J Generic Med. 2022 Dec;18(4):205-213. doi: 10.1177/17411343221115819.

ABSTRACT

With the emergence of new and re-emerging viral diseases, scientists have been working to produce new medications with novel targets and pathways. The discovery of safe and efficacious antiviral medicines is critical due to the constant introduction of new virus types and short lifetime of protection. Since the outbreak, there have been significant efforts to repurpose existing and licensed medications for rapid human testing and possible emergency use authorizations. The exploration of surviving medications for new restorative motives is known as drug repurposing. It is a successful, rapid, and highly reliable alternative to traditional drug methods. COVID-19 is being treated using a number of repurposed and new medicines. Molnupiravir is a repurposed Covid-19 medicine that was specifically developed to cure influenza and is used to treat mild to moderately ill Covid-19 patients with high risk of becoming seriously ill. The importance of medication repurposing, as well as the regulatory procedure for repurposed pharmaceuticals and Emergency Use Authorization in the United States, are summarized in this article.

PMID:38603247 | PMC:PMC9357751 | DOI:10.1177/17411343221115819

Front Immunol. 2024 Mar 27;15:1366197. doi: 10.3389/fimmu.2024.1366197. eCollection 2024.

ABSTRACT

INTRODUCTION: Chemotherapy remains the mainstay treatment for triple-negative breast cancer (TNBC) due to the lack of specific targets. Given a modest response of immune checkpoint inhibitors in TNBC patients, improving immunotherapy is an urgent and crucial task in this field. CD73 has emerged as a novel immunotherapeutic target, given its elevated expression on tumor, stromal, and specific immune cells, and its established role in inhibiting anti-cancer immunity. CD73-generated adenosine suppresses immunity by attenuating tumor-infiltrating T- and NK-cell activation, while amplifying regulatory T cell activation. Chemotherapy often leads to increased CD73 expression and activity, further suppressing anti-tumor immunity. While debulking the tumor mass, chemotherapy also enriches heterogenous cancer stem cells (CSC), potentially leading to tumor relapse. Therefore, drugs targeting both CD73, and CSCs hold promise for enhancing chemotherapy efficacy, overcoming treatment resistance, and improving clinical outcomes. However, safe and effective inhibitors of CD73 have not been developed as of now.

METHODS: We used in silico docking to screen compounds that may be repurposed for inhibiting CD73. The efficacy of these compounds was investigated through flow cytometry, RT-qPCR, CD73 activity, cell viability, tumorsphere formation, and other in vitro functional assays. For assessment of clinical translatability, TNBC patient-derived xenograft organotypic cultures were utilized. We also employed the ovalbumin-expressing AT3 TNBC mouse model to evaluate tumor-specific lymphocyte responses.

RESULTS: We identified quercetin and luteolin, currently used as over-the-counter supplements, to have high in silico complementarity with CD73. When quercetin and luteolin were combined with the chemotherapeutic paclitaxel in a triple-drug regimen, we found an effective downregulation in paclitaxel-enhanced CD73 and CSC-promoting pathways YAP and Wnt. We found that CD73 expression was required for the maintenance of CD44highCD24low CSCs, and co-targeting CD73, YAP, and Wnt effectively suppressed the growth of human TNBC cell lines and patient-derived xenograft organotypic cultures. Furthermore, triple-drug combination inhibited paclitaxel-enriched CSCs and simultaneously improved lymphocyte infiltration in syngeneic TNBC mouse tumors.

DISCUSSION: Conclusively, our findings elucidate the significance of CSCs in impairing anti-tumor immunity. The high efficacy of our triple-drug regimen in clinically relevant platforms not only underscores the importance for further mechanistic investigations but also paves the way for potential development of new, safe, and cost-effective therapeutic strategies for TNBC.

PMID:38601156 | PMC:PMC11004431 | DOI:10.3389/fimmu.2024.1366197

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 8:167163. doi: 10.1016/j.bbadis.2024.167163. Online ahead of print.

