Pharmaceutics. 2023 Feb 11;15(2):615. doi: 10.3390/pharmaceutics15020615.

ABSTRACT

Poly(lactic-co-glycolic acid) (PLGA) particles are a widely used and extensively studied drug delivery system. The favorable properties of PLGA such as good bioavailability, controlled release, and an excellent safety profile due to the biodegradable polymer backbone qualified PLGA particles for approval by the authorities for the application as a drug delivery platform in humas. In recent years, immunotherapy has been established as a potent treatment option for a variety of diseases. However, immunomodulating drugs rely on targeted delivery to specific immune cell subsets and are often rapidly eliminated from the system. Loading of PLGA particles with drugs for immunotherapy can protect the therapeutic compounds from premature degradation, direct the drug delivery to specific tissues or cells, and ensure sustained and controlled drug release. These properties present PLGA particles as an ideal platform for immunotherapy. Here, we review recent advances of particulate PLGA delivery systems in the application for immunotherapy in the fields of allergy, autoimmunity, infectious diseases, and cancer.

PMID:36839937 | DOI:10.3390/pharmaceutics15020615

J Fungi (Basel). 2023 Feb 20;9(2):275. doi: 10.3390/jof9020275.

ABSTRACT

The dermatophyte Trichophyton rubrum is responsible for most human cutaneous infections. Its treatment is complex, mainly because there are only a few structural classes of fungal inhibitors. Therefore, new strategies addressing these problems are essential. The development of new drugs is time-consuming and expensive. The repositioning of drugs already used in medical practice has emerged as an alternative to discovering new drugs. The antidepressant sertraline (SRT) kills several important fungal pathogens. Accordingly, we investigated the inhibitory mechanism of SRT in T. rubrum to broaden the knowledge of its impact on eukaryotic microorganisms and to assess its potential for future use in dermatophytosis treatments. We performed next-generation sequencing (RNA-seq) to identify the genes responding to SRT at the transcript level. We identified that a major effect of SRT was to alter expression for genes involved in maintaining fungal cell wall and plasma membrane stability, including ergosterol biosynthetic genes. SRT also altered the expression of genes encoding enzymes related to fungal energy metabolism, cellular detoxification, and defense against oxidative stress. Our findings provide insights into a specific molecular network interaction that maintains metabolic stability and is perturbed by SRT, showing potential targets for its strategic use in dermatophytosis.

PMID:36836389 | DOI:10.3390/jof9020275

Int J Mol Sci. 2023 Feb 20;24(4):4192. doi: 10.3390/ijms24044192.

ABSTRACT

Drugs against novel targets are needed to treat COVID-19 patients, especially as SARS-CoV-2 is capable of rapid mutation. Structure-based de novo drug design and repurposing of drugs and natural products is a rational approach to discovering potentially effective therapies. These in silico simulations can quickly identify existing drugs with known safety profiles that can be repurposed for COVID-19 treatment. Here, we employ the newly identified spike protein free fatty acid binding pocket structure to identify repurposing candidates as potential SARS-CoV-2 therapies. Using a validated docking and molecular dynamics protocol effective at identifying repurposing candidates inhibiting other SARS-CoV-2 molecular targets, this study provides novel insights into the SARS-CoV-2 spike protein and its potential regulation by endogenous hormones and drugs. Some of the predicted repurposing candidates have already been demonstrated experimentally to inhibit SARS-CoV-2 activity, but most of the candidate drugs have yet to be tested for activity against the virus. We also elucidated a rationale for the effects of steroid and sex hormones and some vitamins on SARS-CoV-2 infection and COVID-19 recovery.

PMID:36835602 | DOI:10.3390/ijms24044192

Int J Mol Sci. 2023 Feb 19;24(4):4154. doi: 10.3390/ijms24044154.

