drug Discov. 2024 Sep 11:1-11. doi: 10.1080/17460441.2024.2402413. Online ahead of print.

ABSTRACT

INTRODUCTION: Neuroblastoma (NB) remains a challenging pediatric malignancy with limited treatment options, particularly for high-risk cases. Drug repurposing offers a convenient and cost-effective strategy for treating rare diseases like NB. Using existing drugs with known safety profiles accelerates the availability of new treatments, reduces development costs, and mitigates risks, offering hope for improved patient outcomes in challenging conditions.

AREAS COVERED: This review provides an overview of the advances in approaches used to repurpose drugs for NB therapy. The authors discuss strategies employed in drug repurposing, including computational and experimental methods, and rational drug design, highlighting key examples of repurposed drugs with promising clinical results. Additionally, the authors examine the challenges and opportunities associated with drug repurposing in NB and discuss future directions and potential areas for further research.

EXPERT OPINION: The fact that only one new drug has been approved in the last 30 years for the treatment of neuroblastoma plus a significant proportion of high-risk NB patients that remain uncurable, evidences the need for new fast and cost-effective alternatives. Drug repurposing may accelerate the treatment development process while reducing expenses and risks. This approach can swiftly bring effective NB therapies to market, enhancing survival rates and patient quality of life.

PMID:39258785 | DOI:10.1080/17460441.2024.2402413

BMC Med Genomics. 2024 Sep 10;17(1):228. doi: 10.1186/s12920-024-01988-3.

ABSTRACT

BACKGROUND: Drugs targeting disease causal genes are more likely to succeed for that disease. However, complex disease causal genes are not always clear. In contrast, Mendelian disease causal genes are well-known and druggable. Here, we seek an approach to exploit the well characterized biology of Mendelian diseases for complex disease drug discovery, by exploiting evidence of pathogenic processes shared between monogenic and complex disease. One way to find shared disease etiology is clinical association: some Mendelian diseases are known to predispose patients to specific complex diseases (comorbidity). Previous studies link this comorbidity to pleiotropic effects of the Mendelian disease causal genes on the complex disease.

METHODS: In previous work studying incidence of 90 Mendelian and 65 complex diseases, we found 2,908 pairs of clinically associated (comorbid) diseases. Using this clinical signal, we can match each complex disease to a set of Mendelian disease causal genes. We hypothesize that the drugs targeting these genes are potential candidate drugs for the complex disease. We evaluate our candidate drugs using information of current drug indications or investigations.

RESULTS: Our analysis shows that the candidate drugs are enriched among currently investigated or indicated drugs for the relevant complex diseases (odds ratio = 1.84, p = 5.98e-22). Additionally, the candidate drugs are more likely to be in advanced stages of the drug development pipeline. We also present an approach to prioritize Mendelian diseases with particular promise for drug repurposing. Finally, we find that the combination of comorbidity and genetic similarity for a Mendelian disease and cancer pair leads to recommendation of candidate drugs that are enriched for those investigated or indicated.

CONCLUSIONS: Our findings suggest a novel way to take advantage of the rich knowledge about Mendelian disease biology to improve treatment of complex diseases.

PMID:39256819 | DOI:10.1186/s12920-024-01988-3

Mamm Genome. 2024 Sep 10. doi: 10.1007/s00335-024-10069-w. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by excessive collagen deposition and fibrosis of the lung parenchyma, leading to respiratory failure. The molecular mechanisms underlying IPF pathogenesis remain incompletely understood, hindering the development of effective therapeutic strategies. We have used a network medicine approach to comprehensively analyze molecular interactions and identify novel molecular signatures and potential therapeutics associated with IPF progression. Our integrative analysis revealed dysregulated molecular networks that are central to IPF pathophysiology. We have highlighted key molecular players and signaling pathways that are implicated in aberrant fibrotic processes. This systems-level understanding enables the identification of new biomarkers and therapeutic targets for IPF, providing potential avenues for precision medicine. Drug repurposing analysis revealed several drug candidates with anti-fibrotic, anti-inflammatory, and anti-cancer activities that could potentially slow fibrotic progression and improve patient outcomes. This study offers new insights into the molecular underpinnings of IPF and highlights network medicine approaches in uncovering complex disease mechanisms. The molecular signatures and therapeutic targets identified hold promise for developing precision therapies tailored to individual patients, ultimately advancing the management of this debilitating lung disease.

