Abstract: We sought to craft a drug safety signalling pipeline associating latent information in clinical free text with exposures to single drugs and drug pairs. Data arose from 12 secondary and tertiary public hospitals in two Danish regions, comprising approximately half the Danish population. Notes were operationalised with a fastText embedding, based on which we trained 10 270 neural-network models (one for each distinct single-drug/drug-pair exposure) predicting the risk of exposure given an embedding vector. We included 2 905 251 admissions between May 2008 and June 2016, with 13 740 564 distinct drug prescriptions; the median number of prescriptions was 5 (IQR: 3-9) and in 1 184 340 (41%) admissions patients used >/=5 drugs concomitantly. A total of 10 788 259 clinical notes were included, with 179 441 739 tokens retained after pruning. Of 345 single-drug signals reviewed, 28 (8.1%) represented possibly undescribed relationships; 186 (54%) signals were clinically meaningful. Sixteen (14%) of the 115 drug-pair signals were possible interactions, and two (1.7%) were known. In conclusion, we built a language-agnostic pipeline for mining associations between free-text information and medication exposure without manual curation, predicting not the likely outcome of a range of exposures but also the likely exposures for outcomes of interest. Our approach may help overcome limitations of text mining methods relying on curated data in English and can help leverage non-English free text for pharmacovigilance.

Abstract: BACKGROUND: The anti-carcinogenic properties of aspirin have been observed in some solid tumors. However, the molecular mechanism of therapeutic effects of aspirin on bladder cancer is still indistinct. We introduced a bioinformatics analysis approach, to explore the targets of aspirin in bladder cancer (BC). METHODS: To find out the potential targets of aspirin in BC, we analyzed direct protein targets (DPTs) of aspirin in Drug Bank 5.0. The protein-protein interaction (PPI) network and signaling pathway of aspirin DPTs were then analyzed subsequently. A detailed analysis of the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway has shown that aspirin is linked to BC. We identified overexpressed genes in BC comparing with normal samples by Oncomine and genes that interlinked with aspirin target genes in BC by STRING. RESULTS: Firstly, we explored 16 direct protein targets (DPT) of aspirin. We analyzed the protein-protein interaction (PPI) network and signaling pathways of aspirin DPT. We found that aspirin is closely associated with a variety of cancers, including BC. Then, we classified mutations in 3 aspirin DPTs (CCND1, MYC and TP53) in BC using the cBio Portal database. In addition, we extracted the top 50 overexpressed genes in bladder cancer by Oncomine and predicted the genes associated with the 3 aspirin DPTs (CCND1, MYC and TP53) in BC by STRING. Finally, 5 exact genes were identified as potential therapeutic targets of aspirin in bladder cancer. CONCLUSION: The analysis of relevant databases will improve our mechanistic understanding of the role of aspirin in bladder cancer. This will guide the direction of our next drug-disease interaction studies.

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.

Abstract: Background: The association between exposure to anti-hyperglycemic medications (A-HgM) for Type 2 Diabetes Mellitus (T2D) treatment and Multiple Sclerosis (MS) in T2D patients is unclear. Methods: This retrospective cohort analysis used the Mariner claims database. Patient records were surveyed for a diagnosis of MS starting 12 months after diagnosis of T2D. Patients were required to be actively enrolled in the Mariner claims records for six months prior and at least three years after the diagnosis of T2D without a history of previous neurodegenerative disease. Survival analysis was used to determine the association between A-HgM exposure and diagnosis of MS. A propensity score approach was used to minimize measured and unmeasured selection bias. The analyses were conducted between January 1st and April 28th, 2021. Findings: In T2D patients younger than 45, A-HgM exposure was associated with a reduced risk of developing MS (RR: 0.22, 95%CI: 0.17-0.29, p-value <0.001). In contrast, A-HgM exposure in patients older than 45 was associated with an increased risk of MS with women exhibiting greater risk (RR: 1.53, 95%CI: 1.39-1.69, p < 0.001) than men (RR: 1.17, 95%CI: 1.01-1.37, p = 0 . 04). Patients who developed MS had a higher incidence of baseline comorbidities. Mean follow-up was 6.2 years with a standard deviation of 1.8 years. Interpretation: In this study, A-HgM exposure in patients with T2D was associated with reduced risk of MS in patients younger than 45 whereas in patients older than 45, exposure to A-HgM was associated with an increased risk of newly diagnosed MS, particularly in women.