ABSTRACT

Worldwide, prostate cancer (PC) is the second most frequent cancer among men and the fifth leading cause of death; moreover, standard treatments for PC have several issues, such as side effects and mechanisms of resistance. Thus, it is urgent to find drugs that can fill these gaps, and instead of developing new molecules requiring high financial and time investments, it would be useful to select non-cancer approved drugs that have mechanisms of action that could help in PC treatment, a process known as repurposing drugs. In this review article, drugs that have potential pharmacological efficacy are compiled to be repurposed for PC treatment. Thus, these drugs will be presented in the form of pharmacotherapeutic groups, such as antidyslipidemic drugs, antidiabetic drugs, antiparasitic drugs, antiarrhythmic drugs, anti-inflammatory drugs, antibacterial drugs, antiviral drugs, antidepressant drugs, antihypertensive drugs, antifungal drugs, immunosuppressant drugs, antipsychotic drugs, antiepileptic and anticonvulsant drugs, bisphosphonates and drugs for alcoholism, among others, and we will discuss their mechanisms of action in PC treatment.

PMID:36835564 | DOI:10.3390/ijms24044154

Int J Mol Sci. 2023 Feb 5;24(4):3135. doi: 10.3390/ijms24043135.

ABSTRACT

Prostate cancer (PC) is one of the most common types of cancer in males. Although early stages of PC are generally associated with favorable outcomes, advanced phases of the disease present a significantly poorer prognosis. Moreover, currently available therapeutic options for the treatment of PC are still limited, being mainly focused on androgen deprivation therapies and being characterized by low efficacy in patients. As a consequence, there is a pressing need to identify alternative and more effective therapeutics. In this study, we performed large-scale 2D and 3D similarity analyses between compounds reported in the DrugBank database and ChEMBL molecules with reported anti-proliferative activity on various PC cell lines. The analyses included also the identification of biological targets of ligands with potent activity on PC cells, as well as investigations on the activity annotations and clinical data associated with the more relevant compounds emerging from the ligand-based similarity results. The results led to the prioritization of a set of drugs and/or clinically tested candidates potentially useful in drug repurposing against PC.

PMID:36834548 | DOI:10.3390/ijms24043135

Cancers (Basel). 2023 Feb 7;15(4):1044. doi: 10.3390/cancers15041044.

ABSTRACT

Acute myeloid leukaemia (AML) affects predominantly elderly people and has an incidence of 1% of all cancers and 2% of all cancer deaths. Despite using intensive chemotherapy and allogeneic stem cell transplantation, the treatment options for AML remain open for innovation. Thus, there is a need to explore alternative therapies such as less toxic targeted therapies in AML. Aurora A kinase is a well-established target for the treatment of various cancers, including AML. This kinase plays a pivotal role in the cell-division cycle, particularly in different stages of mitosis, and is also involved in many other cellular regulatory processes. In a previous study, we demonstrated that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In the current study, we have further explored the selectivity of rilpivirine for Aurora A kinase inhibition by testing this drug against a panel of 429 kinases. Concurrently, we demonstrated that rilpivirine significantly inhibited the proliferation of AML cells in a time- and concentration-dependent manner that was preceded by G2/M cell-cycle arrest leading to the induction of apoptosis. Consistent with its kinase inhibitory role, rilpivirine modulated the expression of critical proteins in the Aurora A kinase-signalling pathway. Importantly, orally administered rilpivirine significantly inhibited tumour growth in an HL-60 xenograft model without showing body weight changes or other clinical signs of toxicity. Furthermore, rilpivirine enhanced the anti-proliferative efficacy of the conventional anti-leukaemic chemotherapeutic agent cytarabine. Collectively, these findings provide the stimulus to explore further the anti-leukaemic activity of the anti-viral drug rilpivirine.

PMID:36831387 | DOI:10.3390/cancers15041044

Cells. 2023 Feb 20;12(4):671. doi: 10.3390/cells12040671.