PMID:39254743 | DOI:10.1007/s00335-024-10069-w

Neural Regen Res. 2025 Jul 1;20(7):1997-1998. doi: 10.4103/NRR.NRR-D-24-00334. Epub 2024 Jul 10.

NO ABSTRACT

PMID:39254556 | DOI:10.4103/NRR.NRR-D-24-00334

J Cachexia Sarcopenia Muscle. 2024 Sep 10. doi: 10.1002/jcsm.13575. Online ahead of print.

ABSTRACT

BACKGROUND: The effects of lipid-lowering drugs [including statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors] on hyperlipidaemia have been established. Some may have treatment effects beyond their reported properties, offering potential opportunities for drug repurposing. Epidemiological studies have reported conflicting findings on the relationship between lipid-lowering medication use and sarcopenia risk.

METHODS: We performed a two-sample Mendelian randomization (MR) study to investigate the causal association between the use of genetically proxied lipid-lowering drugs (including statins, ezetimibe, and PCSK9 inhibitors, which use low-density lipoprotein as a biomarker), and sarcopenia risk. The inverse-variance weighting method was used with pleiotropy-robust methods (MR-Egger regression and weighted median) and colocalization as sensitivity analyses.

RESULTS: According to the positive control analysis, genetically proxied inhibition in lipid-lowering drug targets was associated with a lower risk of coronary heart disease [PCSK9 (OR, 0.67; 95% CI, 0.61 to 0.72; P = 7.7E-21); 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR; OR, 0.68; 95% CI, 0.57 to 0.82; P = 4.6E-05), and Niemann-Pick C1-like 1 (NPC1L1; OR, 0.53; 95% CI, 0.40 to 0.69; P = 3.3E-06)], consistent with drug mechanistic actions and previous trial evidence. Genetically proxied inhibition of PCSK9 (beta, -0.040; 95% CI, -0.068 to -0.012; P = 0.005) and circulating PCSK9 levels (beta, -0.019; 95% CI, -0.033 to -0.005; P = 0.006) were associated with reduced appendicular lean mass (ALM) with concordant estimates in terms of direction and magnitude. Validation analyses using a second instrument for PCSK9 yielded consistent results in terms of direction and magnitude [(PCSK9 to ALM; beta, -0.052; 95% CI, -0.074 to -0.032; P = 7.1E-7); (PCSK9 protein to ALM; beta, -0.060; 95% CI, -0.106 to -0.014; P = 0.010)]. Genetically proxied inhibition of PCSK9 gene expression in the liver may be associated with reduced ALM (beta, -0.013; 95% CI, -0.035 to 0.009; P = 0.25), consistent with the results of PCSK9 drug-target and PCSK9 protein MR analyses, but the magnitude was less precise. No robust association was found between HMGCR inhibition (beta, 0.048; 95% CI, -0.015 to 0.110; P = 0.14) or NPC1L1 (beta, 0.035; 95% CI, -0.074 to 0.144; P = 0.53) inhibition and ALM, and validation and sensitivity MR analyses showed consistent estimates.

CONCLUSIONS: This MR study suggested that PCSK9 is involved in sarcopenia pathogenesis and that its inhibition is associated with reduced ALM. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of sarcopenia.

PMID:39254080 | DOI:10.1002/jcsm.13575

J Pain Res. 2024 Sep 5;17:2937-2947. doi: 10.2147/JPR.S469229. eCollection 2024.

ABSTRACT

PURPOSE: Pain related to bone may occur as a result of trauma, bone fracture, genetic disease, arthritis, benign or malignant primary bone tumors and bone cancer metastases. We discuss the pathophysiology of chronic bone-related pain, treatment options and therapeutic perspectives.

METHODS: Using predefined terms, we searched PubMed, MEDLINE, and Google Scholar for meta-analyses, evidence-based reviews, and clinical practice guidelines. This narrative article reviews pathologies linked to chronic bone pain and discusses the preventive and therapeutic strategies for better bone pain management.

RESULTS: Pathophysiology of bone-related pain is complex, especially in cancer conditions and missing gaps are underlined. Treatment of pain, after adequate evaluation, includes classical analgesics, adjuvants for neuropathic and refractory pain, specific bone drugs, surgery and non-pharmacological approaches. Prevention of chronic bone pain encompasses prevention of central sensitization and of causal diseases.

