ABSTRACT
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor associated with limited treatment options and high drug resistance, presenting significant challenges in the pursuit of effective treatment strategies. Epigenetic modifications have emerged as promising diagnostic biomarkers and therapeutic targets for GBM. For instance, histone deacetylase 6 (HDAC6) has been identified as a potential pharmacological target for GBM. Furthermore, the overexpression of monoamine oxidase A (MAO A) in glioma has been linked to tumor progression, making it an attractive target for therapy. In this study, we successfully engineered HDAC-MB, an activatable multifunctional small-molecule probe with the goal of efficiently detecting and killing glioma cells. HDAC-MB can be selectively activated by HDAC6, leading to the "turn on" of near-infrared fluorescence and effective inhibition of MAO A, along with potent photodynamic therapy (PDT) effects. Consequently, HDAC-MB not only enables the imaging of HDAC6 in live glioma cells but also exhibits the synergistic effect of MAO A inhibition and PDT, effectively inhibiting glioma invasion and inducing cellular apoptosis. The distinctive combination of features displayed by HDAC-MB positions it as a versatile and highly effective tool for the accurate diagnosis and treatment of glioma cells. This opens up opportunities to enhance therapy outcomes and explore future applications in glioma theranostics.
Subject(s)
Glioblastoma , Glioma , Humans , Histone Deacetylase 6/pharmacology , Histone Deacetylase 6/therapeutic use , Glioma/diagnostic imaging , Glioma/drug therapy , Glioblastoma/pathology , Apoptosis , Monoamine Oxidase , Cell Line, Tumor , Histone Deacetylase Inhibitors/pharmacologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The radix of Paeonia lactiflora Pall. (PaeR) is a traditional Chinese medicine (TCM) clinically used for treating depression. Although it has been established that PaeR can protect the liver and alleviate depressive-like behaviors, its bioactive chemicals and antidepressant mechanism remain unclear. Our pilot study showed that PaeR reduced the expression of the L-tryptophan- catabolizing enzyme tryptophan 2,3-dioxygenase (TDO) in the livers of stress-induced depression-like mice. AIM OF THE STUDY: This study aimed to screen potential TDO inhibitors from PaeR and investigate the potential therapeutic use of TDO inhibition for treating depression. MATERIALS AND METHODS: Molecular docking, magnetic ligand fishing, and secrete-pair dual luminescence assay were conducted for in vitro ligand discovery and high-throughput screening of TDO inhibitors. Stable TDO overexpression was achieved in HepG2 cell lines to evaluate the TDO inhibitory activities of drugs in vitro by RT-PCR and Western blot analyses of TDO at mRNA and protein levels. In vivo validation of TDO inhibitory potency and evaluation of TDO inhibition as a potential therapeutic strategy for major depressive disorder (MDD) were performed using mice subjected to "3 + 1â³ combined stresses for at least 30 days to induce depression-like behaviors. A well-known TDO inhibitor, LM10, was evaluated in parallel. RESULTS: The PaeR extract significantly ameliorated depressive-like behaviors of stressed mice, attributed to inhibition of TDO expression and tryptophan modulation metabolism. After a comprehensive analysis of molecular docking, ligand fishing, and luciferase assay, paeoniflorin was screened as a TDO inhibitor from the PaeR extract. This compound, structurally different from LM10, potently inhibited human and mouse TDO in cell- and animal-based assays. The effects of TDO inhibitors on MDD symptoms were evaluated in a stress-induced depression-like mouse model. In mice, both inhibitors had beneficial effects on stress-induced depressive-like behavioral despair and unhealthy physical status. Moreover, both inhibitors increased the liver serotonin/tryptophan ratio and decreased the kynurenine/tryptophan ratio after oral administration, demonstrating in vivo inhibition of TDO activity. Our data substantiated the potential of TDO inhibition as a therapeutic strategy to improve behavioral activity and decrease despair symptoms in major depressive disorder. CONCLUSIONS: This study introduced a hitherto undocumented comprehensive screening strategy to identify TDO inhibitors in PaeR extract. Our findings also highlighted the potential of PaeR as a source of antidepressant constituents and pinpointed the inhibition of TDO as a promising therapeutic approach for managing major depressive disorder.
