Expert Rev Clin Pharmacol. 2022 Nov 1. doi: 10.1080/17512433.2022.2142114. Online ahead of print.

ABSTRACT

INTRODUCTION: : In light of the widespread use of non-prescribed and prescribed cannabidiol, the use of cannabidiol with other medications is likely, and this may result in drug interactions.

AREAS COVERED: : We aimed to ascertain if clinical guidance could be provided on the dose range at which cannabidiol drug interactions are likely to occur with concurrently prescribed medicines. Literature searches were conducted in Embase, MEDLINE, and PubMed from database inception to January 2022 using Emtree and MeSH terms. Reference list screening yielded further studies. Using currently available data, likely drug interactions of which prescribers of cannabidiol need to be aware, at the doses likely to cause clinically significant interactions, and drug dosing changes that may be needed are highlighted.

EXPERT OPINION: : We have provided an overview of evidence-based pharmacokinetic predictions and general guidance about the dose range at which clinically relevant cannabidiol drug interactions are likely. For an individual patient, there are inherent limitations in providing clinical guidance due to gaps in specific drug dose-response data and knowledge of individual pharmacokinetic profiles, including different co-morbidities, and concurrent medicines. Clinician awareness of cannabinoid pharmacology, along with clinical and therapeutic drug monitoring are current best practice approaches to manage cannabinoid drug interactions.

PMID:36317739 | DOI:10.1080/17512433.2022.2142114

Iran J Public Health. 2021 Dec;50(12):2461-2472. doi: 10.18502/ijph.v50i12.7928.

ABSTRACT

BACKGROUND: The tumor suppressor genes play a critical role in cellular and molecular mechanisms such as cell cycle processes, cell differentiation and apoptosis. Aberrant DNA methylation of tumor suppressor genes and subsequent gene expression changes have shown to be involved in the initiation and progression of various malignancies including thyroid malignancies. In this review, we investigated what is known about the impact of promoter hypermethylation on the key tumor suppressor genes known to be involved in cell growth and/or apoptosis of thyroid cancer.

METHODS: The most important databases were searched for research articles until June 2020 to identify reported tumor suppressor genes that are modulated by methylation modulation changes in thyroid carcinoma. Following the inclusion and exclusion criteria, 26 studies were reviewed using the full text to meet the inclusion and exclusion criteria.

RESULTS: The tumor suppressor genes reviewed here are suggestive biomarkers and potential targetable drugs. Inactivation of RASSF1A, DAPK1, SLCFA8, and TSHR through aberrant epigenetic methylation could activate BRAF/MEK/ERK kinase pathways with potential clinical implications in thyroid cancer patients. RARβ2 and RUNX3 could suppress cell cycle and induce apoptosis in malignant cells. TIMP3 and PTEN could prevent angiogenesis and invasion through PIP3 pathway and arrest VEFG activity.

CONCLUSION: The methylation status of key genes in various types of thyroid malignancies could be used in early diagnosis as well as differentiation of malignant and benign thyroid. This is valuable in drug repurposing and discovering alternative treatments or preventions in thyroid cancer.

PMID:36317025 | PMC:PMC9577160 | DOI:10.18502/ijph.v50i12.7928

Sci Rep. 2022 Oct 31;12(1):18332. doi: 10.1038/s41598-022-22822-9.

ABSTRACT

The relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) is so strong that scientists called it "brain diabetes". According to several studies, the critical factor in this relationship is brain insulin resistance. Due to the rapid global spread of both diseases, overcoming this cross-talk has a significant impact on societies. Long non-coding RNAs (lncRNAs), on the other hand, have a substantial impact on complex diseases due to their ability to influence gene expression via a variety of mechanisms. Consequently, the regulation of lncRNA expression in chronic diseases permits the development of innovative therapeutic techniques. However, developing a new drug requires considerable time and money. Recently repurposing existing drugs has gained popularity due to the use of low-risk compounds, which may result in cost and time savings. in this study, we identified drug repurposing candidates capable of controlling the expression of common lncRNAs in the cross-talk between DM and AD. We also utilized drugs that interfered with this cross-talk. To do this, high degree common lncRNAs were extracted from microRNA-lncRNA bipartite network. The drugs that interact with the specified lncRNAs were then collected from multiple data sources. These drugs, referred to as set D, were classified in to positive (D+) and negative (D-) groups based on their effects on the expression of the interacting lncRNAs. A feature selection algorithm was used to select six important features for D. Using a random forest classifier, these features were capable of classifying D+ and D- with an accuracy of 82.5%. Finally, the same six features were extracted for the most recently Food and Drug Administration (FDA) approved drugs in order to identify those with the highest likelihood of belonging to D+ or D-. The most significant FDA-approved positive drugs, chromium nicotinate and tapentadol, were presented as repurposing candidates, while cefepime and dihydro-alpha-ergocryptine were recommended as significant adverse drugs. Moreover, two natural compounds, curcumin and quercetin, were recommended to prevent this cross-talk. According to the previous studies, less attention has been paid to the role of lncRNAs in this cross-talk. Our research not only did identify important lncRNAs, but it also suggested potential repurposed drugs to control them.

