Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in Alzheimer's disease models.

Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in AD models.

Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy.

Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal autophagy inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD. Thus we synthesized various derivatives of Cory B to find more potent autophagy inducers with improved brain bioavailability. In this study, we evaluated the autophagy-enhancing effect of CB6 derivative and its neuroprotective action against PD in vitro and in vivo. We showed that CB6 (5-40 µM) dose-dependently accelerated autophagy flux in cultured N2a neural cells through activating the PIK3C3 complex and promoting PI3P production. In MPP+-treated PC12 cells, CB6 inhibited cell apoptosis and increased cell viability by inducing autophagy. In MPTP-induced mouse model of PD, oral administration of CB6 (10, 20 mg· kg-1· d-1, for 21 days) significantly improved motor dysfunction and prevented the loss of dopaminergic neurons in the striatum and substantia nigra pars compacta. Collectively, compound CB6 is a brain-permeable autophagy enhancer via PIK3C3 complex activation, which may help the prevention or treatment of PD.

Renoprotective activity of a new amide and a new hydroxycinnamic acid derivative from the fresh roots of Rehmannia glutinosa.

A new amide, named rehmagluamide (1), and a new hydroxycinnamic acid derivative, named nepetoidin F (2), together with six known compounds, 2'-O-methyluridine (3), puroglutamic acid (4), biliverdic acid (5), peterolactam (6), nicotinic acid (7), nicotinamide (8), were isolated from the fresh roots of Rehmannia glutinosa. All the structures of compounds were identified by the interpretation of their spectroscopic data and comparison with those reported in the literatures. The protective effects of compounds 1-7 on normal rat kidney tubule epithelioid (NRK-52e) cells injury induced by LPS were investigated. The results indicated that compounds 1, 2, and 7 exhibited protective effects against LPS-induced NRK 52e cells injury.

[DuzhongButiansu Capsules improve adenine-induced reproductive dysfunction in male rats].

OBJECTIVE: To study the effect of DuzhongButiansu Capsules (DBC) on adenine-induced reproductive dysfunction (RD) in male rats. METHODS: Eighty male SD rats were randomly divided into six groups, blank control (n = 8), solvent control (n = 8), RD model control (n = 16), Shengjing Capsules (SJC) (n = 16), low-dose DBC (n = 16) and high-dose DBC (n = 16). The RD model was made by intragastric administration of adenine at 200 mg/kg/d for 5 successive weeks in the latter four groups of animals, and in the meantime the rats in the latter three groups were treated intragastrically with SJC at 0.560 mg/kg/d and DBC at 0.242 and 0.968 mg/kg/d, respectively. At the end of the fourth week, all the rats were mated with female ones in a 1:1 ratio for 7 days. Then the male rats were killed and the right epididymides collected for detection of sperm concentration and motility, and the female ones sacrificed after fed for another 2 weeks and the numbers of pregnancies and fetal rats were recorded. The heart, liver, spleen, lung, kidney, thymus, testis, epididymis and seminal vesicle were harvested for obtainment of the visceral coefficients and semen parameters, observation of the histopathological changes in the testis, epididymis and kidneys by HE staining, measurement of the levels of serum T, E2, FSH and LH by ELISA, detection of the contents of serum glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), malondialdehyde (MDA) and creatinine (Scr), blood urea nitrogen (BUN), and determination of the expressions of Bax, Bcl-2, Caspase-3 and Caspase-9 proteins in the renal tissue by immunohistochemistry. RESULTS: No statistically significant difference was observed between the blank control and solvent control groups in any of the indexes obtained (P > 0.05).Compared with the blank controls, the rats in the RD model control group showed significantly decreased sperm concentration (ï¼»40.67 ± 7.37ï¼½vs ï¼»27.10 ± 2.72ï¼½ ×106/ml, P < 0.01), sperm motility (ï¼»54.75 ± 3.92ï¼½%vs ï¼»25.60 ± 4.83ï¼½%, P < 0.01) and pregnancy rate (85.7% vs 43.8%, P < 0.01). The rats in thelow- and high-dose DBCgroups exhibited remarkable increases in sperm concentration (ï¼»53.00 ± 4.55ï¼½% and ï¼»65.63 ± 12.47ï¼½% ×106/ml, P < 0.01) and sperm motility (ï¼»53.50 ± 8.83ï¼½% and ï¼»54.33 ± 7.92ï¼½ %, P < 0.01), and so did those in the high-dose DBC group in pregnancy rate (54.5%, P < 0.01).After medication, the animals showed markedly increased body weight and visceral coefficients of the testis, epididymis and seminal vesicle (P < 0.05 or P < 0.01), recovered morphology of the testis, epididymis and kidneys, reduced levels of Scr, BUN, FSH, LH and MDA in the serum (P < 0.05 or P < 0.01), increased contents of T, SOD and GSH-PX (P < 0.05 or P < 0.01), down-regulated expressions of Bax, Caspase-3 and Caspase-9 and up-regulated expression of Bcl-2 in the renal tissue (P < 0.05 or P < 0.01). CONCLUSIONS: DBC can improve adenine-induced reproductive dysfunction in male rats, which may be attributed to its effects of inhibiting the apoptosis of proteins, improving oxidative stress and elevating the levels of reproductive hormones.