Abstract: Injuries to the central nervous system (CNS) such as stroke, brain, and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration. The brain has a surprising intrinsic capability of recovering itself after injury. However, the hostile extrinsic microenvironment significantly hinders axon regeneration. Recent advances have indicated that the inactivation of intrinsic regenerative pathways plays a pivotal role in the failure of most adult CNS neuronal regeneration. Particularly, substantial evidence has convincingly demonstrated that the mechanistic target of rapamycin (mTOR) signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries. In this review, we will discuss the recent findings and highlight the critical roles of mTOR pathway in axon regeneration in different types of CNS injury. Importantly, we will demonstrate that the reactivation of this regenerative pathway can be achieved by blocking the key mTOR signaling components such as phosphatase and tensin homolog (PTEN). Given that multiple mTOR signaling components are endogenous inhibitory factors of this pathway, we will discuss the promising potential of RNA-based therapeutics which are particularly suitable for this purpose, and the fact that they have attracted substantial attention recently after the success of coronavirus disease 2019 vaccination. To specifically tackle the blood-brain barrier issue, we will review the current technology to deliver these RNA therapeutics into the brain with a focus on nanoparticle technology. We will propose the clinical application of these RNA-mediated therapies in combination with the brain-targeted drug delivery approach against mTOR signaling components as an effective and feasible therapeutic strategy aiming to enhance axonal regeneration for functional recovery after CNS injury.

Abstract: Plasmodium parasites are reliant on the Apicomplexan AP2 (ApiAP2) transcription factor family to regulate gene expression programs. AP2 DNA binding domains have no homologs in the human or mosquito host genomes, making them potential antimalarial drug targets. Using an in-silico screen to dock thousands of small molecules into the crystal structure of the AP2-EXP (Pf3D7_1466400) AP2 domain (PDB:3IGM), we identified putative AP2-EXP interacting compounds. Four compounds were found to block DNA binding by AP2-EXP and at least one additional ApiAP2 protein. Our top ApiAP2 competitor compound perturbs the transcriptome of P. falciparum trophozoites and results in a decrease in abundance of log2 fold change > 2 for 50% (46/93) of AP2-EXP target genes. Additionally, two ApiAP2 competitor compounds have multi-stage anti-Plasmodium activity against blood and mosquito stage parasites. In summary, we describe a novel set of antimalarial compounds that interact with AP2 DNA binding domains. These compounds may be used for future chemical genetic interrogation of ApiAP2 proteins or serve as starting points for a new class of antimalarial therapeutics.

Abstract: Metabolic reprogramming is a key attribute of cancer progression. An altered expression of pyruvate kinase M2 (PKM2), a phosphotyrosine-binding protein is observed in many human cancers. PKM2 plays a vital role in metabolic reprogramming, transcription and cell cycle progression and thus is deliberated as an attractive target in anticancer drug development. The expression of PKM2 is essential for aerobic glycolysis and cell proliferation, especially in cancer cells, facilitating selective targeting of PKM2 in cell metabolism for cancer therapeutics. We have screened a virtual library of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database of Indian medicinal plants to identify potential activators of PKM2. The initial screening was carried out for the physicochemical properties of the compounds, and then structure-based molecular docking was performed to select compounds based on their binding affinity towards PKM2. Subsequently, the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties, PAINS (Pan-assay interference compounds) patterns, and PASS evaluation were carried out to find more potent hits against PKM2. Here, Tuberosin was identified from the screening process bearing appreciable binding affinity toward the PKM2-binding pocket and showed a worthy set of drug-like properties. Finally, molecular dynamics simulation for 100 ns was performed, which showed decent stability of the protein-ligand complex and relatival conformational dynamics throughout the trajectory. The study suggests that modulating PKM2 with natural compounds is an attractive approach in treating human malignancy after required validation.