PMID:36316461 | DOI:10.1038/s41598-022-22822-9

Cancer Genomics Proteomics. 2022 Nov-Dec;19(6):727-739. doi: 10.21873/cgp.20355.

ABSTRACT

BACKGROUND/AIM: Artemisinin and its derivatives are not only approved antimalarial drugs but also exert strong anticancer activity. Based on the clinical activity of artesunate (ART) that has been previously reported in cervix carcinoma, we investigated a panel of 12 different biomarkers and identified the Wilms Tumor 1 (WT1) protein as a potential target of ART.

PATIENTS AND METHODS: Matched biopsies of cervical carcinoma before, during, and after therapy from patients treated with ART were investigated for induction of apoptosis (TUNEL assay) and expression of Wilms Tumor protein 1 (WT1), 14-3-3 ζ, cluster of differentiation markers (CD4, CD8, CD56), ATP-binding cassette transporter B5 (ABCB5), glutathione S-transferase P1 (GSTP1), inducible nitric oxide synthase (iNOS), translationally controlled tumor protein (TCTP), eukaryotic elongation factor 3 (eIF3), and ADP/ATP translocase by immunohistochemistry. WT1 has been selected for more detailed analyses using molecular docking in silico, microscale thermophoresis using recombinant WT1, and cytotoxicity testing (resazurin assay) using HEK293 cells transfected with four different WT1 splice variants.

RESULTS: The fraction of apoptotic cells and the expression of WT1, 14-3-3 ζ, and CD4 increased upon ART treatment in tumors of patients. ART was bound in silico to a domain located at the DNA-binding site of WT1, while dihydroartemisinin (DHA) was bound with low affinity to a different site of WT1 not related to DNA-binding. The results were verified using microscale thermophoresis, where ART but not DHA bound to recombinant WT1. Transfectants overexpressing different WT1 splice variants exerted low but significant resistance to ART (≈2-fold).

CONCLUSION: WT1 may represent a novel target of ART in cancer cells that contribute to the response of tumor cells to this drug.

PMID:36316038 | DOI:10.21873/cgp.20355

Antimicrob Agents Chemother. 2022 Oct 31:e0028422. doi: 10.1128/aac.00284-22. Online ahead of print.

ABSTRACT

Drug combinations and drug repurposing have emerged as promising strategies to develop novel treatments for infectious diseases, including Chagas disease. In this study, we aimed to investigate whether the repurposed drugs chloroquine (CQ) and colchicine (COL), known to inhibit Trypanosoma cruzi infection in host cells, could boost the anti-T. cruzi effect of the trypanocidal drug benznidazole (BZN), increasing its therapeutic efficacy while reducing the dose needed to eradicate the parasite. The combination of BZN and COL exhibited cytotoxicity to infected cells and low antiparasitic activity. Conversely, a combination of BZN and CQ significantly reduced T. cruzi infection in vitro, with no apparent cytotoxicity. This effect seemed to be consistent across different cell lines and against both the partially BZN-resistant Y and the highly BZN-resistant Colombiana strains. In vivo experiments in an acute murine model showed that the BZN+CQ combination was eight times more effective in reducing T. cruzi infection in the acute phase than BZN monotherapy. In summary, our results demonstrate that the concomitant administration of CQ and BZN potentiates the trypanocidal activity of BZN, leading to a reduction in the dose needed to achieve an effective response. In a translational context, it could represent a higher efficacy of treatment while also mitigating the adverse effects of high doses of BZN. Our study also reinforces the relevance of drug combination and repurposing approaches in the field of Chagas disease drug discovery.