ABSTRACT

Drug repurposing aims to identify new therapeutic uses for drugs that have already been approved for other conditions. This approach can save time and resources compared to traditional drug development, as the safety and efficacy of the repurposed drug have already been established. In the context of cancer, drug repurposing can lead to the discovery of new treatments that can target specific cancer cell lines and improve patient outcomes. Vasodilators are a class of drugs that have been shown to have the potential to influence various types of cancer. These medications work by relaxing the smooth muscle of blood vessels, increasing blood flow to tumors, and improving the delivery of chemotherapy drugs. Additionally, vasodilators have been found to have antiproliferative and proapoptotic effects on cancer cells, making them a promising target for drug repurposing. Research on vasodilators for cancer treatment has already shown promising results in preclinical and clinical studies. However, additionally research is needed to fully understand the mechanisms of action of vasodilators in cancer and determine the optimal dosing and combination therapy for patients. In this review, we aim to explore the molecular mechanisms of action of vasodilators in cancer cell lines and the current state of research on their repurposing as a treatment option. With the goal of minimizing the effort and resources required for traditional drug development, we hope to shed light on the potential of vasodilators as a viable therapeutic strategy for cancer patients.

PMID:36831338 | DOI:10.3390/cells12040671

Biomedicines. 2023 Feb 13;11(2):542. doi: 10.3390/biomedicines11020542.

ABSTRACT

Small molecules have demonstrated promising results as successful alternatives to growth factors. In this study, focus was drawn to CHIR99021 and tideglusib as GSK-3 inhibitors known for their anti-inflammatory and regenerative potential. The effect of both tideglusib and CHIR99021 on the proliferation, viability, and stemness of human dental pulp stem cells (hDPSCs) was investigated to assess their possible role in regenerative dentistry. Briefly, hDPSCs were isolated from sound premolars extracted for orthodontic purposes. Cytotoxicity and proliferation assessment were performed via cell counting kit-8 followed by flow cytometric analysis of apoptotic marker ANNEXIN V. The effect of both small molecules on the stemness of hDPSCs was analyzed by qRT-PCR. Both tideglusib and CHIR99021 were proven to be safe on hDPSCs. The tideglusib concentration that resulted in higher viable cells was 100 nM, while the concentration for CHIR99021 was 5 nM. Both small molecules successfully induced cellular proliferation and demonstrated minimal expression of ANNEXIN V, indicative of the absence of cellular apoptosis and further confirming their positive effect on proliferation. Finally, both small molecules enhanced stemness markers expression as evidenced by qRT-PCR, which, again, highlighted the positive effect of both tideglusib and CHIR99021 on safely promoting the proliferation of hDPSCs while maintaining their stemness.

PMID:36831078 | DOI:10.3390/biomedicines11020542

Biomedicines. 2023 Feb 2;11(2):432. doi: 10.3390/biomedicines11020432.

ABSTRACT

Oxaliplatin is a well-known chemotherapeutic drug that is widely used to treat colorectal cancer. However, it can induce acute side effects in up to 90% of patients. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are used as first-choice drugs; however, even SNRIs are known to be effective only in treatment and not for prevention. Therefore, finding a drug that can prevent the development of cold and mechanical forms of allodynia induced by oxaliplatin is needed. This study demonstrated that multiple oral administrations of 100 mg/kg and 300 mg/kg of red ginger extract could significantly prevent pain development in mice. The role of the noradrenergic system was investigated as an underlying mechanism of action. Both the spinal α1- and α2-adrenergic receptors were significantly downregulated after treatment. Furthermore, the noradrenaline levels in the serum and spinal cord were upregulated and downregulated after treatment with paclitaxel and red ginger, respectively. As the active sub-component of red ginger, ginsenoside Rg3 (Rg3) was identified and quantified using HPLC. Moreover, multiple intraperitoneal injections of Rg3 prevented the development of pain in paclitaxel-treated mice, suggesting that RG3 may induce the effect of red ginger extract.

PMID:36830967 | DOI:10.3390/biomedicines11020432

Biomedicines. 2023 Jan 19;11(2):278. doi: 10.3390/biomedicines11020278.

