Exp Dermatol. 2025 Feb;34(2):e70060. doi: 10.1111/exd.70060.

ABSTRACT

Globally, chronic wounds impact the health of millions of people, negatively affecting quality of life and healthcare budgets. Some of the crucial steps and pathways in healing mechanisms are the hypoxic response and the expression of host defence peptides, which are decreased in diseases related to chronic wounds such as diabetes mellitus and cardiovascular diseases. It has been shown that histone deacetylase inhibitors can induce the expression of Host Defence Peptides (HDP) by inducing the stabilisation and activation of hypoxia-inducible factor 1-α (HIF-1α), promoting wound healing pathways, although their high cost and side effects limit clinical research. With the help of bioinformatics tools, we found potential histone deacetylase inhibitor candidates in an FDA-approved drugs database. The candidates, 1,3-Diphenylurea (DiPU), 2'-Aminoacetanilide (Ace), and Tert-butyl (2-aminophenyl) carbamate (N-boc), show wound healing effects in HaCaT cells, increasing cell migration possibly via HIF-1α, inducing the expression of LL-37 and vascular endothelial growth factor (VEGF), while in a mouse ring angiogenesis model, Ace and N-boc have angiogenic effects. In a model of basal primary keratinocytes from donors with diabetes mellitus (DM), without DM, and from Diabetic Foot Ulcers (DFU), it was observed that only DiPU is capable of inducing LL-37 in all scenarios. There is limited information about histone deacetylase inhibitors and wound healing but in this paper, we observe promising results and a proposed mechanism that involved specifically Histone Deacetylase 1 inhibition (HDAC1).

PMID:39989310 | DOI:10.1111/exd.70060

Br J Haematol. 2025 Feb 23. doi: 10.1111/bjh.20026. Online ahead of print.

ABSTRACT

We sought to identify new candidate drugs for repurposing to myelodysplastic syndromes (MDS). Connectivity map analysis was performed on gene expression signatures generated from bone marrow CD34+ cells of splicing factor mutant MDS patients. Celastrol and Withaferin A (WA), two top-ranking compounds identified, markedly inhibited proliferation, arrested the cell cycle and induced apoptosis in leukaemia cells. These compounds also inhibited the viability of primary bone marrow MDS cells. We showed that Celastrol and WA inhibit interleukin-1 receptor-associated kinase 4-mediated nuclear factor kappa-light-chain-enhancer of activated B cells signalling activation in splicing factor mutant MDS and leukaemia cells. Celastrol and WA may represent novel candidate drugs for the treatment of MDS.

PMID:39988885 | DOI:10.1111/bjh.20026

Microb Pathog. 2025 Feb 20:107398. doi: 10.1016/j.micpath.2025.107398. Online ahead of print.

ABSTRACT

The COVID-19 disease has spread rapidly across the world within just six months, affecting 169 million people and causing 3.5 million deaths globally (2021). The most affected countries include the USA, Brazil, India, and several European countries such as the UK and Russia. Healthcare professionals face new challenges in finding better ways to manage patients and save lives. In this regard, more comprehensive research is needed, including genomic and proteomic studies, personalized medicines and the design of suitable treatments. However, finding novel molecular entities (NME) using a standard or de novo strategy to drug development is a time-consuming and costly process. Another alternate strategy is discovering new therapeutic uses for old/existing/available medications, known as drug repurposing. There are a variety of computational repurposing methodologies, and some of them have been used to counter the coronavirus disease pandemic of 2019 (COVID-19). This review article compiles recently published data on the origin, transmission, pathogenesis, diagnosis, and management of the coronavirus by drug repurposing and vaccine development approach. We have attempted to screen probable drugs in clinical trials by using literature survey. This systematic review aims to create priorities for future research of drugs repurposed and vaccine development for COVID-19.

PMID:39986548 | DOI:10.1016/j.micpath.2025.107398

Artif Intell Med. 2025 Feb 19;162:103090. doi: 10.1016/j.artmed.2025.103090. Online ahead of print.