ABSTRACT

PMM2-CDG (MIM # 212065), the most common congenital disorder of glycosylation, is caused by the deficiency of phosphomannomutase 2 (PMM2). It is a multisystemic disease of variable severity that particularly affects the nervous system; however, its molecular pathophysiology remains poorly understood. Currently, there is no effective treatment. We performed an RNA-seq based transcriptomic study using patient-derived fibroblasts to gain insight into the mechanisms underlying the clinical symptomatology and to identify druggable targets. Systems biology methods were used to identify cellular pathways potentially affected by PMM2 deficiency, including Senescence, Bone regulation, Cell adhesion and Extracellular Matrix (ECM) and Response to cytokines. Functional validation assays using patients' fibroblasts revealed defects related to cell proliferation, cell cycle, the composition of the ECM and cell migration, and showed a potential role of the inflammatory response in the pathophysiology of the disease. Furthermore, treatment with a previously described pharmacological chaperone reverted the differential expression of some of the dysregulated genes. The results presented from transcriptomic data might serve as a platform for identifying therapeutic targets for PMM2-CDG, as well as for monitoring the effectiveness of therapeutic strategies, including pharmacological candidates and mannose-1-P, drug repurposing.

PMID:38599261 | DOI:10.1016/j.bbadis.2024.167163

Cancer Rep (Hoboken). 2024 Apr;7(4):e2031. doi: 10.1002/cnr2.2031.

ABSTRACT

BACKGROUND: NSCLC is a lethal cancer that is highly prevalent and accounts for 85% of cases of lung cancer. Conventional cancer treatments, such as chemotherapy and radiation, frequently exhibit limited efficacy and notable adverse reactions. Therefore, a drug repurposing method is proposed for effective NSCLC treatment.

AIMS: This study aims to evaluate candidate drugs that are effective for NSCLC at the clinical level using a systems biology and network analysis approach.

METHODS: Differentially expressed genes in transcriptomics data were identified using the systems biology and network analysis approaches. A network of gene co-expression was developed with the aim of detecting two modules of gene co-expression. Following that, the Drug-Gene Interaction Database was used to find possible drugs that target important genes within two gene co-expression modules linked to non-small cell lung cancer (NSCLC). The use of Cytoscape facilitated the creation of a drug-gene interaction network. Finally, gene set enrichment analysis was done to validate candidate drugs.

RESULTS: Unlike previous research on repositioning drugs for NSCLC, which uses a gene co-expression network, this project is the first to research both gene co-expression and co-occurrence networks. And the co-occurrence network also accounts for differentially expressed genes in cancer cells and their adjacent normal cells. For effective management of non-small cell lung cancer (NSCLC), drugs that show higher gene regulation and gene affinity within the drug-gene interaction network are thought to be important. According to the discourse, NSCLC genes have a lot of control over medicines like vincristine, fluorouracil, methotrexate, clotrimazole, etoposide, tamoxifen, sorafenib, doxorubicin, and pazopanib.

CONCLUSION: Hence, there is a possibility of repurposing these drugs for the treatment of non-small-cell lung cancer.

PMID:38600056 | DOI:10.1002/cnr2.2031

Annu Rev Biomed Data Sci. 2024 Apr 10. doi: 10.1146/annurev-biodatasci-110123-025333. Online ahead of print.

ABSTRACT

Drug repurposing refers to the inference of therapeutic relationships between a clinical indication and existing compounds. As an emerging paradigm in drug development, drug repurposing enables more efficient treatment of rare diseases, stratified patient populations, and urgent threats to public health. However, prioritizing well-suited drug candidates from among a nearly infinite number of repurposing options continues to represent a significant challenge in drug development. Over the past decade, advances in genomic profiling, database curation, and machine learning techniques have enabled more accurate identification of drug repurposing candidates for subsequent clinical evaluation. This review outlines the major methodologic classes that these approaches comprise, which rely on (a) protein structure, (b) genomic signatures, (c) biological networks, and (d) real-world clinical data. We propose that realizing the full impact of drug repurposing methodologies requires a multidisciplinary understanding of each method's advantages and limitations with respect to clinical practice.

PMID:38598857 | DOI:10.1146/annurev-biodatasci-110123-025333

Proc Natl Acad Sci U S A. 2024 Apr 16;121(16):e2400077121. doi: 10.1073/pnas.2400077121. Epub 2024 Apr 10.

