Genomics Proteomics Bioinformatics. 2022 Sep 28:S1672-0229(22)00122-X. doi: 10.1016/j.gpb.2022.09.006. Online ahead of print.

ABSTRACT

Transcriptional phenotypic drug discovery has achieved great success, and various compound perturbation-based data resources, such as connectivity map (CMap) and library of integrated network-based cellular signatures (LINCS), have been presented. Computational strategies fully mining these resources for phenotypic drug discovery have been proposed. Among them, the fundamental issue is to define the proper similarity between transcriptional profiles. Traditionally, such similarity has been defined in an unsupervised way. However, due to the high dimensionality and the existence of high noise in high-throughput data, it lacks robustness with limited performance. To this end, we present DrSim, which is a learning-based framework that automatically infers similarity rather than that of manually designing. We evaluated DrSim on publicly available in vitro and in vivo datasets in drug annotation and repositioning. The results indicated that DrSim outperforms the existing methods. In conclusion, by learning transcriptional similarity, DrSim facilitates the broad utility of high-throughput transcriptional perturbation data for phenotypic drug discovery. The source code and manual of DrSim are available at https://github.com/bm2-lab/DrSim/.

PMID:36182102 | DOI:10.1016/j.gpb.2022.09.006

J Gene Med. 2022 Sep 30:e3451. doi: 10.1002/jgm.3451. Online ahead of print.

ABSTRACT

BACKGROUND: The abnormal modification of chondroitin sulfate is one of the leading causes of disease, including cancer progression. During chondroitin sulfate biosynthesis, the CHST11 enzyme plays a vital role in its modification, but its role in cancer is not fully understood. Therefore, understanding the relationship between CHST11 and pulmonary-related diseases through clinically relevant information may be useful for diagnosis or treatment.

METHODS: A variety of pulmonary fibrosis clinical gene expression omnibus (GEO) datasets were used to assess the association between CHST11-related manifestations and fibrosis. Multiple lung cancer-related databases, including The Cancer Genome Atlas (TCGA), GEO datasets, UCSC Xena, GEPIA2, Cbioportal and Ingenuity Pathway Analysis, have been used to evaluate the clinical correlation between CHST11 and lung cancer and potential molecular mechanisms. For drug repurposing prediction, the molecules that correlated with CHST11 were subjected to the LINCS L1000 algorithm. A variety of in vitro assays were performed to evaluate the in-silico models, including RNA and protein expression, proliferation, migration, and invasion.

RESULTS: Clinical analyses indicate that the levels of CHST11 are significantly elevated in cases of pulmonary-related diseases, including fibrosis and lung cancer. According to multiple lung cancer cohorts, CHST11 is the only member of the carbohydrate sulfotransferase family associated with overall survival for lung adenocarcinomas (LUAD), and it is highly related to smoking-induced lung cancer patients. Based on the results of in vitro experiments, CHST11 expression contributes to tumor malignancy and promotes multiple fibrotic activators. Correlation-based-ingenuity pathway analysis (IPA) indicated that CHST11-related molecules contributed to pulmonary fibrosis or LUAD via similar upstream stimulators. Based on known molecular regulatory relationships, CHST11 has been associated with the regulation of TGF-β and INFγ as important molecules contributing to fibrosis and cancer progression. Interestingly, WordCloud analysis revealed that CHST11-related molecules are involved in regulation primarily by integrin signaling, and these relationships were consistently reflected in the analysis of cell lines and the clinical correlation. A CHST11 signature-based drug repurposing analysis demonstrated that the CHST11/integrin axis could be targeted by AG-1478 (Tyrphostin AG 1478), brefeldin A, geldanamycin and importazole.

CONCLUSIONS: This study provides the first demonstration that CHST11 may be used as a biomarker for pulmonary fibrosis or lung cancer, and the levels of CHST11 were increased by TGF-β and INFγ. The molecular simulation analyses demonstrate that the CHST11/integrin axis is a potential therapeutic target for treating lung cancer.

PMID:36181245 | DOI:10.1002/jgm.3451

J Transl Med. 2022 Sep 30;20(1):436. doi: 10.1186/s12967-022-03643-w.