ABSTRACT

New drug discovery has always been a costly, time-consuming process with a high failure rate. Repurposing existing drugs offers a valuable alternative and reduces the risks associated with developing new drugs. Various experimental methods have been employed to facilitate drug repositioning; however, associations prediction between drugs and diseases through biological experiments is both expensive and time-consuming. Consequently, it is imperative to develop efficient and highly precise computational methods for predicting these associations. Based on this, we propose a drug-disease associations prediction method based on Hyperbolic Multivariate feature Learning in High-order Heterogeneous Networks for Drug-Disease Prediction, called H3ML. Our approach begins by mining high-order information from protein-disease and drug-protein networks to construct high-order heterogeneous networks. Subsequently, we employ multivariate feature learning to create hyperbolic representations, and then enhance the features of the heterogeneous network. Finally, we utilize a hyperbolic graph attention network in the hyperbolic space to aggregate neighbor information and perform the final prediction task. In addition, we evaluate the performance of H3ML by comparing it with some state-of-the-art methods across different datasets. The case study further validate the effectiveness of H3ML. Our implementation will be publicly available at: https://github.com/jianruichen/H-3ML.

PMID:39985835 | DOI:10.1016/j.artmed.2025.103090

Comput Biol Med. 2025 Feb 20;188:109757. doi: 10.1016/j.compbiomed.2025.109757. Online ahead of print.

ABSTRACT

Cancer treatment is often confounded by development of resistance to chemotherapy. This research explores the complex relationship between p62 (also known as SQSTM1), a multifunctional protein central in cancer signaling pathways - especially the NF-κB pathway - and chemoresistance. Our data indicate that disruption of the interaction between p62 and the serine/threonine protein kinase RIP1 is a viable strategy to counteract NF-κB activation and overcome chemoresistance. Employing a comprehensive drug repositioning approach, we utilized bioinformatics tools to perform docking, virtual screening, absorption, distribution, metabolism, and excretion analyses, toxicity analysis, and molecular dynamics simulations to identify FDA-approved drugs that prevent the binding of p62 to RIP1. Notable candidates, particularly montelukast and asunaprevir, blocked the p62-RIP1 interaction, establishing a basis for potential therapeutic interventions against chemoresistant cancers. This study highlights the critical role of the ZZ domain of p62 protein in chemotherapy resistance and sheds light on the possibility of repurposing existing drugs for novel applications in cancer treatment. Our findings provide a solid groundwork for preclinical studies.

PMID:39983356 | DOI:10.1016/j.compbiomed.2025.109757

Front Pharmacol. 2025 Jan 24;16:1492517. doi: 10.3389/fphar.2025.1492517. eCollection 2025.

ABSTRACT

Polyphenols, naturally occurring phytonutrients found in plant-based foods, have attracted significant attention for their potential therapeutic effects in neurological diseases and neuroinflammation. These compounds possess diverse neuroprotective capabilities, including antioxidant, anti-inflammatory, and anti-amyloid properties, which contribute to mitigating the progression of neurodegenerative conditions such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Dementia, Multiple Sclerosis (MS), Stroke, and Huntington's Disease (HD). Polyphenols have been extensively studied for their ability to regulate inflammatory responses by modulating the activity of pro-inflammatory genes and influencing signal transduction pathways, thereby reducing neuroinflammation and neuronal death. Additionally, polyphenols have shown promise in modulating various cellular signaling pathways associated with neuronal viability, synaptic plasticity, and cognitive function. Epidemiological and clinical studies highlight the potential of polyphenol-rich diets to decrease the risk and alleviate symptoms of neurodegenerative disorders and neuroinflammation. Furthermore, polyphenols have demonstrated their therapeutic potential through the regulation of key signaling pathways such as Akt, Nrf2, STAT, and MAPK, which play critical roles in neuroprotection and the body's immune response. This review emphasizes the growing body of evidence supporting the therapeutic potential of polyphenols in combating neurodegeneration and neuroinflammation, as well as enhancing brain health. Despite the substantial evidence and promising hypotheses, further research and clinical investigations are necessary to fully understand the role of polyphenols and establish them as advanced therapeutic targets for age-related neurodegenerative diseases and neuroinflammatory conditions.

PMID:39981183 | PMC:PMC11840759 | DOI:10.3389/fphar.2025.1492517

Biomed Pharmacother. 2025 Feb 19;184:117931. doi: 10.1016/j.biopha.2025.117931. Online ahead of print.