ABSTRACT

Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to lower airway repair. Agents that promote the selective expansion of these cells might stimulate regeneration of the compromised alveolar epithelium, an etiology-defining event in several pulmonary diseases. From a high-content imaging screen of the drug repurposing library ReFRAME, we identified that dipeptidyl peptidase 4 (DPP4) inhibitors, widely used type 2 diabetes medications, selectively expand AEC2s and are broadly efficacious in several mouse models of lung damage. Mechanism of action studies revealed that the protease DPP4, in addition to processing incretin hormones, degrades IGF-1 and IL-6, essential regulators of AEC2 expansion whose levels are increased in the luminal compartment of the lung in response to drug treatment. To selectively target DPP4 in the lung with sufficient drug exposure, we developed NZ-97, a locally delivered, lung persistent DPP4 inhibitor that broadly promotes efficacy in mouse lung damage models with minimal peripheral exposure and good tolerability. This work reveals DPP4 as a central regulator of AEC2 expansion and affords a promising therapeutic approach to broadly stimulate regenerative repair in pulmonary disease.

PMID:38598345 | DOI:10.1073/pnas.2400077121

J Community Hosp Intern Med Perspect. 2023 Nov 4;13(6):71-75. doi: 10.55729/2000-9666.1267. eCollection 2023.

ABSTRACT

Multiple cranial nerve palsies frequently accompany hypoglossal nerve palsy, potentially indicating malignancy, such as lymphoma, nasopharyngeal carcinoma, or metastases. However, when solely the hypoglossal nerve is affected, the causes may involve Chiari malformation, arachnoid cyst, or infectious mononucleosis, suggesting a positive prognosis. Craniocervical junction tuberculosis (TB), is an uncommon cause of isolated hypoglossal nerve palsy and has been reported infrequently in the literature. Craniocervical junction tuberculosis accounts for only 0.5% of TB cases overall and 6% of extra-pulmonary TB cases. We present here one such case of a 17-year-old male of Indian origin with a subacute history of tongue deviation and neck pain. Additionally, the patient reported loss of weight and appetite. The patient had significant posterior cervical lymphadenopathy. Neurological examination revealed findings suggestive of right peripheral hypoglossal nerve involvement. Blood investigations showed lymphocytosis along with an elevated erythrocyte sedimentation rate of 45 mm/h and elevated lactate dehydrogenase levels of 325 U/L. Tuberculin skin testing was positive and sputum acid-fast staining confirmed acid-fast bacilli. Magnetic Resonance Imaging of the cervical spine revealed a soft tissue component in the prevertebral space measuring 3.5×4.8 cm with a right paraspinal component adjoining the hypoglossal canal with peripheral contrast enhancement. Histological findings on the lymph node showed granulomatous lymphadenitis, suggestive of tuberculosis. The patient was started on 4-drug anti-tubercular therapy consisting of Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol for a period of 18 months. He was subsequently followed up for 6 months till the resolution of palsy. This case emphasizes the importance of thorough evaluation and a meticulous workup to identify the underlying cause of hypoglossal nerve palsy and the importance of considering tuberculosis as a potential cause of isolated hypoglossal nerve palsy in everyday practice.

PMID:38596544 | PMC:PMC11000838 | DOI:10.55729/2000-9666.1267

MicroPubl Biol. 2024 Mar 25;2024. doi: 10.17912/micropub.biology.001173. eCollection 2024.

ABSTRACT

Glioblastoma (GBM) stands as the predominant primary malignant brain tumor in adults, characterized by an exceedingly grim prognosis. Urgent efforts are essential to pioneer effective therapeutics capable of addressing both the intrinsic and acquired resistance exhibited by GBM towards existing treatments. This study employs a drug repurposing strategy to explore the anti-cancer potential of vortioxetine in malignant U251 and T98G glioblastoma cells. Findings from the WST-8 cell counting assay and clonogenic assays indicated that vortioxetine effectively suppressed the short-term viability and long-term survival of glioblastoma cells. We also showed that vortioxetine inhibited the migration of glioblastoma cells as compared to the control. Our findings encourage further exploration and validation of the use of vortioxetine in the treatment of glioblastoma.

PMID:38596362 | PMC:PMC11002643 | DOI:10.17912/micropub.biology.001173

Exp Parasitol. 2024 Apr 7:108748. doi: 10.1016/j.exppara.2024.108748. Online ahead of print.