ABSTRACT

BACKGROUND: The clinical observation showed a potential additive effect of anti-PD-1 agents and cetirizine in patients with advanced melanoma.

METHODS: Clinical outcomes of concomitant cetirizine/anti-PD-1 treatment of patients with stage IIIb-IV melanoma were retrospectively collected, and a transcriptomic analysis was performed on blood samples obtained at baseline and after 3 months of treatment.

RESULTS: Patients treated with cetirizine concomitantly with an anti-PD-1 agent had significantly longer progression-free survival (PFS; mean PFS: 28 vs 15 months, HR 0.46, 95% CI: 0.28-0.76; p = 0.0023) and OS (mean OS was 36 vs 23 months, HR 0.48, 95% CI: 0.29-0.78; p = 0.0032) in comparison with those not receiving cetirizine. The concomitant treatment was significantly associated with ORR and DCR (p < 0.05). The expression of FCGR1A/CD64, a specific marker of macrophages, was increased after the treatment in comparison with baseline in blood samples from patients receiving cetirizine, but not in those receiving only the anti-PD1, and positively correlated with the expression of genes linked to the interferon pathway such as CCL8 (rho = 0.32; p = 0.0111), IFIT1 (rho = 0.29; p = 0.0229), IFIT3 (rho = 0.57; p < 0.0001), IFI27 (rho = 0.42; p = 0.008), MX1 (rho = 0.26; p = 0.0383) and RSAD2 (rho = 0.43; p = 0.0005).

CONCLUSIONS: This retrospective study suggests that M1 macrophage polarization may be induced by cetirizine through the interferon-gamma pathway. This effect may synergize with the immunotherapy of advanced melanoma with anti-PD-1 agents.

PMID:36180872 | DOI:10.1186/s12967-022-03643-w

BMC Bioinformatics. 2022 Sep 30;23(Suppl 6):407. doi: 10.1186/s12859-022-04934-1.

ABSTRACT

BACKGROUND: To date, there are no effective treatments for most neurodegenerative diseases. Knowledge graphs can provide comprehensive and semantic representation for heterogeneous data, and have been successfully leveraged in many biomedical applications including drug repurposing. Our objective is to construct a knowledge graph from literature to study the relations between Alzheimer's disease (AD) and chemicals, drugs and dietary supplements in order to identify opportunities to prevent or delay neurodegenerative progression. We collected biomedical annotations and extracted their relations using SemRep via SemMedDB. We used both a BERT-based classifier and rule-based methods during data preprocessing to exclude noise while preserving most AD-related semantic triples. The 1,672,110 filtered triples were used to train with knowledge graph completion algorithms (i.e., TransE, DistMult, and ComplEx) to predict candidates that might be helpful for AD treatment or prevention.

RESULTS: Among three knowledge graph completion models, TransE outperformed the other two (MR = 10.53, Hits@1 = 0.28). We leveraged the time-slicing technique to further evaluate the prediction results. We found supporting evidence for most highly ranked candidates predicted by our model which indicates that our approach can inform reliable new knowledge.

CONCLUSION: This paper shows that our graph mining model can predict reliable new relationships between AD and other entities (i.e., dietary supplements, chemicals, and drugs). The knowledge graph constructed can facilitate data-driven knowledge discoveries and the generation of novel hypotheses.

PMID:36180861 | DOI:10.1186/s12859-022-04934-1

J Mol Neurosci. 2022 Sep 30. doi: 10.1007/s12031-022-02071-1. Online ahead of print.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neurons that mainly affects the motor cortex, brainstem, and spinal cord. Under disease conditions, microglia could possess two distinct profiles, M1 (toxic) and M2 (protective), with the M2 profile observed at disease onset. SOD1 (superoxide dismutase 1) gene mutations account for up to 20% of familial ALS cases. Comparative gene expression differences in M2-protective (early) stage SOD1G93A microglia and age-matched SOD1G93A motor neurons are poorly understood. We evaluated the differential gene expression profiles in SOD1G93A microglia and SOD1G93A motor neurons utilizing publicly available transcriptomics data and bioinformatics analyses, constructed biomolecular networks around them, and identified gene clusters as potential drug targets. Following a drug repositioning strategy, 5 small compounds (belinostat, auranofin, BRD-K78930611, AZD-8055, and COT-10b) were repositioned as potential ALS therapeutic candidates that mimic the protective state of microglia and reverse the toxic state of motor neurons. We anticipate that this study will provide new insights into the ALS pathophysiology linking the M2 state of microglia and drug repositioning.

