Cells. 2023 Jul 23;12(14):1917. doi: 10.3390/cells12141917.

ABSTRACT

Breast cancer treatment can be improved with biomarkers for early detection and individualized therapy. A set of 86 microRNAs (miRNAs) were identified to separate breast cancer tumors from normal breast tissues (n = 52) with an overall accuracy of 90.4%. Six miRNAs had concordant expression in both tumors and breast cancer patient blood samples compared with the normal control samples. Twelve miRNAs showed concordant expression in tumors vs. normal breast tissues and patient survival (n = 1093), with seven as potential tumor suppressors and five as potential oncomiRs. From experimentally validated target genes of these 86 miRNAs, pan-sensitive and pan-resistant genes with concordant mRNA and protein expression associated with in-vitro drug response to 19 NCCN-recommended breast cancer drugs were selected. Combined with in-vitro proliferation assays using CRISPR-Cas9/RNAi and patient survival analysis, MEK inhibitors PD19830 and BRD-K12244279, pilocarpine, and tremorine were discovered as potential new drug options for treating breast cancer. Multi-omics biomarkers of response to the discovered drugs were identified using human breast cancer cell lines. This study presented an artificial intelligence pipeline of miRNA-based discovery of biomarkers, therapeutic targets, and repositioning drugs that can be applied to many cancer types.

PMID:37508580 | PMC:PMC10378316 | DOI:10.3390/cells12141917

Viruses. 2023 Jun 28;15(7):1465. doi: 10.3390/v15071465.

ABSTRACT

Flaviviruses, including Dengue (DENV), Zika (ZIKV), and Yellow Fever (YFV) viruses, represent a significant global health burden. The development of effective antiviral therapies against these viruses is crucial to mitigate their impact. This study investigated the antiviral potential of the cholesterol-lowering drugs atorvastatin and ezetimibe in monotherapy and combination against DENV, ZIKV, and YFV. In vitro results demonstrated a dose-dependent reduction in the percentage of infected cells for both drugs. The combination of atorvastatin and ezetimibe showed a synergistic effect against DENV 2, an additive effect against DENV 4 and ZIKV, and an antagonistic effect against YFV. In AG129 mice infected with DENV 2, monotherapy with atorvastatin or ezetimibe significantly reduced clinical signs and increased survival. However, the combination of both drugs did not significantly affect survival. This study provides valuable insights into the potential of atorvastatin and ezetimibe as antiviral agents against flaviviruses and highlights the need for further investigations into their combined therapeutic effects.

PMID:37515153 | PMC:PMC10383882 | DOI:10.3390/v15071465

Methods. 2023 Jul 27:S1046-2023(23)00119-6. doi: 10.1016/j.ymeth.2023.07.008. Online ahead of print.

ABSTRACT

Drug repurposing, which typically applies the procedure of drug-disease associations (DDAs) prediction, is a feasible solution to drug discovery. Compared with traditional methods, drug repurposing can reduce the cost and time for drug development and advance the success rate of drug discovery. Although many methods for drug repurposing have been proposed and the obtained results are relatively acceptable, there is still some room for improving the predictive performance, since those methods fail to consider fully the issue of sparseness in known drug-disease associations. In this paper, we propose a novel multi-task learning framework based on graph representation learning to identify DDAs for drug repurposing. In our proposed framework, a heterogeneous information network is first constructed by combining multiple biological datasets. Then, a module consisting of multiple layers of graph convolutional networks is utilized to learn low-dimensional representations of nodes in the constructed heterogeneous information network. Finally, two types of auxiliary tasks are designed to help to train the target task of DDAs prediction in the multi-task learning framework. Comprehensive experiments are conducted on real data and the results demonstrate the effectiveness of the proposed method for drug repurposing.

PMID:37516260 | DOI:10.1016/j.ymeth.2023.07.008

Ir J Med Sci. 2023 Jul 29. doi: 10.1007/s11845-023-03473-9. Online ahead of print.

ABSTRACT

OBJECTIVE: The COVID-19 pandemic has been recognized as severe acute respiratory syndrome, one of the worst and disastrous infectious diseases in human history. Until now, there is no cure to this contagious infection although some multinational pharmaceutical companies have synthesized the vaccines and injecting them into humans, but a drug treatment regimen is yet to come.