ABSTRACT

Triple-negative breast cancer (TNBC), a highly invasive type of cancer, is difficult to treat due to insufficient specific targets and low survival rates. Current therapy often encounters drug resistance or relapse; thus, repurposing existing drugs could revolutionize cancer treatment. This study examined the anticancer effects of the antipsychotics Cariprazine (CAR), Olanzapine (OLZ), and Clozapine (CLZ), and the immunomodulatory potential of CAR, in vitro and in vivo in TNBC models. In vitro, CAR, OLZ, and CLZ significantly inhibited the proliferation of TNBC cells. This inhibition occurred via the induction of mitochondrial apoptosis, G0/G1 cell cycle arrest, and the suppression of autophagy, as evidenced by the down-regulation of Bcl-2, p62, and pAKT; the upregulation of Bax and active caspase 3; the decrease of ΔΨM; and the promotion of cytochrome c release. In addition, CAR inhibited MDA-MB-231 cells migration. In vivo, CAR inhibited tumor growth in the 4T1 xenograft model without causing adverse effects and resulted in the mRNA upregulation caspase 9, p53, p21, and Beclin-1. In addition, CAR influenced the immune response by promoting the production of proinflammatory cytokines TNF-α, IFN-γ, IL-17, and IL-1β and increasing the percentage of TNF-α+, IL-17+, IL-1β+, and IFN-γ+ CD3+ splenocytes. In conclusion, compared with other antipsychotics, 5-FU, and cisplatin, CAR exerted the most potent anticancer activity in TNBC in vitro and in vivo. This efficacy may be attributed to its ability to regulate apoptosis and autophagy, promote G0/G1 cell cycle arrest, and modulate antitumor immune response, suggesting its therapeutic potential in breast cancer.

PMID:39978031 | DOI:10.1016/j.biopha.2025.117931

ArXiv [Preprint]. 2025 Jan 20:arXiv:2411.15418v2.

ABSTRACT

Virtual screening of small molecules against protein targets can accelerate drug discovery and development by predicting drug-target interactions (DTIs). However, structure-based methods like molecular docking are too slow to allow for broad proteome-scale screens, limiting their application in screening for off-target effects or new molecular mechanisms. Recently, vector-based methods using protein language models (PLMs) have emerged as a complementary approach that bypasses explicit 3D structure modeling. Here, we develop SPRINT, a vector-based approach for screening entire chemical libraries against whole proteomes for DTIs and novel mechanisms of action. SPRINT improves on prior work by using a self-attention based architecture and structure-aware PLMs to learn drug-target co-embeddings for binder prediction, search, and retrieval. SPRINT achieves SOTA enrichment factors in virtual screening on LIT-PCBA, DTI classification benchmarks, and binding affinity prediction benchmarks, while providing interpretability in the form of residue-level attention maps. In addition to being both accurate and interpretable, SPRINT is ultra-fast: querying the whole human proteome against the ENAMINE Real Database (6.7B drugs) for the 100 most likely binders per protein takes 16 minutes. SPRINT promises to enable virtual screening at an unprecedented scale, opening up new opportunities for in silico drug repurposing and development. SPRINT is available on the web as ColabScreen: https://bit.ly/colab-screen.

PMID:39975427 | PMC:PMC11838698

ACS Pharmacol Transl Sci. 2025 Jan 23;8(2):308-338. doi: 10.1021/acsptsci.4c00679. eCollection 2025 Feb 14.