PMID:36178612 | DOI:10.1007/s12031-022-02071-1

R Soc Open Sci. 2022 Sep 28;9(9):220369. doi: 10.1098/rsos.220369. eCollection 2022 Sep.

ABSTRACT

The Ebola virus (EBOV) outbreak was recorded as the largest in history and caused many fatalities. As seen in previous studies, drug repurposing and database filtration were the two major pathways to searching for potent compounds against EBOV. In this study, a deep learning (DL) approach via the LigDream tool was employed to obtain novel and effective anti-EBOV inhibitors. Based on the galidesivir (BCX4430) chemical structure, 100 compounds were collected and inspected using various in silico approaches. Results from the molecular docking study indicated that mol1_069 and mol1_092 were the best two potent compounds with a docking score of -7.1 kcal mol-1 and -7.0 kcal mol-1, respectively. Molecular dynamics simulations, in addition to binding energy calculations, were conducted over 100 ns. Both compounds exhibited lower binding energies than BCX4430. Furthermore, compared with BCX4430 (%Absorption = 60.6%), mol1_069 and mol1_092 scored higher values of % Absorption equal to 68.1% and 63.7%, respectively. The current data point to the importance of using DL in the drug design process instead of conventional methods such as drug repurposing or database filtration. In conclusion, mol1_069 and mol1_092 are promising anti-EBOV drug candidates that require further in vitro and in vivo investigations.

PMID:36177201 | PMC:PMC9515638 | DOI:10.1098/rsos.220369

J Biomol Struct Dyn. 2022 Sep 29:1-18. doi: 10.1080/07391102.2022.2127902. Online ahead of print.

ABSTRACT

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since its emergence in 2019 has yielded several new viral variants with varied infectivity, disease severity, and antigenicity. Although most mutations are expected to be relatively neutral, mutations at the Spike region of the genome have shown to have a major impact on the viral transmission and infection in humans. Therefore, it is crucial to survey the structures of spike protein across the global virus population to contextualize the rate of therapeutic success against these variants. In this study, high-frequency mutational variants from different geographic regions were pooled in order to study the structural evolution of the spike protein through drug docking and MD simulations. We investigated the mutational burden in the spike subregions and have observed that the different variants harbour unique signature patterns in the spike subregions, with certain domains being highly prone to mutations. Further, the MD simulations and docking study revealed that different variants show differential stability when docked for the same set of drug targets. This work sheds light on the mutational burden and the stability landscape of the spike protein across the variants from different geographical regions.Communicated by Ramaswamy H. Sarma.

PMID:36173706 | DOI:10.1080/07391102.2022.2127902

Biochem Genet. 2022 Sep 29. doi: 10.1007/s10528-022-10282-9. Online ahead of print.

ABSTRACT

Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have used bioinformatics to investigate seventeen mutations in the spike protein of SARS-CoV-2, as this mediates infection of human cells and is the target of most vaccine strategies and antibody-based therapies. Two mutations, H146Y and S221W, were identified as being most pathogenic. Mutations at positions D614G, A829T, and P1263L might also have deleterious effects on protein function. We hypothesized that candidate small molecules may be repurposed to combat viral infection. We investigated changes in binding energies of the ligands and the mutant proteins by assessing molecular docking. For an understanding of cellular function and organization, protein-protein interactions are also critical. Protein-protein docking for naïve and mutated structures of SARS-CoV-2 S protein was evaluated for their binding energy with the angiotensin-converting enzyme 2 (ACE2). These interactions might limit the binding of the SARS-CoV-2 spike protein to the ACE2 receptor or may have a deleterious effect on protein function that may limit infection. These results may have important implications for the transmission of SARS-CoV-2, its pathogenesis, and the potential for drug repurposing and immune therapies.

PMID:36173498 | DOI:10.1007/s10528-022-10282-9

Protein Sci. 2022 Oct;31(10):e4427. doi: 10.1002/pro.4427.