ABSTRACT

The monkeypox disease (MPX) outbreak of 2022 has been reported in more than one hundred countries and is becoming a global concern. Unfortunately, only a few treatments, such as tecovirimat (TCV), are available against MPX. Brincidofovir (BCV) is a United States Food and Drug Administration (USFDA)-approved antiviral against smallpox. This article reviews the potential of BCV for treating MPX and other Orthopoxvirus (OPXVs) diseases. The literature for this review was collected from PubMed, authentic websites (USFDA, Chimerix), and freely available patent databases (USPTO, Espacenet, and Patentscope). BCV (a lipophilic derivative of cidofovir) has been discovered and developed by Chimerix Incorporation, USA. Besides smallpox, BCV has also been tested clinically for various viral infections (adenovirus, cytomegalovirus, ebola virus, herpes simplex virus, and double-stranded DNA virus). Many health agencies and reports have recommended using BCV for MPX. However, no health agency has yet approved BCV for MPX. Accordingly, the off-label use of BCV is anticipated for MPX and various viral diseases. The patent literature revealed some important antiviral compositions of BCV. The authors believe there is a huge opportunity to create novel, inventive, and patentable BCV-based antiviral therapies (new combinations with existing antivirals) for OPXVs illnesses (MPX, smallpox, cowpox, camelpox, and vaccinia). It is also advised to conduct drug interaction (food, drug, and disease interaction) and drug resistance investigations on BCV while developing its combinations with other medications. The BCV-based drug repurposing options are also open for further exploration. BCV offers a promising opportunity for biosecurity against OPXV-based bioterrorism attacks and to control the MPX outbreak of 2022.

PMID:36830816 | DOI:10.3390/biomedicines11020278

J Biomol Struct Dyn. 2023 Feb 24:1-13. doi: 10.1080/07391102.2023.2182129. Online ahead of print.

ABSTRACT

Chagas disease is a well-known Neglected Tropical Disease, mostly endemic in continental Latin America, but that has spread to North America and Europe. Unfortunately, current treatments against such disease are ineffective and produce known and undesirable side effects. To find novel effective drug candidates to treat Chagas disease, we uniquely explore the Trypanosoma cruzi proteasome as a recent biological target and, also, apply drug repurposing through different computational methodologies. For this, we initially applied protein homology modeling to build a robust model of proteasome β4/β5 subunits, since there is no crystallographic structure of this target. Then, we used it on a drug repurposing via a virtual screening campaign starting with more than 8,000 drugs and including the methodologies: ligand-based similarity, toxicity predictions, and molecular docking. Three drugs were selected concerning their favorable interactions at the protein binding site and subsequently submitted to molecular dynamics simulations, which allowed us to elucidate their behavior and compare such theoretical results with experimental ones, obtained in biological assays also described in this paper.Communicated by Ramaswamy H. Sarma.

PMID:36826433 | DOI:10.1080/07391102.2023.2182129

bioRxiv. 2023 Feb 16:2023.02.15.528673. doi: 10.1101/2023.02.15.528673. Preprint.

ABSTRACT

OBJECTIVE: Identifying sets of rare diseases with shared aspects of etiology and pathophysiology may enable drug repurposing and/or platform based therapeutic development. Toward that aim, we utilized an integrative knowledge graph-based approach to constructing clusters of rare diseases.

MATERIALS AND METHODS: Data on 3,242 rare diseases were extracted from the National Center for Advancing Translational Science (NCATS) Genetic and Rare Diseases Information center (GARD) internal data resources. The rare disease data was enriched with additional biomedical data, including gene and phenotype ontologies, biological pathway data and small molecule-target activity data, to create a knowledge graph (KG). Node embeddings were used to convert nodes into vectors upon which k-means clustering was applied. We validated the disease clusters through semantic similarity and feature enrichment analysis.