PMID:36314800 | DOI:10.1128/aac.00284-22

Future Microbiol. 2022 Oct 31. doi: 10.2217/fmb-2022-0159. Online ahead of print.

ABSTRACT

Background: Drug repurposing is a viable approach to expediting the tedious conventional drug discovery process, given rapidly increasing bacterial resistance. In this context, we have repurposed pyrvinium pamoate (PP) for its antibacterial activity against Staphylococcus aureus. Methods: US FDA-approved non-antibiotics were screened against clinically relevant bacterial pathogens to identify antibacterials. The hits were further evaluated utilizing a variety of preclinical parameters, following which in vivo efficacy was estimated in isolation and in combination in a murine neutropenic thigh infection model. Result: The screening identified PP exhibiting potent activity against S. aureus along with concentration-dependent killing. PP also showed a post-antibiotic effect of >22 h and significantly eradicated preformed S. aureus biofilms and intracellular S. aureus at 1× and 5× MIC, respectively. PP synergized with levofloxacin both in vitro and in vivo, resulting in ∼1.5 and ∼0.5 log10 CFU/g reduction against susceptible and resistant S. aureus infections, respectively, as compared with untreated control. Conclusion: Pyrvinium potentiates levofloxacin against levofloxacin-resistant S. aureus.

PMID:36314364 | DOI:10.2217/fmb-2022-0159

Front Pharmacol. 2022 Oct 12;13:995459. doi: 10.3389/fphar.2022.995459. eCollection 2022.

ABSTRACT

Complex diseases are associated with a wide range of cellular, physiological, and clinical phenotypes. To advance our understanding of disease mechanisms and our ability to treat these diseases, it is critical to delineate the molecular basis and therapeutic avenues of specific disease phenotypes, especially those that are associated with multiple diseases. Inflammatory processes constitute one such prominent phenotype, being involved in a wide range of health problems including ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, and autoimmune and neurodegenerative conditions. While hundreds of genes might play a role in the etiology of each of these diseases, isolating the genes involved in the specific phenotype (e.g., inflammation "component") could help us understand the genes and pathways underlying this phenotype across diseases and predict potential drugs to target the phenotype. Here, we present a computational approach that integrates gene interaction networks, disease-/trait-gene associations, and drug-target information to accomplish this goal. We apply this approach to isolate gene signatures of complex diseases that correspond to chronic inflammation and use SAveRUNNER to prioritize drugs to reveal new therapeutic opportunities.

PMID:36313344 | PMC:PMC9597699 | DOI:10.3389/fphar.2022.995459

Front Pharmacol. 2022 Oct 14;13:1011115. doi: 10.3389/fphar.2022.1011115. eCollection 2022.

ABSTRACT

Ulcerative colitis (UC) is a chronic relapsing disease featuring aberrant accumulation of neutrophils in colonic mucosa and the luminal space. Although significant advances in UC therapy have been made with the development of novel biologics and small molecules targeting immune responses, success of most current therapies is still limited, with significant safety concerns. Thus, there is a need to develop additional safe and effective therapies for the treatment of UC. Antimalarial drugs have been safely used for many years to resolve tissue inflammation and the associated pathologies. Atovaquone is a recent FDA-approved antimalarial drug that has shown anti-viral and tumor-suppressive properties in vitro however, its role in mucosal inflammation has not been evaluated. Using pre-clinical murine DSS-induced colitis model combined with complementary in vivo peritonitis and ex vivo human neutrophil activation and chemotaxis assays we investigated functional and mechanistic impacts of atovaquone on disease resolution and neutrophil trafficking. We demonstrate that atovaquone promotes resolution of DSS-induced murine colitis by reducing neutrophil accumulation in the inflamed colonic mucosa. Mechanistically, we show that atovaquone suppressed induction of CD11b expression in neutrophils, reducing their polarization and migratory ability. Thus, our findings identify a new role of atovaquone in promoting resolution of mucosal inflammation, supporting the idea of potential repurposing of this FDA-approved drug as UC therapeutic.

PMID:36313299 | PMC:PMC9614091 | DOI:10.3389/fphar.2022.1011115

Nanomedicine. 2022 Oct 26:102623. doi: 10.1016/j.nano.2022.102623. Online ahead of print.

