Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022568 (keratitis)
 5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The free-living amebae Naegleria, Acanthamoeba, and Balamuthia cause rare but life-threatening infections. All three parasites can cause meningoencephalitis. Acanthamoeba can also cause chronic keratitis and both Balamuthia and Acanthamoeba can cause skin and systemic infections. There are minimal drug development pipelines for these pathogens despite a lack of available treatment regimens and high fatality rates. To identify anti-amebic drugs, we screened 159 compounds from a high-value repurposed library against trophozoites of the three amebae. Our efforts identified 38 compounds with activity against at least one ameba. Multiple drugs that bind the ATP-binding pocket of mTOR and PI3K are active, highlighting these compounds as important inhibitors of these parasites. Importantly, 24 active compounds have progressed at least to phase II clinical studies and overall 15 compounds were active against all three amebae. Based on central nervous system (CNS) penetration or exceptional potency against one amebic species, we identified sixteen priority compounds for the treatment of meningoencephalitis caused by these pathogens. The top five compounds are (i) plicamycin, active against all three free-living amebae and previously U.S. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis.
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PMID:Identification of plicamycin, TG02, panobinostat, lestaurtinib, and GDC-0084 as promising compounds for the treatment of central nervous system infections caused by the free-living amebae Naegleria, Acanthamoeba and Balamuthia. 3170 63

The bacterial keratitis causes viability loss and apoptosis in the corneal epithelial cells (CECs). The cyanidin-3-O-glucoside (C3G) benefits visual system and also possess anti-bacterial and anti-inflammatory potentials. In the current study, the effects of C3G on human CECs (HCECs) against bacterial lipopolysaccharide (LPS)-induced disorders were assessed, and the mechanism driving the protective effect was explored by focusing on let-7b-5p-mediated HMGA2/PI3K/Akt pathway. The HCECs were incubated LPS of P. aeruginosa to induce inflammation and apoptosis, and then treated with C3G. The changes in cell viability, apoptosis, and inflammation were detected. Moreover, the effects of LPS and C3G on let-7b-5p level and HMGA2/PI3K/Akt pathway activity were also assessed. Thereafter, the HCECs were further transfected with let-7b-5p inhibitor to confirm its role in the vision-protective effects of C3G. The interaction between let-7b-5p and HMGA2 was verified with dual luciferase assay. The LPS treatment suppressed viability and induced apoptosis and inflammation in HCECs, which was associated with the down-regulated let-7b-5p level and up-regulated HMGA2/PI3K/Akt pathway activity. The impairments of LPS on HCECs were attenuated by C3G: the compound increased cell viability and inhibited apoptosis and inflammation. The C3G also induced let-7b-5p level and inactivated HMGA2/PI3K/Akt pathway. However, after the inhibition of let-7b-5p, the protective effects of C3G on HCECs against LPS were blocked. The results of dual luciferase assay showed the direct binding let-7b-5p to the promoter of HMGA2 gene. It was inferred that the C3G could ameliorate the LPS-induced disorders in HCECs. The effect depended on the induced level of let-7b-5p, which then inhibited HMGA2/PI3K/Akt pathway.
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PMID:Cyanidin-3-O-Glucoside Attenuates Lipopolysaccharide-Induced Inflammation in Human Corneal Epithelial Cells by Inducing Let-7b-5p-Mediated HMGA2/PI3K/Akt Pathway. 3224 30