ABSTRACT

Skin cancer represents a major health concern due to its rising incidence and limited treatment options. Current treatments (surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy) often entail high costs, patient inconvenience, significant adverse effects, and limited therapeutic efficacy. The search for novel treatment options is also marked by the high capital investment and extensive development involved in the drug discovery process. In response to these challenges, repurposing existing drugs for topical application and optimizing their delivery through nanotechnology could be the answer. This innovative strategy aims to combine the advantages of the known pharmacological background of commonly used drugs to expedite therapeutic development, with nanosystem-based formulations, which among other advantages allow for improved skin permeation and retention and overall higher therapeutic efficacy and safety. The present review provides a critical analysis of repurposed drugs such as doxycycline, itraconazole, niclosamide, simvastatin, leflunomide, metformin, and celecoxib, formulated into different nanosystems, namely, nanoemulsions and nanoemulgels, nanodispersions, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanoparticles, hybrid lipid-polymer nanoparticles, hybrid electrospun nanofibrous scaffolds, liposomes and liposomal gels, ethosomes and ethosomal gels, and aspasomes, for improved outcomes in the battle against skin cancer. Enhanced antitumor effects on melanoma and nonmelanoma research models are highlighted, with some nanoparticles even showing intrinsic anticancer properties, leading to synergistic effects. The explored research findings highly evidence the potential of these approaches to complement the currently available therapeutic strategies in the hope that these treatments might one day reach the pharmaceutical market.

PMID:39974652 | PMC:PMC11833728 | DOI:10.1021/acsptsci.4c00679

In Silico Pharmacol. 2025 Feb 17;13(1):30. doi: 10.1007/s40203-025-00316-6. eCollection 2025.

ABSTRACT

In COVID-19 patients, respiratory failure was reported due to damage to the respiratory centers of the brainstem. Molecular mimicry of three brainstem pre-Botzinger complex proteins (DAB1, AIFM and SURF1) was regarded as the underlying reason for respiratory failure and the autoimmune neurological sequelae. Of the three brainstem proteins mimicked by SARS CoV-2, corresponding sequences to two of the mimicry peptides were located in the N-protein of SARS CoV-2. N-protein is important for viral RNA synthesis and genome packaging. Here, we have used molecular modeling, docking and MD simulations to discern potential drugs which can inhibit molecular mimicry of DAB1 by SARS CoV-2 and also eliminate it by interfering in genome packaging. The binding site (drug target) for molecular docking was defined as the amino acid sequence extending from position 168-185 of the N-protein which was a SLiM region and also included the mimicry hexapeptide. Molecular docking after MD simulations was used to discern probable inhibitors of the drug-target from FDA-approved neurological drugs in the Broad Institute's Drug Repurposing Hub. Our results revealed that an anti-anxiety drug afobazole qualified the ADMET parameters, formed a stable complex with the drug-target and exhibited the highest binding energy (-88.21 kJ/mol). This suggests that afobazole can be repurposed against SARS CoV-2 for disrupting molecular mimicry of human DAB1 protein and also eliminate the etiopathological agent by interfering in viral genome packaging.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00316-6.

PMID:39974371 | PMC:PMC11832858 | DOI:10.1007/s40203-025-00316-6

Arterioscler Thromb Vasc Biol. 2025 Feb 20. doi: 10.1161/ATVBAHA.124.321579. Online ahead of print.

ABSTRACT

BACKGROUND: Thiol isomerases play essential and nonredundant roles in platelet activation, aggregation, and thrombus formation. Thiol isomerase inhibitors have the potential to overcome the 2 major drawbacks of current antithrombotic therapies, as they target both arterial and venous thrombosis without enhancing bleeding risks. Recently, a Food and Drug Administration-approved drug, zafirlukast (ZAF), was shown to be a promising pan-thiol isomerase inhibitor. The objective of this study is to develop analogues of ZAF with optimized thiol isomerase inhibition and antithrombotic activity.

METHODS: Thirty-five ZAF analogues were tested in an insulin turbidometric assay for thiol isomerase inhibition. Analogues were tested for platelet activation, aggregation, P-selectin expression, and laser-induced thrombosis in mice and compared with the parent compound.

RESULTS: Of the 35 analogues, 12 retained activity, with 1, compound 21, that demonstrated a greater potency than that of ZAF, 5 had a similar potency to that of ZAF, and 6 had a weaker potency. Analogues demonstrated inhibition of platelet aggregation and P-selectin expression as compared with ZAF, consistent with their potencies. ZAF and compound 21 were shown to be reversible inhibitors of thiol isomerases, and not cytotoxic to cultured, lung, liver, and kidney cells. Finally, in an in vivo assessment of thrombus formation, compound 21 was able to significantly inhibit thrombus formation without affecting bleeding times.