ABSTRACT

In a context of drug repurposing, pentamidine (PTM), an FDA-approved antiparasitic drug, has been proposed to reverse the splicing defects associated in myotonic dystrophy type 1 (DM1). However, clinical use of PTM is hinder by substantial toxicity, leading to find alternative delivery strategies. In this work we proposed hyaluronic acid-based nanoparticles as a novel encapsulation strategy to efficiently deliver PTM to skeletal muscles cells. In vitro studies on C2C12 myoblasts and myotubes showed an efficient nanoparticles' internalization with minimal toxicity. More interestingly, our findings evidenced for the first time the endosomal escape of hyaluronic acid-based nanocarriers. Ex vivo studies showed an efficient nanoparticles' internalization within skeletal muscle fibers. Finally, the therapeutic efficacy of PTM-loaded nanosystems to reduce the number of nuclear foci has been demonstrated in a novel DM1 in vitro model. So far, current data demonstrated the potency of hyaluronic acid-based nanosystems as efficient nanocarrier for delivering PTM into skeletal muscle and mitigate DM1 pathology.

PMID:36309185 | DOI:10.1016/j.nano.2022.102623

Expert Rev Clin Pharmacol. 2022 Oct 29. doi: 10.1080/17512433.2022.2142560. Online ahead of print.

ABSTRACT

INTRODUCTION: Transforming growth factor beta induced (TGFBI) gene mutations have been reported as the cause of a group of genetically inherited, visually debilitating, corneal dystrophies (CD). A scoping literature review to identify and categorize compounds that inhibit corneal TGFBI expression and/or promote TGFBIp degradation was performed. Emphasis was given to their potential to be used as a cost-effective approach via drug repurposing.

AREAS COVERED: We performed a thorough search of original peer-reviewed literature using electronic bibliographic databases and selected articles according to a set of criteria. The total number of articles retrieved from the search terms applied to the databases was 2344. The number of relevant full text articles included added up to 19. We identified 16 compounds that can theoretically reduce the levels of mutant TGFBIp in human corneal cells.

EXPERT OPINION: Currently, the only temporary treatments available for this condition are lubricant drops and surgery. Here we explored the crosstalk between cascades that regulate TGFBI expression and identified compounds that target these pathways. Compounds that inhibit DNA synthesis and function, increase elimination of TGFBIp or bind to mutant TGFBIp were also explored with the aim of highlighting promising compounds that can be used in future cost-effective drug-repurposing studies.

PMID:36308770 | DOI:10.1080/17512433.2022.2142560

Sci Rep. 2022 Oct 28;12(1):18200. doi: 10.1038/s41598-022-23014-1.

ABSTRACT

The substantial cost of new drug research and development has consistently posed a huge burden for both pharmaceutical companies and patients. In order to lower the expenditure and development failure rate, repurposing existing and approved drugs by identifying interactions between drug molecules and target proteins based on computational methods have gained growing attention. Here, we propose the DeepLPI, a novel deep learning-based model that mainly consists of ResNet-based 1-dimensional convolutional neural network (1D CNN) and bi-directional long short term memory network (biLSTM), to establish an end-to-end framework for protein-ligand interaction prediction. We first encode the raw drug molecular sequences and target protein sequences into dense vector representations, which go through two ResNet-based 1D CNN modules to derive features, respectively. The extracted feature vectors are concatenated and further fed into the biLSTM network, followed by the MLP module to finally predict protein-ligand interaction. We downloaded the well-known BindingDB and Davis dataset for training and testing our DeepLPI model. We also applied DeepLPI on a COVID-19 dataset for externally evaluating the prediction ability of DeepLPI. To benchmark our model, we compared our DeepLPI with the baseline methods of DeepCDA and DeepDTA, and observed that our DeepLPI outperformed these methods, suggesting the high accuracy of the DeepLPI towards protein-ligand interaction prediction. The high prediction performance of DeepLPI on the different datasets displayed its high capability of protein-ligand interaction in generalization, demonstrating that the DeepLPI has the potential to pinpoint new drug-target interactions and to find better destinations for proven drugs.

PMID:36307509 | DOI:10.1038/s41598-022-23014-1

J Endocrinol Invest. 2022 Oct 28. doi: 10.1007/s40618-022-01923-2. Online ahead of print.