Subject(s)
Depressive Disorder, Major , Dioxygenases , Paeonia , Mice , Humans , Animals , Tryptophan/metabolism , Tryptophan Oxygenase/metabolism , Ligands , Molecular Docking Simulation , Pilot Projects , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolismABSTRACT
Super-resolution imaging provides a powerful approach to image dynamic biomolecule events at nanoscale resolution. An ingenious method involving tuning intramolecular spirocyclization in rhodamine offers an appealing strategy to design cell-permeable fluorogenic probes for super-resolution imaging. Nevertheless, precise control of rhodamine spirocyclization presents a significant challenge. Through detailed study of the structure-activity relationship, we identified that multiple key factors control rhodamime spirocyclization. The findings provide opportunities to create fluorogenic probes with tailored properties. On the basis of our findings, we constructed self-assembling rhodamine probes for no-wash live-cell confocal and super-resolution imaging. The designed self-assembling probe Rho-2CF3 specifically labeled its target proteins and displayed high ring-opening ability, fast labeling kinetics (<1 min), and large turn-on fold (>80 folds), which is very difficult to be realized by the existing methods. Using the probe, we achieved high-contrast super-resolution imaging of nuclei and mitochondria with a spatial resolution of up to 42 nm. The probe also showed excellent photostability and proved ideal for real-time and long-term tracking of mitochondrial fission and fusion events with high spatiotemporal resolution. Furthermore, Rho-2CF3 could resolve the ultrastructure of mitochondrial cristae and quantify their morphological changes under drug treatment at nanoscale. Our strategy thus demonstrates its usefulness in designing self-assembling probes for super-resolution imaging.
Subject(s)
Fluorescent Dyes , Mitochondria , Rhodamines/chemistry , Fluorescent Dyes/chemistry , Microscopy, Fluorescence/methods , ProteinsABSTRACT
Flavivirus and enterovirus can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases or even death. Since effective vaccine is currently unavailable against most of these deadly viruses, antiviral chemical drugs remain in urgent need. To meet this unmet demand, we developed a series of 10,10'-bis(trifluoromethyl) marinopyrrole A derivates bearing various substituents at C5'-positions, which exhibited impressive in vitro activities against flaviviruses (ZIKV, DENV, YFV, JEV) and enteroviruses (EV71, CA6, CA16). The lead compound 10,10'-bis(trifluoromethyl) marinopyrrole A 3 was highly effective against enteroviruses EV71 and CA16 in cultured cells, but with low inhibitory activities against flavivirus. Elaborately modified from compound 3, compounds 32 and 33 with sulfhydryl aliphatic chains were found as promising ZIKV and DENV inhibitor; pyrazine-containing compound 19 is a potent broad-spectrum flavivirus inhibitor; thiophene compound 15 exhibited prominent selective inhibitory effect against JEV-SA14, YFV-17D, in addition to broad-spectrum enterovirus inhibitory effect. These results thus suggest that the 5'-sulfhydryl derivates of 10,10'-bis(trifluoromethyl) marinopyrrole A may be promising lead compounds for the development of novel anti-flavivirus and anti-enterovirus drugs.
Subject(s)
Enterovirus Infections , Enterovirus , Flavivirus , Zika Virus Infection , Zika Virus , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Humans , PyrrolesABSTRACT
The aminated mimetics of 2-keto-3-deoxy-sugar acids such as the anti-influenza clinical drugs oseltamivir (Tamiflu) and zanamivir (Relenza) are important bioactive molecules. Development of synthetic methodologies for accessing such compound collections is highly desirable. Herein, we describe a simple, catalyst-free glycal diazidation protocol enabled by visible light-driven conditions. This new method requires neither acid promoters nor transition-metal catalysts and takes place at ambient temperature within 1-2 hours. Notably, the desired transformations could be promoted by thermal conditions as well, albeit with lower efficacy compared to the light-induced conditions. Different sugar acid-derived glycal templates have been converted into a range of 2,3-diazido carbohydrate analogs by harnessing this mild and scalable approach, leading to the discovery of new antiviral agents.