CONCLUSIONS: A ZAF analogue, compound 21, with properties superior to those of ZAF was synthesized, demonstrating improved inhibition of platelet activation, aggregation, and thrombus formation as compared with the parent ZAF. This approach could yield a promising clinical candidate for treatment and prophylaxis of arterial and venous thrombosis.

PMID:39973747 | DOI:10.1161/ATVBAHA.124.321579

Infect Dis (Lond). 2025 Feb 20:1-8. doi: 10.1080/23744235.2025.2468510. Online ahead of print.

ABSTRACT

BACKGROUND: Tick-borne encephalitis (TBE) is a neurological disease caused by the tick-borne encephalitis virus (TBEV). Despite available vaccines, breakthrough infections occur, some fatal.

OBJECTIVES: As no antiviral therapy for TBE is currently approved, this study evaluated the in vitro activity of already licenced remdesivir (RDV) and sofosbuvir (SOF) for possible drug repurposing against TBEV.

METHODS: TBEV was cultured in A549 cells, and the inhibitory effects of RDV (GS-5734), its parent nucleotide GS-441524, and SOF (GS-7977) were assessed.

RESULTS: After 78 h, RDV demonstrated significantly lower EC50 values than SOF (0.14 vs. 11 µM) based on TBEV RNA levels measured by RT-qPCR. RDV also had a lower mean EC50 (0.55 µM) compared to GS-441524 and SOF (>8.9 and 13.1 µM, respectively) using crystal violet staining after 5 days. After 11 passages of TBEV in the presence of RDV, emergence of virus with a higher EC50 (1.32 vs. 0.55 µM) was detected with two mutations (L3122F and Y3278F) in NS5, the viral RNA-dependent RNA polymerase (RdRp), and one substitution in envelope (E) protein (E402G). Similarly, SOF resistance appeared after 20 passages, increasing EC50 values (35.5 vs. 10 µM).

CONCLUSION: RDV exhibits potent in vitro antiviral activity against TBEV via specific targeting of the viral RdRp as confirmed by the emergence of resistance-associated double NS5 substitutions in vitro in the presence of RDV. While the potential in vivo implications of the observed RDV resistance remain to be determined, these in vitro data support further assessment of RDV for the treatment of TBEV infection.

PMID:39973341 | DOI:10.1080/23744235.2025.2468510

Brief Bioinform. 2024 Nov 22;26(1):bbaf054. doi: 10.1093/bib/bbaf054.

ABSTRACT

Combination therapy has become increasingly important for treating complex diseases which often involve multiple pathways and targets. However, experimental screening of drug combinations is costly and time-consuming. The availability of large-scale transcriptomic datasets (e.g. CMap and LINCS) from in vitro drug treatment experiments makes it possible to computationally predict drug combinations with synergistic effects. Towards this end, we developed a computational approach, termed Identification of Drug Combinations via Multi-Set Operations (iDOMO), to predict drug synergy based on multi-set operations of drug and disease gene signatures. iDOMO quantifies the synergistic effect of a pair of drugs by taking into account the combination's beneficial and detrimental effects on treating a disease. We evaluated iDOMO, in a DREAM Challenge dataset with the matched, pre- and post-treatment gene expression data and cell viability information. We further evaluated the performance of iDOMO by concordance index and Spearman correlation on predicting the Highest Single Agency (HSA) synergy scores for four most common cancer types in two large-scale drug combination databases, showing that iDOMO significantly outperformed two existing popular drug combination approaches including the Therapeutic Score and the SynergySeq Orthogonality Score. Application of iDOMO to triple-negative breast cancer (TNBC) identified drug pairs with potential synergistic effects, with the combination of trifluridine and monobenzone being the most synergistic. Our in vitro experiments confirmed that the top predicted drug combination exerted a significant synergistic effect in inhibiting TNBC cell growth. In summary, iDOMO is an effective method for the in silico screening of synergistic drug combinations and will be a valuable tool for the development of novel therapeutics for complex diseases.

PMID:39973082 | DOI:10.1093/bib/bbaf054

Nat Commun. 2025 Feb 19;16(1):1755. doi: 10.1038/s41467-025-56690-4.