AIM: Among the multiple areas of SARS-CoV-2 that can be targeted, protease protein has significant values due to its essential role in viral replication and life. The repurposing of FDA-approved drugs for the treatment of COVID-19 has been a critical strategy during the pandemic due to the urgency of effective therapies. The novelty in this work refers to the innovative use of existing drugs with greater safety, speed, cost-effectiveness, broad availability, and diversity in the mechanism of action that have been approved and developed for other medical conditions.

METHODS: In this research work, we have engaged drug reprofiling or drug repurposing to recognize possible inhibitors of protease protein 6M03 in an instantaneous approach through computational docking studies.

RESULTS: We screened 16 FDA-approved anti-viral drugs that were known for different viral infections to be tested against this contagious novel strain. Through these reprofiling studies, we come up with 5 drugs, namely, Delavirdine, Fosamprenavir, Imiquimod, Stavudine, and Zanamivir, showing excellent results with the negative binding energies in Kcal/mol as - 8.5, - 7.0, - 6.8, - 6.8, and - 6.6, respectively, in the best binding posture. In silico studies allowed us to demonstrate the potential role of these drugs against COVID-19.

CONCLUSION: In our study, we also observed the nucleotide sequence of protease protein consisting of 316 amino acid residues and the influence of these pronouncing drugs over these sequences. The outcome of this research work provides researchers with a track record for carrying out further investigational procedures by applying docking simulations and in vitro and in vivo experimentation with these reprofile drugs so that a better drug can be formulated against coronavirus.

PMID:37515684 | DOI:10.1007/s11845-023-03473-9

Vaccines (Basel). 2023 Jul 10;11(7):1222. doi: 10.3390/vaccines11071222.

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the causative agent of the COVID-19 pandemic, a global public health problem. Despite the numerous studies for drug repurposing, there are only two FDA-approved antiviral agents (Remdesivir and Nirmatrelvir) for non-hospitalized patients with mild-to-moderate COVID-19 symptoms. Consequently, it is pivotal to search for new molecules with anti-SARS-CoV-2 activity and to study their effects in the human immune system. Ebselen (Eb) is an organoselenium compound that is safe for humans and has antioxidant, anti-inflammatory, and antimicrobial properties. Diphenyl diselenide ((PhSe)2) shares several pharmacological properties with Eb and is of low toxicity to mammals. Herein, we investigated Eb and (PhSe)2 anti-SARS-CoV-2 activity in a human pneumocytes cell model (Calu-3) and analyzed their toxic effects on human peripheral blood mononuclear cells (PBMCs). Both compounds significantly inhibited the SARS-CoV-2 replication in Calu-3 cells. The EC50 values for Eb and (PhSe)2 after 24 h post-infection (hpi) were 3.8 µM and 3.9 µM, respectively, and after 48 hpi were 2.6 µM and 3.4 µM. These concentrations are safe for non-infected cells, since the CC50 values found for Eb and (PhSe)2 on Calu-3 were greater than 200 µM. Importantly, the concentration rates tested on viral replication were not toxic to human PBMCs. Therefore, our findings reinforce the efficacy of Eb and demonstrate (PhSe)2 as a new candidate to be tested in future trials against SARS-CoV-2 infection/inflammation conditions.

PMID:37515038 | DOI:10.3390/vaccines11071222

Pharmaceutics. 2023 Jul 10;15(7):1919. doi: 10.3390/pharmaceutics15071919.