CONCLUSION: Translational research, drug repurposing, an interdisciplinary approach and a person-centered assessment to evaluate, beyond pain, physical, social and functional abilities, are proposed future directions to improve chronic bone pain management and optimize independence and quality of life.

SUMMARY: Chronic bone-related pain is frequent and is associated with an impairment of quality of life. In this review, we summarize the pathophysiology of chronic bone pain, describe treatment approaches and envisage new avenues for pain alleviation. Our article will help doctors manage chronic bone pain and address unmet needs for future research to alleviate bone-related pain.

PMID:39253740 | PMC:PMC11382656 | DOI:10.2147/JPR.S469229

Heliyon. 2024 Aug 11;10(16):e35988. doi: 10.1016/j.heliyon.2024.e35988. eCollection 2024 Aug 30.

ABSTRACT

Following the coronavirus disease-2019 outbreak caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an ongoing need to seek drugs that target COVID-19. First off, novel drugs have a long development cycle, high investment cost, and are high risk. Second, novel drugs must be evaluated for activity, efficacy, safety, and metabolic performance, contributing to the development cycle, investment cost, and risk. We searched the Cochrane COVID-19 Study Register (including PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and WHO COVID-19 Coronaviral Disease Global Literature to identify completed and ongoing studies as of February 20, 2024. We evaluated the pharmacological effects, in vivo and in vitro data of the 16 candidates in the paper. The difficulty of studying these candidates in clinical trials involving COVID-19 patients, dosage of repurposed drugs, etc. is discussed in detail. Ultimately, Metformin is more suitable for prophylactic administration or mildly ill patients; the combination of Oseltamivir, Tamoxifen, and Dexamethasone is suitable for moderately and severely ill patients; and more clinical trials are needed for Azvudine, Ribavirin, Colchicine, and Cepharanthine to demonstrate efficacy.

PMID:39247343 | PMC:PMC11379597 | DOI:10.1016/j.heliyon.2024.e35988

ACS Omega. 2024 Aug 21;9(35):37299-37309. doi: 10.1021/acsomega.4c05089. eCollection 2024 Sep 3.

ABSTRACT

Despite the advent of new treatment strategies, cholinesterase inhibitors (ChEIs) are still the go-to treatment for dementia disorders. ChEIs act by inhibiting the main acetylcholine-degrading enzyme, acetylcholinesterase (AChE). Nonetheless, accumulating evidence indicates that the impact of inhibition of the sister enzyme, butyrylcholinesterase (BChE), could be even broader in older adults due to the multifaceted role of BChE in several biological functional pathways. Therefore, we employed an in silico modeling-based drug repurposing strategy to identify novel potent BChE inhibitors from the FDA drug database. This was followed by in vitro screening and ex vivo enzyme kinetic validation using human plasma samples as the source of BChE. The analysis revealed that the antidepressant drug, duloxetine, inhibited BChE with high selectivity in comparison to AChE. In contrast, two other antidepressants, namely, citalopram and escitalopram exhibited a weak to moderate activity. Ex vivo enzyme inhibition kinetic analyses indicated that duloxetine acted as a competitive inhibitor of BChE with an inhibition constant (K i) of 210 nM. This K i value is comparable with 100-400 nM concentration of duloxetine following normal dosages in humans, thereby indicating that duloxetine should be able to induce a pharmacologically and biologically relevant in vivo inhibition of BChE. Additionally, we performed the enzyme inhibition kinetic assessment in parallel for ethopropazine, a known potent selective BChE inhibitor, and physostigmine, a dual inhibitor of AChE and BChE. These analyses indicated that duloxetine should be considered a potent BChE inhibitor since its K i was comparable with ethopropazine (K i = 150 nM) but was 4 times smaller than that of physostigmine (K i = 840 nM). In conclusion, this study reports the discovery of duloxetine being a highly potent selective competitive BChE inhibitor. This, in turn, indicates that duloxetine could be the choice of antidepressive treatment in older adults with both depressive and dementia symptoms since it may offer additional clinically beneficial effects via this secondary mode of cholinergic enhancing action.