RESULTS: A node embedding model was trained on the ontology enriched rare disease KG and k-means clustering was applied to the embedding vectors resulting in 37 disease clusters with a mean size of 87 diseases. We validate the disease clusters quantitatively by looking at semantic similarity of clustered diseases, using the Orphanet Rare Disease Ontology. In addition, the clusters were analyzed for enrichment of associated genes, revealing that the enriched genes within clusters were shown to be highly related.

DISCUSSION: We demonstrate that node embeddings are an effective method for clustering diseases within a heterogenous KG. Semantically similar diseases and relevant enriched genes have been uncovered within the clusters. Connections between disease clusters and approved or investigational drugs are enumerated for follow-up efforts.

CONCLUSION: Our study lays out a method for clustering rare diseases using the graph node embeddings. We develop an easy to maintain pipeline that can be updated when new data on rare diseases emerges. The embeddings themselves can be paired with other representation learning methods for other data types, such as drugs, to address other predictive modeling problems. Detailed subnetwork analysis and in-depth review of individual clusters may lead to translatable findings. Future work will focus on incorporation of additional data sources, with a particular focus on common disease data.

PMID:36824742 | PMC:PMC9949046 | DOI:10.1101/2023.02.15.528673

BMC Cancer. 2023 Feb 23;23(1):185. doi: 10.1186/s12885-023-10659-y.

ABSTRACT

BACKGROUND: Glioblastoma, the most common primary malignant brain tumour in adults, is a highly vascular tumour characterised by abnormal angiogenesis. Additional mechanisms of tumour vascularisation have also been reported in glioblastoma, including the formation of tumour cell-derived vessels by vasculogenic mimicry (VM) or the transdifferentiation of tumour cells to endothelial cells. VM and endothelial transdifferentiation have frequently been reported as distinct processes, however, the use of both terms to describe a single process of vascularisation also occurs. Some overlapping characteristics have also been reported when identifying each process. We therefore aimed to determine the markers consistently attributed to VM and endothelial transdifferentiation in the glioblastoma literature.

METHODS: Ovid MEDLINE and Ovid Embase were searched for studies published between January 1999 and July 2021 that assessed VM or tumour to endothelial transdifferentiation in human glioblastoma. The online systematic review tool Covidence was used for screening and data extraction. Extracted data included type of tumour-derived vasculature reported, methods and techniques used, and markers investigated. Studies were grouped based on type of vasculature reported for further assessment.

RESULTS: One hundred and thirteen of the 419 unique records identified were included for analysis. VM was reported in 64/113 studies, while tumour to endothelial transdifferentiation was reported in 16/113 studies. The remaining studies used both terms to describe a single process, did not define the process that occurred, or concluded that neither VM nor endothelial transdifferentiation occurred. Absence of CD34 and/or CD31 in vascular structures was the most common indicator of VM, while expression of CD34 and/or CD31, in addition to various other endothelial, stem cell or tumour cell markers, indicated tumour to endothelial transdifferentiation.

CONCLUSION: Cells derived from tumour to endothelial transdifferentiation express typical endothelial markers including CD34 and CD31, while tumour cells contributing to VM lack CD34 and CD31 expression. Additional tumour markers are required to identify transdifferentiation in glioblastoma tissue, and this process requires further characterisation.

PMID:36823554 | DOI:10.1186/s12885-023-10659-y

Medicine (Baltimore). 2023 Feb 10;102(6):e31318. doi: 10.1097/MD.0000000000031318.

ABSTRACT

In December 2019, a COVID-19 outbreak caused by SARS-CoV-2 raised worldwide health concerns. In this case, molecular docking and drug repurposing computational approaches were engaged to check the efficiency of plant-based inhibitory compounds against SARS-CoV-2 main protease enzyme and papain-like protease enzyme. Twenty phytochemical inhibitory compounds were collected. Then these compounds were screened based on Lipinski's rule. As a result of this screening eleven compounds were further selected. Quantitative structure-activity relationships analysis was done before molecular docking to check especially the antiviral activity of inhibitory compounds. Docking validation of these compounds was checked by using online server Database of Useful Decoys: Enhanced. Binding affinity value, and pharmacokinetic properties of Aloin compound indicated that it can be used against main protease enzyme of SARS-CoV-2. So, it makes it a promising compound to follow further in cell and biochemical-based assays to explore its potential use against COVID-19.