ABSTRACT

Acyclovir (ACV) is a promising candidate for drug repurposing because of its potential to provide an effective treatment for viral infections and non-viral diseases, such as cancer, for which limited treatment options exist. However, its poor physicochemical properties limit its application. This study aimed to formulate and evaluate an ACV-loaded red clay nanodrug delivery system exhibiting an effective cytotoxicity. The study focused on the preparation of a complex between ACV and red clay (RC) using sucrose stearate (SS) (nanocomplex F1) as an immediate-release drug-delivery system for melanoma treatment. The synthesized nanocomplex, which had nanosized dimensions, a negative zeta potential and the drug release of approximately 85% after 3 h, was found to be promising. Characterization techniques, including FT-IR, XRD and DSC-TGA, confirmed the effective encapsulation of ACV within the nanocomplex and its stability due to intercalation. Cytotoxicity experiments conducted on melanoma cancer cell lines SK-MEL-3 revealed that the ACV release from the nanocomplex formulation F1 effectively inhibited the growth of melanoma cancer cells, with an IC50 of 25 ± 0.09 µg/mL. Additionally, ACV demonstrated a significant cytotoxicity at approximately 20 µg/mL in the melanoma cancer cell line, indicating its potential repurposing for skin cancer treatment. Based on these findings, it can be suggested that the RC-SS complex could be an effective drug delivery carrier for localized cancer therapy. Furthermore, the results of an in silico study suggested the addition of chitosan to the formulation for a more effective drug delivery. Energy and interaction analyses using various modules in a material studio demonstrated the high stability of the composite comprising red clay, sucrose stearate, chitosan and ACV. Thus, it could be concluded that the utilization of the red clay-based drug delivery system is a promising strategy to improve the effectiveness of targeted cancer therapy.

PMID:37514105 | DOI:10.3390/pharmaceutics15071919

Pharmaceutics. 2023 Jul 5;15(7):1891. doi: 10.3390/pharmaceutics15071891.

ABSTRACT

Earlier studies with montelukast (M) and telmisartan (T) have revealed their potential antiviral properties against SARS-CoV-2 wild-type (WT) but have not assessed their efficacy against emerging Variants of Concern (VOCs) such as Omicron. Our research fills this gap by investigating these drugs' impact on VOCs, a topic that current scientific literature has largely overlooked. We employed computational methodologies, including molecular mechanics and machine learning tools, to identify drugs that could potentially disrupt the SARS-CoV-2 spike RBD-ACE2 protein interaction. This led to the identification of two FDA-approved small molecule drugs, M and T, conventionally used for treating asthma and hypertension, respectively. Our study presents an additional potential use for these drugs as antivirals. Our results show that both M and T can inhibit not only the WT SARS-CoV-2 but also, in the case of M, the Omicron variant, without reaching cytotoxic concentrations. This novel finding fills an existing gap in the literature and introduces the possibility of repurposing these drugs for SARS-CoV-2 VOCs, an essential step in responding to the evolving global pandemic.

PMID:37514075 | DOI:10.3390/pharmaceutics15071891

Pharmaceutics. 2023 Jun 22;15(7):1792. doi: 10.3390/pharmaceutics15071792.

ABSTRACT

The lethality of patients with ovarian cancer (OC) remains high. Current treatment strategies often do not lead to the desired outcome due to the development of therapy resistance, resulting in high relapse rates. Additionally, clinical trials testing immunotherapy against OC have failed to reach significant results to date. The OC tumor microenvironment and specifically myeloid-derived suppressor cells (MDSC) are known to generate immunosuppression and inhibit the anti-tumor immune response following immunotherapy treatment. Our review aims to characterize potential candidate treatments to target MDSC in OC through drug-repurposing. A literature search identified repurposable compounds with evidence of their suppressing the effect of MDSC. A total of seventeen compounds were withheld, of which four were considered the most promising. Lurbinectedin, metformin, celecoxib, and 5-azacytidine have reported preclinical effects on MDSC and clinical evidence in OC. They have all been approved for a different indication, characterizing them as the most promising candidates for repurposing to treat patients with OC.

PMID:37513979 | DOI:10.3390/pharmaceutics15071792

Pharmaceuticals (Basel). 2023 Jul 18;16(7):1016. doi: 10.3390/ph16071016.