ABSTRACT

Bacteroides fragilis is an abundant commensal component of the healthy human colon. However, under dysbiotic conditions, enterotoxigenic B. fragilis (ETBF) may arise and elicit diarrhea, anaerobic bacteremia, inflammatory bowel disease, and colorectal cancer. Most worrisome, ETBF is resistant to many disparate antibiotics. ETBF's only recognized specific virulence factor is a zinc-dependent metallopeptidase (MP) called B. fragilis toxin (BFT) or fragilysin, which damages the intestinal mucosa and triggers disease-related signaling mechanisms. Thus, therapeutic targeting of BFT is expected to limit ETBF pathogenicity and improve the prognosis for patients. We focused on one of the naturally occurring BFT isoforms, BFT-3, and managed to repurpose several approved drugs as BFT-3 inhibitors through a combination of biophysical, biochemical, structural, and cellular techniques. In contrast to canonical MP inhibitors, which target the active site of mature enzymes, these effectors bind to a distal allosteric site in the proBFT-3 zymogen structure, which stabilizes a partially unstructured, zinc-free enzyme conformation by shifting a zinc-dependent disorder-to-order equilibrium. This yields proBTF-3 incompetent for autoactivation, thus ablating hydrolytic activity of the mature toxin. Additionally, a similar destabilizing effect is observed for the activated protease according to biophysical and biochemical data. Our strategy paves a novel way for the development of highly specific inhibitors of ETBF-mediated enteropathogenic conditions.

PMID:36173175 | DOI:10.1002/pro.4427

Nat Aging. 2021 Oct;1(10):932-947. doi: 10.1038/s43587-021-00122-7. Epub 2021 Oct 11.

ABSTRACT

The evident genetic, pathological, and clinical heterogeneity of Alzheimer's disease (AD) poses challenges for traditional drug development. We conducted a computational drug repurposing screen for drugs to treat apolipoprotein (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Aβ accumulation rescued electrophysiological, pathological, or cognitive deficits. Single-nucleus RNA-sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in apoE4-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.

PMID:36172600 | PMC:PMC9514594 | DOI:10.1038/s43587-021-00122-7

Front Pharmacol. 2022 Sep 12;13:995439. doi: 10.3389/fphar.2022.995439. eCollection 2022.

ABSTRACT

Autism spectrum disorder (ASD) is characterized by high heritability and clinical heterogeneity. The main core symptoms are social communication deficits. There are no medications approved for the treatment of these symptoms, and medications used to treat non-specific symptoms have serious side effects. To identify potential drugs for repurposing to effectively treat ASD core symptoms, we studied ASD risk genes within networks of protein-protein interactions of gene products. We first defined an ASD network from network-based analyses, and identified approved drugs known to interact with proteins within this network. Thereafter, we evaluated if these drugs can change ASD-associated gene expression perturbations in genes in the ASD network. This was done by analyses of drug-induced versus ASD-associated gene expression, where opposite gene expression perturbations in drug versus ASD indicate that the drug could counteract ASD-associated perturbations. Four drugs showing significant (p < 0.05) opposite gene expression perturbations in drug versus ASD were identified: Loperamide, bromocriptine, drospirenone, and progesterone. These drugs act on ASD-related biological systems, indicating that these drugs could effectively treat ASD core symptoms. Based on our bioinformatics analyses of ASD genetics, we shortlist potential drug repurposing candidates that warrant clinical translation to treat core symptoms in ASD.

PMID:36172193 | PMC:PMC9510394 | DOI:10.3389/fphar.2022.995439

JAMA. 2022 Sep 27;328(12):1171. doi: 10.1001/jama.2022.14723.

NO ABSTRACT

PMID:36166031 | DOI:10.1001/jama.2022.14723

J Biomol Struct Dyn. 2022 Sep 27:1-12. doi: 10.1080/07391102.2022.2123402. Online ahead of print.