PMID:36820539 | DOI:10.1097/MD.0000000000031318

Front Mol Biosci. 2023 Feb 1;10:1145834. doi: 10.3389/fmolb.2023.1145834. eCollection 2023.

NO ABSTRACT

PMID:36818044 | PMC:PMC9929556 | DOI:10.3389/fmolb.2023.1145834

Stat Med. 2023 Feb 23. doi: 10.1002/sim.9686. Online ahead of print.

ABSTRACT

Linkage between drug claims data and clinical outcome allows a data-driven experimental approach to drug repurposing. We develop an estimation procedure based on generalized random forests for estimation of time-point specific average treatment effects in a time-to-event setting with competing risks. To handle right-censoring, we propose a two-step procedure for estimation, applying inverse probability weighting to construct time-point specific weighted outcomes as input for the generalized random forest. The generalized random forests adaptively handle covariate effects on the treatment assignment by applying a splitting rule that targets a causal parameter. Using simulated data we demonstrate that the method is effective for a causal search through a list of treatments to be ranked according to the magnitude of their effect on clinical outcome. We illustrate the method using the Danish national health registries where it is of interest to discover drugs with an unexpected protective effect against relapse of severe depression.

PMID:36815690 | DOI:10.1002/sim.9686

Acta Pharm Sin B. 2023 Jan;13(1):54-67. doi: 10.1016/j.apsb.2022.05.004. Epub 2022 May 12.

ABSTRACT

Prediction of the interactions between small molecules and their targets play important roles in various applications of drug development, such as lead discovery, drug repurposing and elucidation of potential drug side effects. Therefore, a variety of machine learning-based models have been developed to predict these interactions. In this study, a model called auxiliary multi-task graph isomorphism network with uncertainty weighting (AMGU) was developed to predict the inhibitory activities of small molecules against 204 different kinases based on the multi-task Graph Isomorphism Network (MT-GIN) with the auxiliary learning and uncertainty weighting strategy. The calculation results illustrate that the AMGU model outperformed the descriptor-based models and state-of-the-art graph neural networks (GNN) models on the internal test set. Furthermore, it also exhibited much better performance on two external test sets, suggesting that the AMGU model has enhanced generalizability due to its great transfer learning capacity. Then, a naïve model-agnostic interpretable method for GNN called edges masking was devised to explain the underlying predictive mechanisms, and the consistency of the interpretability results for 5 typical epidermal growth factor receptor (EGFR) inhibitors with their structure‒activity relationships could be observed. Finally, a free online web server called KIP was developed to predict the kinome-wide polypharmacology effects of small molecules (http://cadd.zju.edu.cn/kip).

PMID:36815050 | PMC:PMC9939366 | DOI:10.1016/j.apsb.2022.05.004

Acta Pharm Sin B. 2023 Jan;13(1):142-156. doi: 10.1016/j.apsb.2022.04.003. Epub 2022 Apr 9.

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis. However, which molecule regulates macrophage polarization in NAFLD remains unclear. Herein, we showed NAFLD mice exhibited increased 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7) expression in hepatic macrophages concomitantly with elevated M1 polarization. Single-cell RNA sequencing on hepatic non-parenchymal cells isolated from wild-type littermates and macrophage-17β-HSD7 knockout mice fed with high fat diet (HFD) for 6 weeks revealed that lipid metabolism pathways were notably changed. Furthermore, 17β-HSD7 deficiency in macrophages attenuated HFD-induced hepatic steatosis, insulin resistance and liver injury. Mechanistically, 17β-HSD7 triggered NLRP3 inflammasome activation by increasing free cholesterol content, thereby promoting M1 polarization of macrophages and the secretion of pro-inflammatory cytokines. In addition, to help demonstrate that 17β-HSD7 is a potential drug target for NAFLD, fenretinide was screened out from an FDA-approved drug library based on its 17β-HSD7 dehydrogenase inhibitory activity. Fenretinide dose-dependently abrogated macrophage polarization and pro-inflammatory cytokines production, and subsequently inhibited fat deposition in hepatocytes co-cultured with macrophages. In conclusion, our findings suggest that blockade of 17β-HSD7 signaling by fenretinide would be a drug repurposing strategy for NAFLD treatment.