ABSTRACT

Repurposed drugs provide a rich source of potential therapies for Alzheimer's disease (AD) and other neurodegenerative disorders (NDD). Repurposed drugs have information from non-clinical studies, phase 1 dosing, and safety and tolerability data collected with the original indication. Computational approaches, "omic" studies, drug databases, and electronic medical records help identify candidate therapies. Generic repurposed agents lack intellectual property protection and are rarely advanced to late-stage trials for AD/NDD. In this review we define repurposing, describe the advantages and challenges of repurposing, offer strategies for overcoming the obstacles, and describe the key contributions of repurposing to the drug development ecosystem.

PMID:39971900 | DOI:10.1038/s41467-025-56690-4

Eur J Med Chem. 2025 Feb 15;288:117385. doi: 10.1016/j.ejmech.2025.117385. Online ahead of print.

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is implicated in steatohepatitis (NASH), liver cirrhosis (LC) to hepatocellular carcinoma (HCC), sequentially. Herein, our aim was to unravel the nuanced key components (compounds, and targets) to deter the progressive severity concerning hepatocellular diseases. We incorporated rigor bioinformatics and computational screening tools to decode effector(s) against NAFLD, NASH, LC, and HCC. The corresponding ligands of PDX1 (transcription factor of INS; one agonist), and IL6 (thirty-two antagonists) were identified by Selleckchem. Molecular docking test (MDT) revealed that PDX1- BRD7552 conformer (-12.1 kcal/mol), and IL6- Forsythoside B (-11.4 kcal/mol) conformer formed most stable complex. In parallel, DFT proposed that BRD7552, and Forsythoside B had significant chemical properties to react the targets, respectively. In conclusion, we decoded causatives of the progressive liver disease with web-based tools in drug repositioning theory. BRD7552 as PDX1 agonist, and Forsythoside B as IL6 antagonist were attributed to synergistic efficacy against NAFLD-derived HCC.

PMID:39970728 | DOI:10.1016/j.ejmech.2025.117385

Cancer Med. 2025 Feb;14(4):e70681. doi: 10.1002/cam4.70681.

ABSTRACT

BACKGROUND: Ovarian cancer (OC) is the most lethal gynecological malignancy and a major global health concern, often diagnosed at advanced stages with poor survival rates. Despite advancements in treatment, resistance to standard chemotherapy remains a critical challenge with limited treatment options available. In recent years, the role of metabolic reprogramming in OC has emerged as a key factor driving tumor progression, therapy resistance, and poor clinical outcomes.

METHODS: This review explores the intricate connections between metabolic syndrome, enhanced glycolysis, and altered lipid metabolism within OC cells, which fuel the aggressive nature of the disease. We discuss how metabolic pathways are rewired in OC to support uncontrolled cell proliferation, survival under hypoxic conditions, and evasion of cell death mechanisms, positioning metabolic alterations as central to disease progression. The review also highlights the potential of repurposed metabolic-targeting drugs, such as metformin and statins, which have shown promise in preclinical studies for their ability to disrupt these altered metabolic pathways.

CONCLUSION: Drug repurposing offers a promising strategy to overcome chemoresistance and improve patient outcomes. Future research should focus on unraveling the complex metabolic networks in OC to develop innovative, targeted therapies that can enhance treatment efficacy and patient survival.

PMID:39969135 | DOI:10.1002/cam4.70681

Expert Rev Neurother. 2025 Feb 19. doi: 10.1080/14737175.2025.2469041. Online ahead of print.

ABSTRACT

INTRODUCTION: Post-traumatic epilepsy (PTE) accounts for 10% to 20% of all symptomatic epilepsies and 5% of all forms of epilepsy, and drug resistance is reported in up to 45% of cases.

AREAS COVERED: This is a focused narrative review that discusses the available data on the current and new PTE treatments, giving particular attention to the last 10 years.

EXPERT OPINION: Despite the disappointing results of many antiseizure medications (ASMs) in preventing epileptogenicity, it is still unclear whether the early intervention could lead to different clinical phenotypes in terms, for example, of seizure severity, drug resistance and comorbidity patterns. The same applies to compounds targeting neuroinflammation, oxidative stress and neurotransmission modulation. The heterogeneity of etiologies leading to PTE has limited the investigation and implementation of specific interventions. New studies must focus on identifying common pathways and mechanisms shared by different etiological processes, identifying biomarkers, and validating animal models of epileptogenesis concerning PTE. Drug repurposing research will facilitate rapid translation into clinical research. Multitarget drug combinations will also receive increasing attention. In terms of non-pharmacological treatments, Vagus Nerve Stimulation seems to be a good option, while epilepsy surgery and Deep Brain Stimulation deserve further attention.