ABSTRACT

Monogeneans are parasitic platyhelminths that can harm the health of farmed fish. Few treatments are available against monogeneans, and the incentive to develop new antiparasitic agents is similar or even lower than the incentive for neglected parasitic diseases in humans. Considering that searching for and developing new antimonogenean compounds may require enormous investments of time, money, and animal sacrifice, the use of a computer-guided drug repositioning approach is a reasonable alternative. Under this context, this study aimed to evaluate the effectiveness of plumbagin and bromocriptine against adults and eggs of the monogenean Rhabdosynochus viridisi (Diplectanidae). Plumbagin is a phytochemical compound that has recently emerged as a potent antimonogenean; however, further investigation is required to determine its effects on different monogenean species. Bromocriptine was selected through a computational approach that included molecular docking analyses of 77 receptors of monogeneans (putative drug targets) and 77 ligands (putative inhibitors). In vitro experiments showed that bromocriptine does not exhibit mortality at concentrations of 0.1, 1, and 10 mg/L whereas plumbagin at 2 and 10 mg/L caused 100% monogenean mortality after 3 h and 30 min, respectively. The most effective concentration of plumbagin (10 mg/L) did not completely inhibit egg hatching. These findings underscore plumbagin as a highly effective agent against adult monogeneans and highlight the need for research to evaluate its effect(s) on fish. Although computational drug repositioning is useful for selecting candidates for experimental testing, it does not guarantee success due to the complexity of biological interactions, as observed here with bromocriptine. Therefore, it is crucial to examine the various compounds proposed by this method.

PMID:38593863 | DOI:10.1016/j.exppara.2024.108748

Gut Microbes. 2024 Jan-Dec;16(1):2337312. doi: 10.1080/19490976.2024.2337312. Epub 2024 Apr 9.

ABSTRACT

Clostridioides difficile causes a range of debilitating intestinal symptoms that may be fatal. It is particularly problematic as a hospital-acquired infection, causing significant costs to the health care system. Antibiotics, such as vancomycin and fidaxomicin, are still the drugs of choice for C. difficile infections, but their effectiveness is limited, and microbial interventions are emerging as a new treatment option. This paper focuses on alternative treatment approaches, which are currently in various stages of development and can be divided into four therapeutic strategies. Direct killing of C. difficile (i) includes beside established antibiotics, less studied bacteriophages, and their derivatives, such as endolysins and tailocins. Restoration of microbiota composition and function (ii) is achieved with fecal microbiota transplantation, which has recently been approved, with standardized defined microbial mixtures, and with probiotics, which have been administered with moderate success. Prevention of deleterious effects of antibiotics on microbiota is achieved with agents for the neutralization of antibiotics that act in the gut and are nearing regulatory approval. Neutralization of C. difficile toxins (iii) which are crucial virulence factors is achieved with antibodies/antibody fragments or alternative binding proteins. Of these, the monoclonal antibody bezlotoxumab is already in clinical use. Immunomodulation (iv) can help eliminate or prevent C. difficile infection by interfering with cytokine signaling. Small-molecule agents without bacteriolytic activity are usually selected by drug repurposing and can act via a variety of mechanisms. The multiple treatment options described in this article provide optimism for the future treatment of C. difficile infection.

PMID:38591915 | DOI:10.1080/19490976.2024.2337312

Acta Biochim Biophys Sin (Shanghai). 2024 Apr 9. doi: 10.3724/abbs.2024040. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers in the world, which is frequently diagnosed at a late stage. HCC patients have a poor prognosis due to the lack of an efficacious therapeutic strategy. Approved drug repurposing is a way for accelerating drug discovery and can significantly reduce the cost of drug development. Carfilzomib (CFZ) is a second-generation proteasome inhibitor, which is highly efficacious against multiple myeloma and has been reported to possess potential antitumor activities against multiple cancers. However, the underlying mechanism of CFZ on HCC is still unclear. Here, we show that CFZ inhibits the proliferation of HCC cells through cell cycle arrest at the G2/M phase and suppresses the migration and invasion of HCC cells by inhibiting epithelial-mesenchymal transition. We also find that CFZ promotes reactive oxygen species production to induce endoplasmic reticulum (ER) stress and activate JNK/p38 MAPK signaling in HCC cells, thus inducing cell death in HCC cells. Moreover, CFZ significantly inhibits HCC cell growth in a xenograft mouse model. Collectively, our study elucidates that CFZ impairs mitochondrial function and activates ER stress and JNK/p38 MAPK signaling, thus inhibiting HCC cell and tumor growth. This indicates that CFZ has the potential as a therapeutic drug for HCC.