PMID:36815031 | PMC:PMC9939369 | DOI:10.1016/j.apsb.2022.04.003

Front Cardiovasc Med. 2023 Feb 6;10:1033832. doi: 10.3389/fcvm.2023.1033832. eCollection 2023.

ABSTRACT

Cardiovascular/renal/metabolic (CVRM) diseases collectively comprise the leading cause of death worldwide and disproportionally affect older demographics and historically underrepresented minority populations. Despite these critical unmet needs, pharmaceutical research and development (R&D) efforts have historically struggled with high drug failure rates, low approval rates, and other challenges. Drug repurposing is one approach to recovering R&D costs and meeting unmet demands in therapeutic markets. While there are multiple approaches to conducting drug repurposing, we recognize the importance of bringing together and consolidating discontinued drug information to help identify prospective repurposing candidates. In this study, we have harmonized and integrated information on all relevant CVRM drug assets from U.S. Securities and Exchange Commission (SEC) filings, clinical trial records, PharmGKB, Open Targets, and other platforms. A list of existing therapeutics discontinued or shelved by pharmaceutical/biotechnology companies in 2011-2022 were manually curated and interpreted for insights using information on each drug's genetic target, mechanism of action (MOA), clinical indication, and R&D information including highest phase of clinical development, year of discontinuation, previous repurposing attempts (if any), and other actionable metadata. This study also summarizes the profiles of CVRM drugs discontinued within the past decade and identifies the limitations of publicly available information on discontinued drug assets. The constructed database could serve as a tool for identifying candidates for drug repurposing and developing query methods for collecting R&D information.

PMID:36815023 | PMC:PMC9940660 | DOI:10.3389/fcvm.2023.1033832

Bioinform Biol Insights. 2023 Feb 17;17:11779322231155068. doi: 10.1177/11779322231155068. eCollection 2023.

ABSTRACT

Hepatic encephalopathy (HE) is a set of complex neurological complications that arise from advanced liver disease. The precise molecular and cellular mechanism of HE is not fully understood. Differentially expressed genes (DEGs) from microarray technologies are powerful approaches to obtain new insight into the pathophysiology of HE. We analyzed microarray data sets of cirrhotic patients with HE from Gene Expression Omnibus to identify DEGs in postmortem cerebral tissues. Consequently, we uploaded significant DEGs into the STRING to specify protein-protein interactions. Cytoscape was used to reconstruct the genetic network and identify hub genes. Target genes were uploaded to different databases to perform comprehensive enrichment analysis and repurpose new therapeutic options for HE. A total of 457 DEGs were identified in 2 data sets totally from 12 cirrhotic patients with HE compared with 12 healthy subjects. We found that 274 genes were upregulated and 183 genes were downregulated. Network analyses on significant DEGs indicated 12 hub genes associated with HE. Enrichment analysis identified fatty acid beta-oxidation, cerebral organic acidurias, and regulation of actin cytoskeleton as main involved pathways associated with upregulated genes; serotonin receptor 2 and ELK-SRF/GATA4 signaling, GPCRs, class A rhodopsin-like, and p38 MAPK signaling pathway were related to downregulated genes. Finally, we predicted 39 probable effective drugs/agents for HE. This study not only confirms main important involved mechanisms of HE but also reveals some yet unknown activated molecular and cellular pathways in human HE. In addition, new targets were identified that could be of value in the future study of HE.

PMID:36814683 | PMC:PMC9940182 | DOI:10.1177/11779322231155068