Abstract: Amphotericin B (AmpB) is a polyene macrolide antibiotic used in the treatment of blood-borne parasitic and fungal infections. However, its use, particularly in the developing world, has been limited by dose-dependent kidney toxicity, other systemic-related toxicity issues following injection, the inconvenience of parenteral administration, and accessibility. Oral formulation approaches have focused on the dual problem of solubility and permeability of AmpB, which is poorly water soluble, amphoteric and has extremely low oral bioavailability. Therefore, to enhance oral absorption, researchers have employed micellar formulations, polymeric nanoparticles, cochleates, pro-drugs, and self-emulsifying drug delivery systems (SEDDS). This paper will highlight current uses of AmpB against parasitic infections such as leishmaniasis, preclinical and clinical formulation strategies, applications in veterinary medicine and the importance of developing a cost-effective and safe oral AmpB formulation.

Abstract: Alzheimer's disease (AD) is a complex and widespread condition, still not fully understood and with no cure yet. Amyloid beta (Abeta) peptide is suspected to be a major cause of AD, and therefore, simultaneously blocking its formation and aggregation by inhibition of the enzymes BACE-1 (beta-secretase) and AChE (acetylcholinesterase) by a single inhibitor may be an effective therapeutic approach, as compared to blocking one of these targets or by combining two drugs, one for each of these targets. We used our ISE algorithm to model each of the AChE peripheral site inhibitors and BACE-1 inhibitors, on the basis of published data, and constructed classification models for each. Subsequently, we screened large molecular databases with both models. Top scored molecules were docked into AChE and BACE-1 crystal structures, and 36 Molecules with the best weighted scores (based on ISE indexes and docking results) were sent for inhibition studies on the two enzymes. Two of them inhibited both AChE (IC(50) between 4-7 muM) and BACE-1 (IC(50) between 50-65 muM). Two additional molecules inhibited only AChE, and another two molecules inhibited only BACE-1. Preliminary testing of inhibition by F681-0222 (molecule 2) on APPswe/PS1dE9 transgenic mice shows a reduction in brain tissue of soluble Abeta42.

Abstract: Crystal engineering of multi-component molecular crystals, cocrystals, is a subject of growing interest, thanks in part to the potential utility of pharmaceutical cocrystals as drug substances with improved properties. Whereas molecular cocrystals (MCCs) are quite well studied from a design perspective, ionic cocrystals (ICCs) remain relatively underexplored despite there being several recently FDA-approved drug products based upon ICCs. Successful cocrystal design strategies typically depend on strong and directional noncovalent interactions between coformers, as exemplified by hydrogen bonds. Understanding of the hierarchy of such interactions is key to successful outcomes in cocrystal design. We herein address the crystal engineering of ICCs comprising azole functional groups, particularly imidazoles and triazoles, which are commonly encountered in biologically active molecules. Specifically, azoles were studied for their propensity to serve as coformers with strong organic (trifluoroacetic acid and p-toluenesulfonic acid) and inorganic (hydrochloric acid, hydrobromic acid and nitric acid) acids to gain insight into the hierarchy of NH(+)...N (azolium-azole) supramolecular heterosynthons. Accordingly, we combined data mining of the Cambridge Structural Database (CSD) with the structural characterization of 16 new ICCs (11 imidazoles, 4 triazoles, one imidazole-triazole). Analysis of the new ICCs and 66 relevant hits archived in the CSD revealed that supramolecular synthons between identical azole rings (A(+)B(-)A) are much more commonly encountered, 71, than supramolecular synthons between different azole rings (A(+)B(-)C), 11. The average NH(+)...N distance found in the new ICCs reported herein is 2.697(3) A and binding energy calculations suggested that hydrogen bond strengths range from 31-46 kJ mol(-1). The azolium-triazole ICC (A(+)B(-)C) was obtained via mechanochemistry and differed from the other ICCs studied as there was no NH(+)...N hydrogen bonding. That the CNC angles in imidazoles and 1,2,4-triazoles are sensitive to protonation, the cationic forms having larger (approximately 4.4 degrees) values than comparable neutral rings, was used as a parameter to distinguish between protonated and neutral azole rings. Our results indicate that ICCs based upon azolium-azole supramolecular heterosynthons are viable targets, which has implications for the development of new azole drug substances with improved properties.