ABSTRACT

The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75-100 mg/kg) for more than 30 years with no serious toxicity. The level of safety and the simple, inexpensive synthesis are some of the many unique properties of L1, which played a major role in the contribution of the drug in the transition of thalassaemia from a fatal to a chronic disease. Other unique and valuable clinical properties of L1 in relation to pharmacology and metabolism include: oral effectiveness, which improved compliance compared to the prototype therapy with subcutaneous deferoxamine; highly effective iron removal from all iron-loaded organs, particularly the heart, which is the major target organ of iron toxicity and the cause of mortality in thalassaemic patients; an ability to achieve negative iron balance, completely remove all excess iron, and maintain normal iron stores in thalassaemic patients; rapid absorption from the stomach and rapid clearance from the body, allowing a greater frequency of repeated administration and overall increased efficacy of iron excretion, which is dependent on the dose used and also the concentration achieved at the site of drug action; and its ability to cross the blood-brain barrier and treat malignant, neurological, and microbial diseases affecting the brain. Some differential pharmacological activity by L1 among patients has been generally shown in relation to the absorption, distribution, metabolism, elimination, and toxicity (ADMET) of the drug. Unique properties exhibited by L1 in comparison to other drugs include specific protein interactions and antioxidant effects, such as iron removal from transferrin and lactoferrin; inhibition of iron and copper catalytic production of free radicals, ferroptosis, and cuproptosis; and inhibition of iron-containing proteins associated with different pathological conditions. The unique properties of L1 have attracted the interest of many investigators for drug repurposing and use in many pathological conditions, including cancer, neurodegenerative conditions, microbial conditions, renal conditions, free radical pathology, metal intoxication in relation to Fe, Cu, Al, Zn, Ga, In, U, and Pu, and other diseases. Similarly, the properties of L1 increase the prospects of its wider use in optimizing therapeutic efforts in many other fields of medicine, including synergies with other drugs.

PMID:37513928 | DOI:10.3390/ph16071016

Pharmaceuticals (Basel). 2023 Jul 7;16(7):974. doi: 10.3390/ph16070974.

ABSTRACT

In the area of drug discovery, repurposing strategies represent an approach to discover new uses of approved drugs besides their original indications. We used this approach to investigate the effects of dimethyl fumarate (DMF), a drug approved for relapsing-remitting multiple sclerosis and psoriasis treatment, on early injury associated with diabetic retinopathy (DR). We used an in vivo streptozotocin (STZ)-induced diabetic rat model. Diabetes was induced by a single injection of STZ in rats, and after 1 week, a group of animals was treated with a daily intraperitoneal injection of DMF or a vehicle. Three weeks after diabetes induction, the retinal expression levels of key enzymes involved in DR were evaluated. In particular, the biomarkers COX-2, iNOS, and HO-1 were assessed via Western blot and immunohistochemistry analysis. Diabetic rats showed a significant retinal upregulation of COX-2 and iNOS compared to the retina of normal rats (non-diabetic), and an increase in HO-1 was also observed in the STZ group. This latter result was due to a mechanism of protection elicited by the pathological condition. DMF treatment significantly induced the retinal expression of HO-1 in STZ-induced diabetic animals with a reduction in iNOS and COX-2 retinal levels. Taken together, these results suggested that DMF might be useful to counteract the inflammatory process and the oxidative response in DR. In conclusion, we believe that DMF represents a potential candidate to treat diabetic retinopathy and warrants further in vivo and clinical evaluation.

PMID:37513886 | DOI:10.3390/ph16070974

Int J Mol Sci. 2023 Jul 14;24(14):11450. doi: 10.3390/ijms241411450.

ABSTRACT

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood-brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer's disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.

PMID:37511207 | DOI:10.3390/ijms241411450

Int J Mol Sci. 2023 Jul 10;24(14):11265. doi: 10.3390/ijms241411265.

ABSTRACT

Natural products provide valuable starting points for new drugs with unique chemical structures. Here, we retrieve and join the LOTUS natural product database and ChEMBL interaction database to explore the relations and rhythm between chemical features of natural products and biotarget spaces. Our analysis revealed relations between the biogenic pathways of natural products and species taxonomy. Nitrogen-containing natural products were more likely to achieve high activity and have a higher potential to become candidate compounds. An apparent trend existed in the target space of natural products originating from different biological sources. Highly active alkaloids were more related to targets of neurodegenerative or neural diseases. Oligopeptides and polyketides were mainly associated with protein phosphorylation and HDAC receptors. Fatty acids readily intervened in various physiological processes involving prostanoids and leukotrienes. We also used FusionDTA, a deep learning model, to predict the affinity between all LOTUS natural products and 622 therapeutic drug targets, exploring the potential target space for natural products. Our data exploration provided a global perspective on the gaps in the chemobiological space of natural compounds through systematic analysis and prediction of their target space, which can be used for new drug design or natural drug repurposing.