PMID:38591121 | DOI:10.3724/abbs.2024040

Front Pharmacol. 2024 Mar 25;15:1375805. doi: 10.3389/fphar.2024.1375805. eCollection 2024.

ABSTRACT

INTRODUCTION: The purine analog 6-thioguanine (6TG), an old drug approved in the 60s to treat acute myeloid leukemia (AML), was tested in the diabetic retinopathy (DR) experimental in vivo setting along with a molecular modeling approach.

METHODS: A computational analysis was performed to investigate the interaction of 6TG with MC1R and MC5R. This was confirmed in human umbilical vein endothelial cells (HUVECs) exposed to high glucose (25 mM) for 24 h. Cell viability in HUVECs exposed to high glucose and treated with 6TG (0.05-0.5-5 µM) was performed. To assess tube formation, HUVECs were treated for 24 h with 6TG 5 µM and AGRP (0.5-1-5 µM) or PG20N (0.5-1-5-10 µM), which are MC1R and MC5R antagonists, respectively. For the in vivo DR setting, diabetes was induced in C57BL/6J mice through a single streptozotocin (STZ) injection. After 2, 6, and 10 weeks, diabetic and control mice received 6TG intravitreally (0.5-1-2.5 mg/kg) alone or in combination with AGRP or PG20N. Fluorescein angiography (FA) was performed after 4 and 14 weeks after the onset of diabetes. After 14 weeks, mice were euthanized, and immunohistochemical analysis was performed to assess retinal levels of CD34, a marker of endothelial progenitor cell formation during neo-angiogenesis.

RESULTS: The computational analysis evidenced a more stable binding of 6TG binding at MC5R than MC1R. This was confirmed by the tube formation assay in HUVECs exposed to high glucose. Indeed, the anti-angiogenic activity of 6TG was eradicated by a higher dose of the MC5R antagonist PG20N (10 µM) compared to the MC1R antagonist AGRP (5 µM). The retinal anti-angiogenic effect of 6TG was evident also in diabetic mice, showing a reduction in retinal vascular alterations by FA analysis. This effect was not observed in diabetic mice receiving 6TG in combination with AGRP or PG20N. Accordingly, retinal CD34 staining was reduced in diabetic mice treated with 6TG. Conversely, it was not decreased in diabetic mice receiving 6TG combined with AGRP or PG20N.

CONCLUSION: 6TG evidenced a marked anti-angiogenic activity in HUVECs exposed to high glucose and in mice with DR. This seems to be mediated by MC1R and MC5R retinal receptors.

PMID:38590636 | PMC:PMC10999531 | DOI:10.3389/fphar.2024.1375805

NPJ Syst Biol Appl. 2024 Apr 8;10(1):37. doi: 10.1038/s41540-024-00359-z.

ABSTRACT

Immunomodulatory peptides, while exhibiting potential antimicrobial, antifungal, and/or antiviral properties, can play a role in stimulating or suppressing the immune system, especially in pathological conditions like breast cancer (BC). Thus, deregulation of these peptides may serve as an immunotherapeutic strategy to enhance the immune response. In this meta-analysis, we utilized single-cell RNA sequencing data and known therapeutic peptides to investigate the deregulation of these peptides in malignant versus normal human breast epithelial cells. We corroborated our findings at the chromatin level using ATAC-seq. Additionally, we assessed the protein levels in various BC cell lines. Moreover, our in-house drug repositioning approach was employed to identify potential drugs that could positively impact the relapse-free survival of BC patients. Considering significantly deregulated therapeutic peptides and their role in BC pathology, our approach aims to downregulate B2M and SLPI, while upregulating PIGR, DEFB1, LTF, CLU, S100A7, and SCGB2A1 in BC epithelial cells through our drug repositioning pipeline. Leveraging the LINCS L1000 database, we propose BRD-A06641369 for B2M downregulation and ST-4070043 and BRD-K97926541 for SLPI downregulation without negatively affecting the MHC complex as a significantly correlated pathway with these two genes. Furthermore, we have compiled a comprehensive list of drugs for the upregulation of other selected immunomodulatory peptides. Employing an immunotherapeutic approach by integrating our drug repositioning pipeline with single-cell analysis, we proposed potential drugs and drug targets to fortify the immune system against BC.