PMID:39246500 | PMC:PMC11375813 | DOI:10.1021/acsomega.4c05089

Eur J Med Chem. 2024 Sep 4;279:116833. doi: 10.1016/j.ejmech.2024.116833. Online ahead of print.

ABSTRACT

The growing prevalence of MDR and XDR bacterial pathogens is posing a critical threat to global health. Traditional antibiotic development paths have encountered significant challenges and are drying up thus necessitating innovative approaches. Drug repurposing, which involves identifying new therapeutic applications for existing drugs, offers a promising alternative to combat resistant pathogens. By leveraging pre-existing safety and efficacy data, drug repurposing accelerates the development of new antimicrobial therapy regimes. This review explores the potential of repurposing existing FDA approved drugs against the ESKAPE and other clinically relevant bacterial pathogens and delves into the identification of suitable drug candidates, their mechanisms of action, and the potential for combination therapies. It also describes clinical trials and patent protection of repurposed drugs, offering perspectives on this evolving realm of therapeutic interventions against drug resistance.

PMID:39243454 | DOI:10.1016/j.ejmech.2024.116833

Transl Psychiatry. 2024 Sep 6;14(1):362. doi: 10.1038/s41398-024-03071-y.

ABSTRACT

Suicidality remains a clear and present danger in society in general, and for mental health patients in particular. Lack of widespread use of objective and/or quantitative information has hampered treatment and prevention efforts. Suicidality is a spectrum of severity from vague thoughts that life is not worth living, to ideation, plans, attempts, and completion. Blood biomarkers that track suicidality risk provide a window into the biology of suicidality, as well as could help with assessment and treatment. Previous studies by us were positive. Here we describe new studies we conducted transdiagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for suicidality, using a multiple independent cohorts design. We found new as well as previously known biomarkers that were predictive of high suicidality states, and of future psychiatric hospitalizations related to them, using cross-sectional and longitudinal approaches. The overall top increased in expression biomarker was SLC6A4, the serotonin transporter. The top decreased biomarker was TINF2, a gene whose mutations result in very short telomeres. The top biological pathways were related to apoptosis. The top upstream regulator was prednisolone. Taken together, our data supports the possibility that biologically, suicidality is an extreme stress-driven form of active aging/death. Consistent with that, the top subtypes of suicidality identified by us just based on clinical measures had high stress and high anxiety. Top therapeutic matches overall were lithium, clozapine and ketamine, with lithium stronger in females and clozapine stronger in males. Drug repurposing bioinformatic analyses identified the potential of renin-angiotensin system modulators and of cyclooxygenase inhibitors. Additionally, we show how patient reports for doctors would look based on blood biomarkers testing, personalized by gender. We also integrated with the blood biomarker testing social determinants and psychological measures (CFI-S, suicidal ideation), showing synergy. Lastly, we compared that to machine learning approaches, to optimize predictive ability and identify key features. We propose that our findings and comprehensive approach can have transformative clinical utility.

PMID:39242534 | DOI:10.1038/s41398-024-03071-y

Genomics Proteomics Bioinformatics. 2024 Jul 3;22(2):qzad008. doi: 10.1093/gpbjnl/qzad008.

ABSTRACT

Gene expression profiling of new or modified cell lines becomes routine today; however, obtaining comprehensive molecular characterization and cellular responses for a variety of cell lines, including those derived from underrepresented groups, is not trivial when resources are minimal. Using gene expression to predict other measurements has been actively explored; however, systematic investigation of its predictive power in various measurements has not been well studied. Here, we evaluated commonly used machine learning methods and presented TransCell, a two-step deep transfer learning framework that utilized the knowledge derived from pan-cancer tumor samples to predict molecular features and responses. Among these models, TransCell had the best performance in predicting metabolite, gene effect score (or genetic dependency), and drug sensitivity, and had comparable performance in predicting mutation, copy number variation, and protein expression. Notably, TransCell improved the performance by over 50% in drug sensitivity prediction and achieved a correlation of 0.7 in gene effect score prediction. Furthermore, predicted drug sensitivities revealed potential repurposing candidates for new 100 pediatric cancer cell lines, and predicted gene effect scores reflected BRAF resistance in melanoma cell lines. Together, we investigated the predictive power of gene expression in six molecular measurement types and developed a web portal (http://apps.octad.org/transcell/) that enables the prediction of 352,000 genomic and cellular response features solely from gene expression profiles.