ABSTRACT

Superbugs producing New Delhi metallo-β-lactamase 1 (NDM-1) enzyme is a growing crisis, that is adversely affecting the global health care system. NDM-1 empowers the bacteria to inactivate entire arsenal of β-lactam antibiotics including carbapenem (the last resort antibiotic) and remains ineffective to all the available β lactamase inhibitors used in the clinics. Limited therapeutic option available for rapidly disseminating NDM-1 producing bacteria makes it imperative to identify a potential inhibitor for NDM-1 enzyme. With drug repurposing approach, in this study, we used virtual screening of available Food and Drug Administration (FDA) approved chemical library (ZINC12 database) and captured 'adapalene' (FDA drug) as a potent inhibitor candidate for NDM-1 enzyme. Active site docking with NDM-1, showed adapalene with binding energy -9.21 kcal/mol and interacting with key amino acid residues (Asp124, His122, His189, His250, Cys208) in the active site of NDM-1. Further, molecular dynamic simulation of NDM-1 docked with the adapalene at 100 ns displayed a stable conformation dynamic, with relative RMSD and RMSF in the acceptable range. Subsequently, in vitro enzyme assays using recombinant NDM-1 protein demonstrated inhibition of NDM-1 by adapalene. Further, the combination of adapalene plus meropenem (carbapenem antibiotic) showed synergistic effect against the NDM-1 producing carbapenem (meropenem) resistant clinical isolates (Escherichia coli and Klebsiella pneumoniae). Overall, our data indicated that adapalene can be a potential inhibitor candidate for NDM-1 enzyme that can contribute to the development of a suitable adjuvant to save the activity of carbapenem antibiotic against infections caused by NDM-1 positive gram-negative bacteria. Communicated by Ramaswamy H. Sarma.

PMID:36165602 | DOI:10.1080/07391102.2022.2123402

J Biomol Struct Dyn. 2022 Sep 27:1-17. doi: 10.1080/07391102.2022.2127903. Online ahead of print.

ABSTRACT

SARS-CoV-2, the novel coronavirus spreading worldwide urges the need to repurpose drugs that can quickly enter clinical trials to combat the on-going global pandemic. A cluster of proteins are encoded for by the viral genome, each assuming a critical role in pathogen endurance inside the host. To handle the adverse circumstances, robust virtual strategies such as repurposing are coming to the fore due to being economical, efficient and rapid. Five FDA approved repurposed drugs proposed to act as inhibitors by targeting SARS-CoV-2 were used for initial evaluation via molecular docking. Moreover, a comparative analysis of the selected SARS-CoV-2 proteins against five ligands (Clemizole hydrochloride, Exemestane, Nafamostat, Pregnenolone and Umifenovir) was designed. In this regard, non-structural proteins (nsp3, nsp5, nsp10, nsp12 and nsp15), structural proteins (Spike, Nucleocapsid protein) and accessory proteins (ORF 3a, ORF 7a and ORF 9 b) were selected. Here, we aim to expedite the search for a potential drug from the five FDA approved repurposing drugs already in use for treatment of multiple diseases. Based on docking analysis, Umifenovir and Pregnenolone are suggested to show potential inhibitory effects against most of the SARS-CoV-2 proteins. These drugs are noteworthy since they exhibit high binding towards target proteins and should be used as lead compounds towards in vitro and in vivo studies. Communicated by Ramaswamy H. Sarma.

PMID:36165445 | DOI:10.1080/07391102.2022.2127903

3 Biotech. 2022 Nov;12(11):287. doi: 10.1007/s13205-022-03363-4. Epub 2022 Sep 21.

ABSTRACT

The outbreak of COVID-19 caused by the coronavirus (SARS-CoV-2) prompted number of computational and laboratory efforts to discover molecules against the virus entry or replication. Simultaneously, due to the availability of clinical information, drug-repurposing efforts led to the discovery of 2-deoxy-d-glucose (2-DG) for treating COVID-19 infection. 2-DG critically accumulates in the infected cells to prevent energy production and viral replication. As there is no clarity on the impact of genetic variations on the efficacy and adverse effects of 2-DG in treating COVID-19 using in silico approaches, we attempted to extract the genes associated with the 2-DG pathway using the Comparative Toxicogenomics Database. The interaction between selected genes was assessed using ClueGO, to identify the susceptible gene loci for SARS-CoV infections. Further, SNPs that were residing in the distinct genomic regions were retrieved from the Ensembl genome browser and characterized. A total of 80 SNPs were retrieved using diverse bioinformatics resources after assessing their (a) detrimental influence on the protein stability using Swiss-model, (b) miRNA regulation employing miRNASNP3, PolymiRTS, MirSNP databases, (c) binding of transcription factors by SNP2TFBS, SNPInspector, and (d) enhancers regulation using EnhancerDB and HaploReg reported A2M rs201769751, PARP1 rs193238922 destabilizes protein, six polymorphisms of XIAP effecting microRNA binding sites, EGFR rs712829 generates 15 TFBS, BECN1 rs60221525, CASP9 rs4645980, SLC2A2 rs5393 impairs 14 TFBS, STK11 rs3795063 altered 19 regulatory motifs. These data may provide the relationship between genetic variations and drug effects of 2-DG which may further assist in assigning the right individuals to benefit from the treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03363-4.