PMID:38589404 | DOI:10.1038/s41540-024-00359-z

J Appl Microbiol. 2024 Apr 8:lxae088. doi: 10.1093/jambio/lxae088. Online ahead of print.

ABSTRACT

AIMS: Drug repurposing is an attractive strategy to control biofilm-related infectious diseases. In this study, two drugs (montelukast and cefoperazone) with well-established therapeutic applications were tested on Pseudomonas aeruginosa quorum sensing (QS) inhibition and biofilm control.

METHODS AND RESULTS: The activity of montelukast and cefoperazone was evaluated for Pqs signal inhibition, pyocyanin synthesis, and prevention and eradication of P. aeruginosa biofilms. Cefoperazone inhibited the Pqs system by hindering the production of the autoinducer molecules 2-heptyl-4-hydroxyquinoline (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (the Pseudomonas quinolone signal or PQS), corroborating in silico results. P. aeruginosa pyocyanin production was reduced by 50%. The combination of the antibiotics cefoperazone and ciprofloxacin was synergistic for P. aeruginosa biofilm control. On the other hand, montelukast had no relevant effects on the inhibition of the Pqs system and against P. aeruginosa biofilm.

CONCLUSION: This study provides for the first time strong evidence that cefoperazone interacts with the Pqs system, hindering the formation of the autoinducer molecules HHQ and PQS, reducing P. aeruginosa pathogenicity and virulence. Cefoperazone demonstrated a potential to be used in combination with less effective antibiotics (e.g. ciprofloxacin) to potentiate the biofilm control action.

PMID:38587815 | DOI:10.1093/jambio/lxae088

Interdiscip Perspect Infect Dis. 2024 Mar 30;2024:9109041. doi: 10.1155/2024/9109041. eCollection 2024.

ABSTRACT

Bacterial multiresistance to drugs is a rapidly growing global phenomenon. New resistance mechanisms have been described in different bacterial pathogens, threatening the effective treatment of even common infectious diseases. The problem worsens in infections associated with biofilms because, in addition to the pathogen's multiresistance, the biofilm provides a barrier that prevents antimicrobial access. Several "non-antibiotic" drugs have antimicrobial activity, even though it is not their primary therapeutic purpose. However, due to the urgent need to develop effective antimicrobials to treat diseases caused by multidrug-resistant pathogens, there has been an increase in research into "non-antibiotic" drugs to offer an alternative therapy through the so-called drug repositioning or repurposing. The prospect of new uses for existing drugs has the advantage of reducing the time and effort required to develop new compounds. Moreover, many drugs are already well characterized regarding toxicity and pharmacokinetic/pharmacodynamic properties. Ebselen has shown promise for use as a repurposing drug for antimicrobial purposes. It is a synthetic organoselenium with anti-inflammatory, antioxidant, and cytoprotective activity. A very attractive factor for using ebselen is that, in addition to potent antimicrobial activity, its minimum inhibitory concentration is very low for microbial pathogens.

PMID:38586592 | PMC:PMC10998725 | DOI:10.1155/2024/9109041

Infect Med (Beijing). 2024 Feb 21;3(1):100095. doi: 10.1016/j.imj.2024.100095. eCollection 2024 Mar.

ABSTRACT

The COVID-19 pandemic has created unprecedented challenges worldwide. Artificial intelligence (AI) technologies hold tremendous potential for tackling key aspects of pandemic management and response. In the present review, we discuss the tremendous possibilities of AI technology in addressing the global challenges posed by the COVID-19 pandemic. First, we outline the multiple impacts of the current pandemic on public health, the economy, and society. Next, we focus on the innovative applications of advanced AI technologies in key areas such as COVID-19 prediction, detection, control, and drug discovery for treatment. Specifically, AI-based predictive analytics models can use clinical, epidemiological, and omics data to forecast disease spread and patient outcomes. Additionally, deep neural networks enable rapid diagnosis through medical imaging. Intelligent systems can support risk assessment, decision-making, and social sensing, thereby improving epidemic control and public health policies. Furthermore, high-throughput virtual screening enables AI to accelerate the identification of therapeutic drug candidates and opportunities for drug repurposing. Finally, we discuss future research directions for AI technology in combating COVID-19, emphasizing the importance of interdisciplinary collaboration. Though promising, barriers related to model generalization, data quality, infrastructure readiness, and ethical risks must be addressed to fully translate these innovations into real-world impacts. Multidisciplinary collaboration engaging diverse expertise and stakeholders is imperative for developing robust, responsible, and human-centered AI solutions against COVID-19 and future public health emergencies.