PMID:39968755 | DOI:10.1080/14737175.2025.2469041

Front Cell Neurosci. 2025 Feb 4;19:1559821. doi: 10.3389/fncel.2025.1559821. eCollection 2025.

NO ABSTRACT

PMID:39968391 | PMC:PMC11832465 | DOI:10.3389/fncel.2025.1559821

Heliyon. 2025 Jan 10;11(3):e41894. doi: 10.1016/j.heliyon.2025.e41894. eCollection 2025 Feb 15.

ABSTRACT

Despite the vast vaccination campaigns against SARS-CoV-2, vaccine-resistant variants have emerged, and COVID-19 is continuing to spread with the fear of emergence of new variants that are resistant to the currently available anti-viral drugs. Hence, there is an urgent need to discover potential host-directed - rather than virus-directed - therapies against COVID-19. SARS-CoV-2 enters host cells through binding of the viral spike (S)-protein to the host angiotensin-converting enzyme 2 (ACE2) receptor, rendering the viral port of entry an attractive therapeutic target. Accordingly, this study aimed to investigate FDA-approved drugs for their potential repurposing to inhibit the entry point of SARS-CoV-2. Accordingly, the FDA-approved drugs library was enrolled in docking simulations to identify drugs that bind to the Spike-ACE2 interface. The drugs list retrieved by the docking simulations was shortlisted to 19 drugs based on docking scores and safety profiles. These drugs were screened for their ability to prevent binding between ACE2 and S-protein using an ELISA-based Spike-ACE2 binding assay. Five drugs showed statistically significant inhibition of binding between ACE2 and S-protein, ranging from 4 % to 37 %. Of those five, argatroban, glimepiride and ranolazine showed potential antiviral activity at IC50 concentrations well below their CC50 assessed by the plaque assay. Their mode of antiviral action was then determined using the plaque assay with some modifications, which revealed that argatroban acted mainly through a direct virucidal mechanism, while glimepiride largely inhibited viral replication, and ranolazine exerted its antiviral impact primarily through inhibiting viral adsorption. In conclusion, this study has identified three FDA-approved drugs - argatroban, glimepiride and ranolazine - which could potentially be repurposed and used for the management of COVID-19.

PMID:39968139 | PMC:PMC11834051 | DOI:10.1016/j.heliyon.2025.e41894

Small. 2025 Feb 19:e2409126. doi: 10.1002/smll.202409126. Online ahead of print.

ABSTRACT

This study advances sustainable pharmaceutical research for endometriosis by developing in vitro 3D cell culture models of endometriotic pathophysiology that allow antifibrotic drug candidates to be tested. Fibrosis is a key aspect of endometriosis, yet current cell models to study it remain limited. This work aims to bridge the translational gap between in vitro fibrosis research and preclinical testing of non-hormonal drug candidates. When grown in a 3D matrix of sustainably produced silk protein functionalized with a fibronectin-derived cell adhesion motif (FN-silk), endometrial stromal and epithelial cells respond to transforming growth factor beta-1 (TGF-β1) in a physiological manner as probed at the messenger RNA (mRNA) level. For stromal cells, this response to TGF-β1 is not observed in spheroids, while epithelial cell spheroids behave similarly to epithelial cell FN-silk networks. Pirfenidone, an antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis, reverses TGF-β1-induced upregulation of mRNA transcripts involved in fibroblast-to-myofibroblast transdifferentiation of endometrial stromal cells in FN-silk networks, supporting pirfenidone's potential as a repurposed non-hormonal endometriosis therapy. Overall, endometrial stromal cells cultured in FN-silk networks-which are composed of a sustainably produced, fully defined FN-silk protein-recapitulate fibrotic cellular behavior with high fidelity and enable antifibrotic drug testing.

PMID:39967482 | DOI:10.1002/smll.202409126