PMID:37511025 | DOI:10.3390/ijms241411265

Genes (Basel). 2023 Jun 28;14(7):1370. doi: 10.3390/genes14071370.

ABSTRACT

Lung cancer is managed using conventional therapies, including chemotherapy, radiation therapy, or a combination of both. Each of these therapies has its own limitations, such as the indiscriminate killing of normal as well as cancer cells, the solubility of the chemotherapeutic drugs, rapid clearance of the drugs from circulation before reaching the tumor site, the resistance of cancer cells to radiation, and over-sensitization of normal cells to radiation. Other treatment modalities include gene therapy, immunological checkpoint inhibitors, drug repurposing, and in situ cryo-immune engineering (ICIE) strategy. Nanotechnology has come to the rescue to overcome many shortfalls of conventional therapies. Some of the nano-formulated chemotherapeutic drugs, as well as nanoparticles and nanostructures with surface modifications, have been used for effective cancer cell killing and radio sensitization, respectively. Nano-enabled drug delivery systems act as cargo to deliver the sensitizer molecules specifically to the tumor cells, thereby enabling the radiation therapy to be more effective. In this review, we have discussed the different conventional chemotherapies and radiation therapies used for inhibiting lung cancer. We have also discussed the improvement in chemotherapy and radiation sensitization using nanoparticles.

PMID:37510275 | DOI:10.3390/genes14071370

Biomedicines. 2023 Jul 14;11(7):1998. doi: 10.3390/biomedicines11071998.

ABSTRACT

Drug repositioning offers the significant advantage of greatly reducing the cost and time of drug discovery by identifying new therapeutic indications for existing drugs. In particular, computational approaches using networks in drug repositioning have attracted attention for inferring potential associations between drugs and diseases efficiently based on the network connectivity. In this article, we proposed a network-based drug repositioning method to construct a drug-gene-disease tensor by integrating drug-disease, drug-gene, and disease-gene associations and predict drug-gene-disease triple associations through tensor decomposition. The proposed method, which ensembles generalized tensor decomposition (GTD) and multi-layer perceptron (MLP), models drug-gene-disease associations through GTD and learns the features of drugs, genes, and diseases through MLP, providing more flexibility and non-linearity than conventional tensor decomposition. We experimented with drug-gene-disease association prediction using two distinct networks created by chemical structures and ATC codes as drug features. Moreover, we leveraged drug, gene, and disease latent vectors obtained from the predicted triple associations to predict drug-disease, drug-gene, and disease-gene pairwise associations. Our experimental results revealed that the proposed ensemble method was superior for triple association prediction. The ensemble model achieved an AUC of 0.96 in predicting triple associations for new drugs, resulting in an approximately 7% improvement over the performance of existing models. It also showed competitive accuracy for pairwise association prediction compared with previous methods. This study demonstrated that incorporating genetic information leads to notable advancements in drug repositioning.

PMID:37509637 | DOI:10.3390/biomedicines11071998

J Exp Clin Cancer Res. 2023 Jul 29;42(1):188. doi: 10.1186/s13046-023-02766-2.

ABSTRACT

BACKGROUND: Lung cancer is one of the most frequent causes of cancer-related deaths worldwide. Drug repurposing and nano-drug delivery systems are attracting considerable attention for improving anti-cancer therapy. Sertaconazole (STZ), an antifungal agent, has been reported to exhibit cytotoxicity against both normal and tumor cells, and its medical use is limited by its poor solubility. In order to overcome such shortcomings, we prepared a drug-repurposed nanoplatform to enhance the anti-tumor efficiency.