ABSTRACT

PURPOSE: Non-functioning pituitary neuroendocrine tumors are challengingly diagnosed tumors in the clinic. Transsphenoidal surgery remains the first-line treatment. Despite the development of state-of-the-art techniques, no drug therapy is currently approved for the treatment. There are also no randomized controlled trials comparing therapeutic strategies or drug therapy for the management after surgery. Therefore, novel therapeutic interventions for the therapeutically challenging NF-PitNETs are urgently needed.

METHODS: We integrated epigenome and transcriptome data (both coding and non-coding) that elucidate disease-specific signatures, in addition to biological and pharmacological data, to utilize rational pathway and drug prioritization in NF-PitNETs. We constructed an epigenome- and transcriptome-based PPI network and proposed hub genes. The signature-based drug repositioning based on the integration of multi-omics data was performed.

RESULTS: The construction of a disease-specific network based on three different biological levels revealed DCC, DLG5, ETS2, FOXO1, HBP1, HMGA2, PCGF3, PSME4, RBPMS, RREB1, SMAD1, SOCS1, SOX2, YAP1, ZFHX3 as hub proteins. Signature-based drug repositioning using hub proteins yielded repositioned drug candidates that were confirmed in silico via molecular docking. As a result of molecular docking simulations, palbociclib, linifanib, trametinib, eplerenone, niguldipine, and zuclopenthixol showed higher binding affinities with hub genes compared to their inhibitors and were proposed as potential repositioned therapeutics for the management of NF-PitNETs.

CONCLUSION: The proposed systems' biomedicine-oriented multi-omics data integration for drug repurposing to provide promising results for the construction of effective clinical therapeutics. To the best of our knowledge, this is the first study reporting epigenome- and transcriptome-based drug repositioning for NF-PitNETs using in silico confirmations.

PMID:36306107 | DOI:10.1007/s40618-022-01923-2

Brief Bioinform. 2022 Oct 27:bbac457. doi: 10.1093/bib/bbac457. Online ahead of print.

ABSTRACT

With the development of research on the complex aetiology of many diseases, computational drug repositioning methodology has proven to be a shortcut to costly and inefficient traditional methods. Therefore, developing more promising computational methods is indispensable for finding new candidate diseases to treat with existing drugs. In this paper, a model integrating a new variant of message passing neural network and a novel-gated fusion mechanism called GLGMPNN is proposed for drug-disease association prediction. First, a light-gated message passing neural network (LGMPNN), including message passing, aggregation and updating, is proposed to separately extract multiple pieces of information from the similarity networks and the association network. Then, a gated fusion mechanism consisting of a forget gate and an output gate is applied to integrate the multiple pieces of information to extent. The forget gate calculated by the multiple embeddings is built to integrate the association information into the similarity information. Furthermore, the final node representations are controlled by the output gate, which fuses the topology information of the networks and the initial similarity information. Finally, a bilinear decoder is adopted to reconstruct an adjacency matrix for drug-disease associations. Evaluated by 10-fold cross-validations, GLGMPNN achieves excellent performance compared with the current models. The following studies show that our model can effectively discover novel drug-disease associations.

PMID:36305457 | DOI:10.1093/bib/bbac457

Curr Top Med Chem. 2022 Oct 26. doi: 10.2174/1568026623666221026091010. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease characterized by progressive memory loss. The main pathological features of the disease are extracellular deposition of amyloid β (Aβ) plaques and intracellular neurofibrillary tangles composed of hyper-phosphorylated tau protein. The understanding of factors contributing to AD progression, number of molecular signatures, and the development of therapeutic agents played a significant role in the discovery of disease-modifying drugs to treat the disease. Bioinformatics has established its significance in many areas of biology. The role of bioinformatics, in drug discovery is emerging significantly and will continue to evolve. In recent years, different bioinformatics methodologies, viz. protein signaling pathway, molecular signature differences between different classes drugs, interacting profiles of drugs and their potential therapeutic mechanisms have been applied to identify potential therapeutic targets of AD. Bioinformatics tools were also found to contribute in the discovery of novel drugs, omics-based biomarkers, and drug repurposing for AD. The review aims to explore the applications of various advanced bioinformatics tools in the identification of targets, biomarkers, pathways, and potential therapeutics for the treatment of the disease.

