Piperine promotes PI3K/AKT/mTOR-mediated gut-brain autophagy to degrade α-Synuclein in Parkinson's disease rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper longum L., a medicinal and food homologous herb, has a traditional history of use in treating gastrointestinal and neurological disorders. Piperine (PIP) the main alkaloid of P. longum, exists neuroprotective effects on various animal models of Parkinson's disease (PD). Nevertheless, the underlying mechanism, particularly the role of PIP in promoting gut-brain autophagy for α-Synuclein (α-Syn) degradation in PD, remains incompletely understood. AIM OF THE STUDY: To explore the role of PIP in regulating the gut-brain autophagy signaling pathway to reduce α-Syn levels in both the colon and substantia nigra (SN) of PD model rats. MATERIALS AND METHODS: Behavioral experiments were conducted to assess the impact of PIP on 6-hydroxydopamine (6-OHDA)-induced PD rats. The intestinal microbiome composition and intestinal metabolites were analyzed by metagenomics and GC-MS/MS. The auto-phagosomes were visualized by transmission electron microscopy. Immunohistochemistry, immunofluorescence, and western blotting were performed to assess the levels of tyrosine hydroxylase (TH), α-Syn, LC3II/LC3I, p62, and the PI3K/AKT/mTOR pathway in both the SN and colon of the rats. The pathway-related inhibitor and agonist were used to verify the autophagy mechanism in the SH-SY5Y cells overexpressing A53T mutant α-Syn (A53T-α-Syn). RESULTS: PIP improved autonomic movement and gastrointestinal dysfunctions, reduced α-Syn aggregation and attenuated the loss of dopaminergic neurons in 6-OHDA-induced PD rats. After oral administration of PIP, the radio of LC3II/LC3I increased and the expression of p62 was degraded, as well as the phosphorylation levels of PI3K, AKT and mTOR decreased in the SN and colon of rats. The effect of PIP on reducing A53T-α-Syn through the activation of the PI3K/AKT/mTOR-mediated autophagy pathway was further confirmed in A53T-α-Syn transgenic SH-SY5Y cells. This effect could be inhibited by the autophagy inhibitor bafilomycin A1 and the PI3K agonist 740 Y-P. CONCLUSIONS: Our findings suggested that PIP could protect neurons by activating autophagy to degrade α-Syn in the SN and colon, which were related to the suppression of PIP on the activation of PI3K/AKT/mTOR signaling pathway.

Extraction, Structures, Bioactivities and Structure-Function Analysis of the Polysaccharides From Safflower (Carthamus tinctorius L.).

Safflower (Carthamus tinctorius L.) is a herbal plant with a long history of clinical application worldwide, such as coronary heart disease, hypertension, dysmenorrhea and amenorrhea. It is also extensively used as an important oilseed plant for hundreds of years in some countries, like China, India, Mexico and the United States. Therefore, safflower is believed as a crop with dual values of medicine and economy as well. Safflower polysaccharides (SPS), from the plant, are believed as one of the most important biologically active components with multiple pharmacological properties, including anti-tumor, immune regulation, anti-oxidation, and anti-cerebral ischemia reperfusion injury effects. The polysaccharides, from bee pollen of safflower, named PBPC, also attract the attention of researchers because of their particular origin and bioactivities. Although the extraction, purification, structure and biological activities of SPS and PBPC have been studied for decades, there is not any available review both concerning SPS and PBPC. In this condition, this paper aims to systematically review the research progress in extraction, purification, structural characteristics, and bioactivities of SPS and PBPC, and provide basis for the in-depth study about their structure-bioactivity relationship. It will serve as a methodological outline for further research in fields of new drug discovery and clinical application of SPS or PBPC, and simultaneously remind us of unresolved problems noted in the polysaccharide research.