METHODS: Nanoplatform was prepared by thin film dispersion. Drug release studies and uptake studies were measured in vitro. Subsequently, we verified the tumor inhibition mechanisms of HTS NPs through apoptosis assay, immunoblotting and reactive oxygen species (ROS) detection analyses. Antitumor activity was evaluated on an established xenograft lung cancer model in vivo.

RESULTS: Our nanoplatform improved the solubility of sertaconazole and increased its accumulation in tumor cells. Mechanistically, HTS NPs was dependent on ROS-mediated apoptosis and pro-apoptotic autophagy to achieve their excellent anti-tumor effects. Furthermore, HTS NPs also showed strong inhibitory ability in nude mouse xenograft models without significant side effects.

CONCLUSIONS: Our results suggest that sertaconazole-repurposed nanoplatform provides an effective strategy for lung cancer treatment.

PMID:37507782 | DOI:10.1186/s13046-023-02766-2

Biomed Pharmacother. 2023 Jul 26;165:115184. doi: 10.1016/j.biopha.2023.115184. Online ahead of print.

ABSTRACT

Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular dephosphorylation of adenosine triphosphate and interacts with cell-surface G-protein-coupled receptors. Adenosine plays a substantial role in protecting against cell damage in areas of increased tissue metabolism and preventing organ dysfunction in pathological states. Targeting adenosine metabolism and receptor signaling may be an effective therapeutic approach for human diseases, including cardiovascular and central nervous system disorders, rheumatoid arthritis, asthma, renal diseases, and cancer. Several lines of evidence have shown that many drugs exert their beneficial effects by modulating adenosine signaling pathways but this knowledge urgently needs to be summarized, and most importantly, actualized. The present review collects pharmaceuticals and pharmacological or diagnostic tools that target adenosine signaling in their primary or secondary mode of action. We overviewed FDA-approved drugs as well as those currently being studied in clinical trials. Among them are already used in clinic A2A adenosine receptor modulators like istradefylline or regadenoson, but also plenty of anti-platelet, anti-inflammatory, or immunosuppressive, and anti-cancer drugs. On the other hand, we investigated dozens of specific adenosine pathway regulators that are tested in clinical trials to treat human infectious and noninfectious diseases. In conclusion, targeting purinergic signaling represents a great therapeutic challenge. The actual knowledge of the involvement of adenosinergic signaling as part of the mechanism of action of old drugs has open a path not only for drug-repurposing but also for new therapeutic strategies.

PMID:37506580 | DOI:10.1016/j.biopha.2023.115184

J Fungi (Basel). 2023 Jul 21;9(7):772. doi: 10.3390/jof9070772.

ABSTRACT

Cryptococcus neoformans is an invasive fungus that causes both acute and chronic infections, especially in immunocompromised patients. Owing to the increase in the prevalence of drug-resistant pathogenic fungi and the limitations of current treatment strategies, drug repositioning has become a feasible strategy to accelerate the development of new drugs. In this study, the minimum inhibitory concentration of vitamin D3 (VD3) against C. neoformans was found to be 0.4 mg/mL by broth microdilution assay. The antifungal activities of VD3 were further verified by solid dilution assays and "time-kill" curves. The results showed that VD3 reduced fungal cell adhesion and hydrophobicity and inhibited biofilm formation at various developmental stages, as confirmed by crystal violet staining and the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Fluorescence staining of cellular components and a stress susceptibility assay indicated that VD3 compromised cell integrity. Reverse transcription quantitative PCR demonstrated that VD3 treatment upregulated the expression of fungal genes related to cell wall synthesis (i.e., CDA3, CHS3, FKS1, and AGS1). Moreover, VD3 enhanced cell membrane permeability and caused the accumulation of intracellular reactive oxygen species. Finally, VD3 significantly reduced the tissue fungal burden and prolonged the survival of Galleria mellonella larvae infected with C. neoformans. These results showed that VD3 could exert significant antifungal activities both in vitro and in vivo, demonstrating its potential application in the treatment of cryptococcal infections.

PMID:37504760 | DOI:10.3390/jof9070772

J Fungi (Basel). 2023 Jul 16;9(7):753. doi: 10.3390/jof9070753.