PMID:36164436 | PMC:PMC9491670 | DOI:10.1007/s13205-022-03363-4

J Nat Prod. 2022 Sep 26. doi: 10.1021/acs.jnatprod.2c00594. Online ahead of print.

ABSTRACT

Operculina hamiltonii is a vine native to the north and northeast region of Brazil, where its roots are traded as a depurative and laxative remedy with the name of Brazilian jalap in traditional medicine. Procedures for the isolation, purification by recycling HPLC, and structure elucidation of three undescribed resin glycosides are presented herein. Hamiltonin I (1) represents a macrocyclic structure of a tetrasaccharide of (11S)-hydroxyhexadecanoic acid. Additionally, two acyclic pentasaccharides, named hamiltoniosides I (2) and II (3), were also isolated, which are related structurally to the known compounds 4 and 5, macrocyclic lactone-type batatinosides. The tetrasaccharide core of 1 was diacylated by n-decanoic acid and the unusual n-hexadecanoic acid moiety, while the pentasaccharides 2-5 were esterified by one unit of n-decanoic or n-dodecanoic acid. All the isolated compounds were found to be inactive as cytotoxic agents. However, when they were evaluated (1-25 μM) in combination with a sublethal concentration of the anticancer agent vinblastine (0.003 μM), a significant enhancement of the resultant cytotoxicity was produced, especially for multidrug-resistant breast carcinoma epithelial cells. Such combined synergistic potency may be beneficial for chemotherapy, making resin glycosides potential candidates for drug repurposing of conventional chemotherapeutic drugs to reduce their side effects.

PMID:36162138 | DOI:10.1021/acs.jnatprod.2c00594

Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2210779119. doi: 10.1073/pnas.2210779119. Epub 2022 Sep 26.

ABSTRACT

Stem cell transplantation and genetic therapies offer potential cures for patients with sickle cell disease (SCD), but these options require advanced medical facilities and are expensive. Consequently, these treatments will not be available for many years to the majority of patients suffering from this disease. What is urgently needed now is an inexpensive oral drug in addition to hydroxyurea, the only drug approved by the FDA that inhibits sickle-hemoglobin polymerization. Here, we report the results of the first phase of our phenotypic screen of the 12,657 compounds of the Scripps ReFRAME drug repurposing library using a recently developed high-throughput assay to measure sickling times following deoxygenation to 0% oxygen of red cells from sickle trait individuals. The ReFRAME library is a very important collection because the compounds are either FDA-approved drugs or have been tested in clinical trials. From dose-response measurements, 106 of the 12,657 compounds exhibit statistically significant antisickling at concentrations ranging from 31 nM to 10 μM. Compounds that inhibit sickling of trait cells are also effective with SCD cells. As many as 21 of the 106 antisickling compounds emerge as potential drugs. This estimate is based on a comparison of inhibitory concentrations with free concentrations of oral drugs in human serum. Moreover, the expected therapeutic potential for each level of inhibition can be predicted from measurements of sickling times for cells from individuals with sickle syndromes of varying severity. Our results should motivate others to develop one or more of these 106 compounds into drugs for treating SCD.

PMID:36161945 | DOI:10.1073/pnas.2210779119

World J Gastrointest Oncol. 2022 Aug 15;14(8):1469-1477. doi: 10.4251/wjgo.v14.i8.1469.