PMID:36305125 | DOI:10.2174/1568026623666221026091010

Front Pharmacol. 2022 Oct 11;13:1010520. doi: 10.3389/fphar.2022.1010520. eCollection 2022.

ABSTRACT

Pharmacogenomic analysis based on drug transcriptomic signatures is widely used to identify mechanisms of action and pharmacological indications. Despite accumulating reports on the efficacy of medicinal herbs, related transcriptome-level analyses are lacking. The aim of the present study was to elucidate the underlying molecular mechanisms of action of Bupleuri Radix (BR), a widely used herbal medicine, through a systematic transcriptomic analysis. We analyzed the drug-responsive transcriptome profiling of A549 lung cancer cell line after treating them with multiple doses of BR water (W-BR) and ethanol (E-BR) extracts and their phytochemicals. In vitro validation experiments were performed using both A549 and the immortalized human keratinocyte line HaCaT. Pathway enrichment analysis revealed the anti-cancer effects of BR treatment via inhibition of cell proliferation and induction of apoptosis. Enhanced cell adhesion and migration were observed with the W-BR but not with the E-BR. Comparison with a disease signature database validated an indication of the W-BR for skin disorders. Moreover, W-BR treatment showed the wound-healing effect in skin and lung cells. The main active ingredients of BR showed only the anti-cancer effect of the E-BR and not the wound healing effect of the W-BR, suggesting the need for research on minor ingredients of BR.

PMID:36304143 | PMC:PMC9592978 | DOI:10.3389/fphar.2022.1010520

R Soc Open Sci. 2022 Oct 26;9(10):220633. doi: 10.1098/rsos.220633. eCollection 2022 Oct.

ABSTRACT

Computer-aided methods can be used to screen potential candidate targets and to reduce the time and cost of drug development. In most of these methods, synthetic lethality is used as a therapeutic criterion to identify drug targets. However, these methods do not consider the side effects during the identification stage. This study developed a fuzzy multi-objective optimization for identifying anti-cancer targets that not only evaluated cancer cell mortality, but also minimized side effects due to treatment. We identified potential anti-cancer enzymes and antimetabolites for the treatment of head and neck cancer (HNC). The identified one- and two-target enzymes were primarily involved in six major pathways, namely, purine and pyrimidine metabolism and the pentose phosphate pathway. Most of the identified targets can be regulated by approved drugs; thus, these drugs are potential candidates for drug repurposing as a treatment for HNC. Furthermore, we identified antimetabolites involved in pathways similar to those identified using a gene-centric approach. Moreover, HMGCR knockdown could not block the growth of HNC cells. However, the two-target combinations of (UMPS, HMGCR) and (CAD, HMGCR) could achieve cell mortality and improve metabolic deviation grades over 22% without reducing the cell viability grade.

PMID:36303939 | PMC:PMC9597175 | DOI:10.1098/rsos.220633

Front Bioinform. 2021 Sep 14;1:710591. doi: 10.3389/fbinf.2021.710591. eCollection 2021.

ABSTRACT

There is a critical requirement for alternative strategies to provide the better treatment in colorectal cancer (CRC). Hence, our goal was to propose novel biomarkers as well as drug candidates for its treatment through differential interactome based drug repositioning. Differentially interacting proteins and their modules were identified, and their prognostic power were estimated through survival analyses. Drug repositioning was carried out for significant target proteins, and candidate drugs were analyzed via in silico molecular docking prior to in vitro cell viability assays in CRC cell lines. Six modules (mAPEX1, mCCT7, mHSD17B10, mMYC, mPSMB5, mRAN) were highlighted considering their prognostic performance. Drug repositioning resulted in eight drugs (abacavir, ribociclib, exemestane, voriconazole, nortriptyline hydrochloride, theophylline, bromocriptine mesylate, and tolcapone). Moreover, significant in vitro inhibition profiles were obtained in abacavir, nortriptyline hydrochloride, exemestane, tolcapone, and theophylline (positive control). Our findings may provide new and complementary strategies for the treatment of CRC.

PMID:36303724 | PMC:PMC9581026 | DOI:10.3389/fbinf.2021.710591

Neurotherapeutics. 2022 Oct 27. doi: 10.1007/s13311-022-01304-w. Online ahead of print.