PMID:39240541 | DOI:10.1093/gpbjnl/qzad008

Cancer Sci. 2024 Sep 6. doi: 10.1111/cas.16317. Online ahead of print.

ABSTRACT

In the colorectal cancer (CRC) niche, the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are hyperactivated in both malignant cells and tumor-infiltrating leukocytes (TILs) and cooperate to maintain cancer cell proliferation/survival and drive protumor inflammation. Through drug repositioning studies, the anthelmintic drug rafoxanide has recently emerged as a potent and selective antitumor molecule for different types of cancer, including CRC. Here, we investigate whether rafoxanide could negatively modulate STAT3/NF-κB and inflammation-associated CRC. The antineoplastic effect of rafoxanide was explored in a murine model of CRC resembling colitis-associated disease. Cell proliferation and/or STAT3/NF-κB activation were evaluated in colon tissues taken from mice with colitis-associated CRC, human CRC cells, and CRC patient-derived explants and organoids after treatment with rafoxanide. The STAT3/NF-κB activation and cytokine production/secretion were assessed in TILs isolated from CRC specimens and treated with rafoxanide. Finally, we investigated the effects of TIL-derived supernatants cultured with or without rafoxanide on CRC cell proliferation and STAT3/NF-κB activation. The results showed that rafoxanide restrains STAT3/NF-κB activation and inflammation-associated colon tumorigenesis in vivo without apparent effects on normal intestinal cells. Rafoxanide markedly reduces STAT3/NF-κB activation in cultured CRC cells, CRC-derived explants/organoids, and TILs. Finally, rafoxanide treatment impairs the ability of TILs to produce protumor cytokines and promote CRC cell proliferation. We report the novel observation that rafoxanide negatively affects STAT3/NF-κB oncogenic activity at multiple levels in the CRC microenvironment. Our data suggest that rafoxanide could potentially be deployed as an anticancer drug in inflammation-associated CRC.

PMID:39239848 | DOI:10.1111/cas.16317

3 Biotech. 2024 Oct;14(10):219. doi: 10.1007/s13205-024-04070-y. Epub 2024 Sep 4.

ABSTRACT

In the post-antibiotic era, antivirulence therapies are becoming refractory to the clinical application of existing antimicrobial regimens. Moreover, in an attempt to explore alternate intervention strategies, drug repurposing is gaining attention over development of novel drugs/antimicrobials. With the prevalence of multidrug resistance and high medical burden associated with Pseudomonas aeruginosa, there is an urgent need to devise novel therapeutics to combat this bacterial pathogen. In this context, the present study was undertaken to scrutinize the anti-quorum sensing (QS) and antivirulence potential of commonly consumed drugs such as fexofenadine (FeX), ivermectin (IvM), nitrofurantoin (NiT), levocetrizine (LvC), atorvastatin (AtS), and aceclofenac (AcF), against P. aeruginosa. The methodology involved assessment of antibacterial activity against P. aeruginosa PAO1 and quorum quenching (QQ) potential using Agrobacterium tumefaciens NTL4 biosensor strain. The antivirulence prospects were investigated by estimating the production of hallmark virulence factors in P. aeruginosa accompanied by molecular docking to predict drug associations with the QS receptors. Interestingly, all the drugs harbored antibacterial, anti-QS, and antivirulence potential in vitro, which consequently disrupted QS circuits and attenuated pseudomonal virulence phenotypically by significantly lowering the production of pyocyanin, hemolysin, pyochelin, and total bacterial protease in vitro. Moreover, the findings were validated by computational studies that predicted strong molecular interactions between the test drugs and QS receptors of P. aeruginosa. Hence, this study is the first to suggest the prospect of repurposing FeX, IvM, NiT, LvC, AtS, and AcF against P. aeruginosa.

PMID:39239248 | PMC:PMC11371971 | DOI:10.1007/s13205-024-04070-y

Bioinform Biol Insights. 2024 Sep 4;18:11779322241272386. doi: 10.1177/11779322241272386. eCollection 2024.