ABSTRACT

Chromoblastomycosis (CBM) is a neglected human implantation mycosis caused by several dematiaceous fungal species. Currently available therapy is usually associated with physical methods, especially surgery, and with high refractoriness. Therefore, drug discovery for CBM is essential. Drug repositioning is a strategy used to facilitate the discovery of new treatments for several diseases. The aim of this study was to discover substances with antifungal activity against CBM agents from a collection of drugs previously approved for use in human diseases. A screening was performed with the NIH Clinical Collection against Fonsecaea pedrosoi. Ten substances, with clinical applicability in CBM, inhibited fungal growth by at least 60%. The minimum inhibitory concentration (MIC) of these substances was determined against other CBM agents, and the benzimidazoles albendazole, mebendazole and thiabendazole presented the lowest MIC values. The selectivity index, based on MIC and cytotoxicity of these substances, revealed albendazole to be more selective. To investigate a possible synergism of this benzimidazole with itraconazole and terbinafine, the chequerboard method was used. All interactions were classified as indifferent. Our current results suggest that benzimidazoles have repositioning potential against CBM agents. Albendazole seems to be the most promising, since it presented the highest selectivity against all dematiaceous fungi tested.

PMID:37504741 | DOI:10.3390/jof9070753

Gigascience. 2022 Dec 28;12:giad047. doi: 10.1093/gigascience/giad047.

ABSTRACT

BACKGROUND: Hetnets, short for "heterogeneous networks," contain multiple node and relationship types and offer a way to encode biomedical knowledge. One such example, Hetionet, connects 11 types of nodes-including genes, diseases, drugs, pathways, and anatomical structures-with over 2 million edges of 24 types. Previous work has demonstrated that supervised machine learning methods applied to such networks can identify drug repurposing opportunities. However, a training set of known relationships does not exist for many types of node pairs, even when it would be useful to examine how nodes of those types are meaningfully connected. For example, users may be curious about not only how metformin is related to breast cancer but also how a given gene might be involved in insomnia.

FINDINGS: We developed a new procedure, termed hetnet connectivity search, that proposes important paths between any 2 nodes without requiring a supervised gold standard. The algorithm behind connectivity search identifies types of paths that occur more frequently than would be expected by chance (based on node degree alone). Several optimizations were required to precompute significant instances of node connectivity at the scale of large knowledge graphs.

CONCLUSION: We implemented the method on Hetionet and provide an online interface at https://het.io/search. We provide an open-source implementation of these methods in our new Python package named hetmatpy.

PMID:37503959 | DOI:10.1093/gigascience/giad047

Res Sq. 2023 Jul 14:rs.3.rs-3147521. doi: 10.21203/rs.3.rs-3147521/v1. Preprint.

ABSTRACT

Background The active pursuit of network medicine for drug repurposing, particularly for combating Covid-19, has stimulated interest in the concept of structural control capability in cellular networks. We sought to extend this theory, focusing on the defense rather than control of the cell against viral infections. Accordingly, we extended structural controllability to total structural controllability and introduced the concept of control hubs. Perturbing any control hub may render the cell uncontrollable by exogenous stimuli like viral infections, so control hubs are ideal drug targets. Results We developed an efficient algorithm to identify all control hubs, applying it to the largest homogeneous network of human protein interactions, including interactions between human and SARS-CoV-2 proteins. Our method recognized 65 druggable control hubs with enriched antiviral functions. Utilizing these hubs, we categorized potential drugs into four groups: antiviral and anti-inflammatory agents, drugs acting on the central nervous system, dietary supplements, and compounds enhancing immunity. An exemplification of our approach's effectiveness, Fostamatinib, a drug initially developed for chronic immune thrombocytopenia, is now in clinical trials for treating Covid-19. Preclinical trial data demonstrated that Fostamatinib could reduce mortality rates, ICU stay length, and disease severity in Covid-19 patients. Conclusions Our findings confirm the efficacy of our novel strategy that leverages control hubs as drug targets. This approach provides insights into the molecular mechanisms of potential therapeutics for Covid-19, making it a valuable tool for interpretable drug discovery.

PMID:37503262 | PMC:PMC10371104 | DOI:10.21203/rs.3.rs-3147521/v1