RESUMO
An unprecedented spiro-C-glycoside adduct, heteryunine A (1), along with two uncommon alkaloids featuring a 2,3-diketopiperazine skeleton, heterpyrazines A (2) and B (3), were discovered in the roots of Heterosmilax yunnanensis. The detailed spectroscopic analysis helped to clarify the planar structures of these compounds. Compound 1, containing 7 chiral centers, features a catechin fused with a spiroketal and connects with a tryptophan derivative by a CC bond. Its complex absolute configuration was elucidated by rotating frame overhauser enhancement spectroscopy (ROESY), specific rotation, and the 13C nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculation. The possible biosynthetic routes for 1 were deduced. Compounds 1 and 2 showed significant antifibrotic effects and further research revealed that they inhibited the activation, migration and proliferation of hepatic stellate cells (HSCs) through suppressing the activity of Ras homolog family member A (RhoA).
RESUMO
Fourteen new 2-benzylbenzofuran O-glycosides (1-13, 15) and one new key precursor, diarylacetone (14) were isolated from the roots of Heterosmilax yunnanensis Gagnep, which all have characteristic 2,3,4-O-trisubstituted benzyl. Their structures were elucidated by 1D and 2D NMR, HRESIMS, UV and IR. The isolated compounds were assessed for their cardioprotective activities and compounds 1, 3 and 6 could significantly improve cardiomyocytes viability. Moreover, the mechanistic study revealed that these three compounds could significantly decrease intracellular ROS levels and maintain mitochondrial homeostasis upon hypoxia inducement. Consequently, 1, 3 and 6 might serve as potential lead compounds to prevent myocardial ischemia.
Assuntos
Benzofuranos , Glicosídeos , Raízes de Plantas , Glicosídeos/farmacologia , Glicosídeos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Raízes de Plantas/química , Benzofuranos/química , Benzofuranos/farmacologiaRESUMO
Notch signaling is highly conserved in most animals and plays critical roles during neurogenesis as well as embryonic development. Synthetic Notch-based systems, modeled from Notch receptors, have been developed to sense and respond to a specific extracellular signal. Recent advancement of synNotch has shown promise for future use in cellular engineering to treat cancers. However, synNotch from Morsut et al. (2016) has a high level of ligand-independent activation, which limits its application. Here we show that adding an intracellular hydrophobic sequence (QHGQLWF, named as RAM7) present in native Notch, significantly reduced ligand-independent activation. Our enhanced synthetic Notch receptor (esNotch) demonstrates up to a 14.6-fold reduction in ligand-independent activation, without affecting its antigen-induced activation efficiency. Our work improves a previously reported transmembrane receptor and provides a powerful tool to develop better transmembrane signaling transduction modules for further advancement of eukaryotic synthetic biology.
Assuntos
Engenharia Celular/métodos , Receptores Artificiais/química , Receptores Artificiais/metabolismo , Receptores Notch/química , Receptores Notch/metabolismo , Sequência de Aminoácidos , Antígenos/metabolismo , Membrana Celular/metabolismo , Clonagem Molecular/métodos , Células HEK293 , Humanos , Ligantes , Plasmídeos/genética , Domínios Proteicos , Proteólise , Receptores Notch/genética , Transdução de Sinais/genética , Anticorpos de Cadeia Única , Biologia Sintética/métodos , TransfecçãoRESUMO
PURPOSE: This study explored the clinical characteristics, diagnosis and treatments of primary blepharospasm. METHODS: In this retrospective analysis, 100 patients with blepharospasm were enrolled. Data were collected from medical records and face-to-face interviews with patients and their families. RESULTS: The age of onset was 56.4 ± 2.7 (range, 32-76 years). The duration between onset and accurate diagnosis was 38.7 ± 36.0 months (range, 2-120 months). Dry eyes occurred in 54% of the patients. The initial diagnostic accuracy was 10%. Dry eye syndrome, conjunctivitis/keratitis and myasthenia gravis caused the most confusion in the differential diagnosis. Regular botulinum toxin type A injections improved both eyelid spasms and subjective ocular symptoms in all patients. CONCLUSIONS: Regular botulinum toxin type A injections improved both eyelid spasms and subjective ocular symptoms in blepharospasm patients. The differentiation of primary blepharospasm differentiation from dry eye syndrome, conjunctivitis/keratitis and myasthenia gravis must be improved.