Background: This study aims to isolate the α-glucosidase inhibitory compounds from mulberry leaves (Morus atropurpurea Roxb., Moraceae) and to develop an analytical method for quantification of the compounds. Methods: Four flavonoids, rutin (1), isoquercetin (2), kaempferol-3-O-rutinoside (3) and astragalin (4), were isolated by column chromatography from mulberry leaf water extracts (MWE). The α-glucosidase inhibitory activities of MWE and the four isolated compounds were evaluated by a microplate-based in vitro assay. The content of the isolated flavonoids in M. atropurpurea leaves purchased from different local herbal stores or collected in different locations was determined by high performance liquid chromatography. Results: The four flavonoids (1–4) showed α-glucosidase inhibitory activities, with rutin (1) and astragalin (4) showing high α-glucosidase inhibitory activities (IC₅₀ values of 13.19 ± 1.10 and 15.82 ± 1.11 μM, respectively). The total contents of the four flavonoids were different among eight samples examined, ranging from 4.34 mg/g to 0.53 mg/g. Conclusions: The four flavonoids in M. atropurpurea leaves could inhibit α-glucosidase activity.

Autophagy is a highly conserved degradation process for long-lived intracellular proteins and organelles mediated by lysosomes. Deficits in the autophagy-lysosome pathway (ALP) have been linked to a variety of human diseases, including neurodegenerative diseases, lysosomal storage disorders, and cancers. Transcription factor EB (TFEB) has been identified as a major regulator of autophagy and lysosomal biogenesis. Increasing evidence has demonstrated that TFEB activation can promote the clearance of toxic protein aggregates and regulate cellular metabolism. Traditional Chinese medicine (TCM)-derived natural products as important sources for drug discovery have been widely used for the treatment of various diseases associated with ALP dysfunction. Herein, we review (1) the regulation of TFEB and ALP; (2) TFEB and ALP dysregulation in human diseases; (3) TFEB activators from natural products and their potential uses.

The abnormal accumulation of α-synuclein (α-syn) is a crucial factor for the onset and pathogenesis of Parkinson’s disease (PD), and the autophagy-lysosome pathway (ALP) contributes to α-syn turnover. AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) regulate autophagy by initiating the macroautophagy cascade and promoting lysosomal biogenesis via increased transcription factor EB (TFEB) activity. Hence, activation of AMPK-mTOR-TFEB axis-mediated autophagy might promote α-syn clearance in PD. Harmol is a β-carboline alkaloid that has been extensively studied in a variety of diseases but rarely in PD models. In this study, we aimed to evaluate the effect and underlying mechanism of harmol in PD models in vitro and in vivo. We show that harmol reduces α-syn via ALP in a dose- and time-dependent manner in cell model that overexpressed human A53T mutant α-syn. We also demonstrate that harmol promotes the translocation of TFEB into the nucleus and accompanies the restoration of autophagic flux and lysosomal biogenesis. Importantly, harmol improves motor impairment and down-regulates α-syn levels in the substantia nigra and prefrontal cortex in the α-syn transgenic mice model. Further studies revealed that harmol might activate ALP through AMPK-mTOR-TFEB to promote α-syn clearance. These in vitro and in vivo improvements demonstrate that harmol activates the AMPK-mTOR-TFEB mediated ALP pathway, resulting in reduced α-syn, and suggesting the potential benefit of harmol in the treatment of PD.

Nine new melodinus-type alkaloids, melohemsines A-I (1–9), together with eight known ones were isolated from Melodinus hemselyanus. The structures of the new alkaloids, including their absolute configurations, were elucidated on the basis of comprehensive spectroscopic and electronic circular dichroism (ECD) analyses and X-ray diffraction. Compound 1 is the first melodinus-type alkaloid with a 6/6/5/5/6/3 hexacyclic ring skeleton system. Compounds 2–3 are the first natural melodinus-type alkaloids with a reduction in two carbon units at C-20.