ABSTRACT

Lafora disease is a fatal form of progressive myoclonic epilepsy caused by mutations in the EPM2A or NHLRC1/EPM2B genes that usually appears during adolescence. The Epm2a-/- and Epm2b-/- knock-out mouse models of the disease develop behavioral and neurological alterations similar to those observed in patients. The aim of this work is to analyze whether early treatment with metformin (from conception to adulthood) ameliorates the formation of Lafora bodies and improves the behavioral and neurological outcomes observed with late treatment (during 2 months at 10 months of age). We also evaluated the benefits of metformin in patients with Lafora disease. To assess neurological improvements due to metformin administration in the two mouse models, we evaluated the effects on pentylenetetrazol sensitivity, posturing, motor coordination and activity, and memory. We also analyzed the effects on Lafora bodies, neurodegeneration, and astrogliosis. Furthermore, we conducted a follow-up study of an initial cohort of 18 patients with Lafora disease, 8 treated with metformin and 10 untreated. Our results indicate that early metformin was more effective than late metformin in Lafora disease mouse models improving neurological alterations of both models such as neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreasing the formation of Lafora bodies. Moreover, patients receiving metformin had a slower progression of the disease. Overall, early treatment improves the outcome seen with late metformin treatment in the two knock-out mouse models of Lafora disease. Metformin-treated patients exhibited an ameliorated course of the disease with slower deterioration of their daily living activities.

PMID:36303102 | DOI:10.1007/s13311-022-01304-w

Viruses. 2022 Sep 29;14(10):2150. doi: 10.3390/v14102150.

ABSTRACT

The rising incidence of dengue virus (DENV) infections in the tropical and sub-tropical regions of the world emphasizes the need to identify effective therapeutic drugs against the disease. Repurposing of drugs has emerged as a novel concept to combat pathogens. In this study, we employed a transcriptomics-based bioinformatics approach for drug identification against DENV. Gene expression omnibus datasets from patients with different grades of dengue disease severity and healthy controls were used to identify differentially expressed genes in dengue cases, which were then applied to the query tool of Connectivity Map to identify the inverse gene-disease-drug relationship. A total of sixteen identified drugs were investigated for their prophylactic, virucidal, and therapeutic effects against DENV. Focus-forming unit assay and quantitative RT-PCR were used to evaluate the antiviral activity. Results revealed that five compounds, viz., resveratrol, doxorubicin, lomibuvir, elvitegravir, and enalaprilat, have significant anti-DENV activity. Further, molecular docking studies showed that these drugs can interact with a variety of protein targets of DENV, including the glycoprotein, the NS5 RdRp, NS2B-NS3 protease, and NS5 methyltransferase The in vitro and in silico results, therefore, reveal that these drugs have the ability to decrease DENV-2 production, suggesting that these drugs or their derivatives could be attempted as therapeutic agents against DENV infections.

PMID:36298705 | DOI:10.3390/v14102150

Mol Cell Biochem. 2022 Oct 27. doi: 10.1007/s11010-022-04584-0. Online ahead of print.

ABSTRACT

Glioblastoma (GBM) is the most prevalent primary central nervous system tumour in adults. The lethality of GBM lies in its highly invasive, infiltrative, and neurologically destructive nature resulting in treatment failure, tumour recurrence and death. Even with current standard of care treatment with surgery, radiotherapy and chemotherapy, surviving tumour cells invade throughout the brain. We have previously shown that this invasive phenotype is facilitated by actin-rich, membrane-based structures known as invadopodia. The formation and matrix degrading activity of invadopodia is enhanced in GBM cells that survive treatment. Drug repurposing provides a means of identifying new therapeutic applications for existing drugs without the need for discovery or development and the associated time for clinical implementation. We investigate several FDA-approved agents for their ability to act as both cytotoxic agents in reducing cell viability and as 'anti-invadopodia' agents in GBM cell lines. Based on their cytotoxicity profile, three agents were selected, bortezomib, everolimus and fludarabine, to test their effect on GBM cell invasion. All three drugs reduced radiation/temozolomide-induced invadopodia activity, in addition to reducing GBM cell viability. These drugs demonstrate efficacious properties warranting further investigation with the potential to be implemented as part of the treatment regime for GBM.

PMID:36302993 | DOI:10.1007/s11010-022-04584-0