PMID:38586543 | PMC:PMC10998276 | DOI:10.1016/j.imj.2024.100095

JID Innov. 2024 Feb 28;4(3):100271. doi: 10.1016/j.xjidi.2024.100271. eCollection 2024 May.

ABSTRACT

Hand-foot skin reaction is the most common adverse event of multikinase inhibitors, such as sorafenib. Although hand-foot skin reaction is not life threatening, severe cases impair quality of life because of pain and reduced activities of daily living. However, the pathological mechanisms of hand-foot skin reaction have not yet been elucidated in detail, and there is currently no effective treatment. We aimed to identify keratinocyte cytoprotectants against sorafenib toxicity. The screening of cytoprotectants against sorafenib toxicity was performed using cultured normal human epidermal keratinocytes or a reconstructed human epidermis model and off-patent approved drugs in the Prestwick Chemical library. Among 1273 drugs in the chemical library, 8 dose-dependently increased cell viability by >200% in the presence of sorafenib. In the presence of sorafenib, the number of proliferating cell nuclear antigen-positive cells was significantly higher in clofazimine-, cyclosporin A-, and itraconazole-treated reconstructed human epidermis models than in sorafenib-treated models, and candidate drugs suppressed sorafenib-induced apoptosis in normal human epidermal keratinocytes. In addition, clofazimine, itraconazole, and pyrvinium pamoate significantly recovered the phosphorylation of extracellular signal-regulated kinase 1/2 in the presence of sorafenib. Collectively, hit drugs promoted cell viability and normalized keratinocyte proliferation in the presence of sorafenib. These candidate drugs have potential as treatments for multikinase inhibitor-induced hand-foot skin reaction.

PMID:38585194 | PMC:PMC10990978 | DOI:10.1016/j.xjidi.2024.100271

Curr Pharm Des. 2024 Apr 5. doi: 10.2174/0113816128304230240327044201. Online ahead of print.

ABSTRACT

Inflammation is critical to the formation and development of tumors and is closely associated with cancer. Therefore, addressing inflammation and the mediators that contribute to the inflammatory process may be a useful strategy for both cancer prevention and treatment. Tumor predisposition can be attributed to inflammation. It has been demonstrated that NSAIDs can modify the tumor microenvironment by enhancing apoptosis and chemosensitivity and reducing cell migration. There has been a recent rise in interest in drug repositioning or repurposing because the development of innovative medications is expensive, timeconsuming, and presents a considerable obstacle to drug discovery. Repurposing drugs is crucial for the quicker and less expensive development of anticancer medicines, according to an increasing amount of research. This review summarizes the antiproliferative activity of derivatives of NSAIDs such as Diclofenac, Etodolac, Celecoxib, Ibuprofen, Tolmetin, and Sulindac, published between 2017 and 2023. Their mechanism of action and structural activity relationships (SARs) were also discussed to set the path for potential future repositioning of NSAIDs for clinical deployment in the treatment of cancer.

PMID:38584541 | DOI:10.2174/0113816128304230240327044201

Br J Dermatol. 2024 Apr 8:ljae143. doi: 10.1093/bjd/ljae143. Online ahead of print.

NO ABSTRACT

PMID:38584300 | DOI:10.1093/bjd/ljae143

Gynecol Oncol. 2024 Apr 5;186:42-52. doi: 10.1016/j.ygyno.2024.03.029. Online ahead of print.

ABSTRACT

BACKGROUND: Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies.

METHODS: We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines.

RESULTS: 16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy.

CONCLUSION: Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation.

PMID:38582027 | DOI:10.1016/j.ygyno.2024.03.029