ABSTRACT

Gastrointestinal stromal tumors (GISTs) are rare neoplasms with an estimated incidence from 0.78 to 1-1.5 patients per 100000. They most commonly occur in the elderly during the eighth decade of life affecting predominantly the stomach, but also the small intestine, the omentum, mesentery and rectosigmoid. The available treatments for GIST are associated with a significant rate of recurrent disease and adverse events. Thorough understanding of GIST's pathophysiology and translation of this knowledge into novel regimens or drug repurposing is essential to counter this challenge. The present review summarizes the existing evidence about the role of angiogenesis in GIST's development and progression and discusses its clinical underpinnings.

PMID:36160752 | PMC:PMC9412926 | DOI:10.4251/wjgo.v14.i8.1469

Immunopharmacol Immunotoxicol. 2022 Sep 26:1-33. doi: 10.1080/08923973.2022.2128370. Online ahead of print.

ABSTRACT

The level of precursors involved in the biosynthesis of glycosaminoglycan (GAG), glucosamine synthase, and N-acetyl glucosamine (NAG), are significantly reduced in inflammatory bowel disease (IBD). This results in deficient GAG content in mucosa, which eventually disrupts the gut wall integrity, provoking abnormal immunological responses. This is characterized by colossal liberation of inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukins (IL), and reactive oxygen species provoking colonic inflammation. D-glucosamine (D-GLU) is reported to suppress oxidative stress, and pro-inflammatory cytokines and acts as a starting material for biosynthesis of NAG. The potential of D-GLU and its combination with mesalamine (5-ASA) was investigated in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-instigated IBD in Wistar rats. Standard and test drugs were given orally for five days to separate groups of rats. Colonic inflammation was evaluated by disease activity score rate (DASR), colon/body weight ratio, colon length, diameter, colon pH, histological injury and score. Inflammatory biomarkers IL-1β, TNF-α, along with reduced glutathione (GSH), and malondialdehyde (MDA) were assessed. Combination of D-GLU +5-ASA significantly ameliorated severity of colonic inflammation by lowering DASR (P < 0.001) and colon/body weight ratio (P < 0.001), restored the colonic architecture and suppressed the histopathological score (P < 0.001), along with the absence of major adverse reactions. The combination suppressed the levels of inflammatory markers (P < 0.001) and MDA (P < 0.001) while enhancing GSH level (P < 0.001). In comparison to individual 5-ASA and D-GLU, combination of drugs significantly diminished colitis severity through their combined anti-inflammatory and antioxidant effects by acting on multiple targets simultaneously. The combination holds remarkable potential in the management of IBD.

PMID:36154797 | DOI:10.1080/08923973.2022.2128370

Curr Neuropharmacol. 2022 Sep 22. doi: 10.2174/1570159X20666220922150456. Online ahead of print.

ABSTRACT

Pediatric malignant brain tumors represent the most frequent cause of cancer-related deaths in childhood. The triad of the therapeutic scheme of surgery, radiotherapy and chemotherapy has improved patient management, but with minimal improvement in patients' prognosis. Emerging molecular targets and mechanisms have pointed out novel approaches and schemes for pediatric brain tumor therapy, enabling personalized medical treatment. Advances in the field of epigenetics and their interplay with genetic changes have enriched our knowledge of the molecular heterogeneity of these neoplasms and have revealed important genes that affect crucial signaling pathways involved in tumor progression. The great potential of epigenetic therapy lies mainly in the widespread location and the reversibility of epigenetic alterations, proposing a wide range of targeting options, including the possible combination with chemo- and immunotherapy, significantly increasing their efficacy. Epigenetic drugs, including inhibitors of DNA methyltransferases, histone deacetylases and demethylases, are currently being tested in clinical trials on pediatric brain tumors. Additional novel epigenetic drugs include protein and enzyme inhibitors that modulate epigenetic modification pathways, such as Bromodomain and Extraterminal (BET) proteins, Cyclin-Dependent Kinase 9 (CDK9), AXL, Facilitates Chromatin Transcription (FACT), BMI1, and CREB Binding Protein (CBP) inhibitors, which can be used either as standalone or in combination with current treatment approaches. In this review, we discuss recent progress on epigenetic drugs that could be possibly used against the most common malignant tumors of childhood, such as medulloblastomas, high- grade gliomas and ependymomas.

PMID:36154607 | DOI:10.2174/1570159X20666220922150456