ABSTRACT

Breast cancer (BC) is a complex disease, which causes of high mortality rate in women. Early diagnosis and therapeutic improvements may reduce the mortality rate. There were more than 74 individual studies that have suggested BC-causing hub-genes (HubGs) in the literature. However, we observed that their HubG sets are not so consistent with each other. It may be happened due to the regional and environmental variations with the sample units. Therefore, it was required to explore hub of the HubG (hHubG) sets that might be more representative for early diagnosis and therapies of BC in different country regions and their environments. In this study, we selected top-ranked 10 HubGs (CCNB1, CDK1, TOP2A, CCNA2, ESR1, EGFR, JUN, ACTB, TP53, and CCND1) as the hHubG set by the protein-protein interaction network analysis based on all of 74 individual HubG sets. The hHubG set enrichment analysis detected some crucial biological processes, molecular functions, and pathways that are significantly associated with BC progressions. The expression analysis of hHubGs by box plots in different stages of BC progression and BC prediction models indicated that the proposed hHubGs can be considered as the early diagnostic and prognostic biomarkers. Finally, we suggested hHubGs-guided top-ranked 10 candidate drug molecules (SORAFENIB, AMG-900, CHEMBL1765740, ENTRECTINIB, MK-6592, YM201636, masitinib, GSK2126458, TG-02, and PAZOPANIB) by molecular docking analysis for the treatment against BC. We investigated the stability of top-ranked 3 drug-target complexes (SORAFENIB vs ESR1, AMG-900 vs TOP2A, and CHEMBL1765740 vs EGFR) by computing their binding free energies based on 100-ns molecular dynamic (MD) simulation based Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach and found their stable performance. The literature review also supported our findings much more for BC compared with the results of individual studies. Therefore, the findings of this study may be useful resources for early diagnosis, prognosis, and therapies of BC.

PMID:39239087 | PMC:PMC11375675 | DOI:10.1177/11779322241272386

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2024 Aug;36(8):829-834. doi: 10.3760/cma.j.cn121430-20231129-01019.

ABSTRACT

OBJECTIVE: To investigate the molecular characteristics of obacunone, and to screen and identify potential targets of obacunone against sepsis.

METHODS: The pharmacological parameters and molecular characteristics of obacunone were analyzed with the aid of the Traditional Chinese Medicine Systems Pharmacology Database Analysis Platform (TCMSP). The potential targets of obacunone against sepsis were screened using SwissTargetPrediction and Drug Repositioning and Adverse Drug Reaction Chemical-Protein Interactome (DRAR-CPI) software, with a Z'-score < -0.5. The anti-sepsis targets of obacunone were selected by Online Mendelian Inheritance in Man (OMIM), Comparative Toxicogenomics Database (CTD) and Therapeutic Target Database (TTD). The anti-sepsis potential target was identified by molecular docking software.

RESULTS: The oral bioavailability of obacunone was 81.58% and the drug-likeness was 0.57 indicating that obacunone showed good drug formation. A total of 242 potential targets were screened through SwissTargetPrediction and DRAR-CPI software, 13 targets were directly related to sepsis. Cathepsin G (CTSG), caspase-1 (CASP1), S100 calcium binding protein A9 (S100A9), protein C (inactivator of coagulation factors V a and VIII a, PROC), mitogen-activated protein kinase 1 (MAPK1), glucose-6-phosphate dehydrogenase (G6PD), interleukin-10 (IL-10), migration inhibitory factor (MIF), complement C5a receptor 1 (C5AR1), caspase-3 (CASP3), CXC chemokine receptor 2 (CXCR2), thrombin receptor (F2R), nicotinamide phosphoribosyltransferase (NAMPT) were identified as the potential targets for anti-sepsis of obacunone by molecular docking software, the free binding energies were -32.55, 1.26, -30.00, 300.08, -31.88, -30.29, -21.38, -30.79, 16 777.84, -21.80, 6 443.36, -20.38, -23.47 kJ/mol, respectively.

CONCLUSIONS: Obacunone can inhibit blood coagulation and improve inflammatory response by regulating PROC and F2R. It regulates MIF, S100A9, G6PD and IL-10 to play a role in immune response. It regulates CTSG, CASP1, MAPK1, C5AR1 and CASP3 to protect sepsis-damaged organs. By regulating CXCR2, it can reduce the excessive migration of neutrophils to the site of inflammation, alleviate tissue damage. By regulating NAMPT, it improves cellular energy status, reduces oxidative stress, and protects cells from damage.

PMID:39238407 | DOI:10.3760/cma.j.cn121430-20231129-01019