Multifunctional osthole liposomes and brain targeting functionality with potential applications in a mouse model of Alzheimer's disease.

Osthole (Ost) is a coumarin compound and a potential drug for Alzheimer's disease (AD). However, the effectiveness of Ost is limited by solubility, bioavailability, and low permeability of the blood-brain barrier. In this study, we constructed Ost liposomes with modified CXCR4 on the surface (CXCR4-Ost-Lips), and investigated the intracellular distribution of liposomes in APP-SH-SY5Y cells. In addition, the neuroprotective effect of CXCR4-Ost-Lips was examined in vitro and in vivo. The results showed that CXCR4-Ost-Lips increased intracellular uptake by APP-SH-SY5Y cells and exerted a cytoprotective effect in vitro. The results of Ost brain distribution showed that CXCR4-Ost-Lips prolonged the cycle time of mice and increased the accumulation of Ost in the brain. In addition, CXCR4-Ost-Lips enhanced the effect of Ost in relieving AD-related pathologies. These results indicate that CXCR4-modified liposomes are a potential Ost carrier to treat AD.

Efficacy of Sijunzi decoction on limb weakness in spleen Qi deficiency model rats through adenosine monophosphate-activated protein kinase/unc-51 like autophagy activating kinase 1 signaling.

OBJECTIVE: To investigate the efficacy of Sijunzi decoction () on limb weakness in a rat model of spleen Qi deficiency (SQD), and to study its effect on mitophagy in skeletal muscle through adenosine monophosphate-activated protein kinase (AMPK) / unc-51 like autophagy activating kinase 1 (ULK1) signaling. METHODS: SQD model rats were produced by fasting combined with forced swimming method for 15 d. After model assessment, rats were randomly divided into four groups of 10 [low/middle/high (L/M/H) Sijunzi decoction dose groups and a normal saline (S) group]. Limb holding power (HP) and body mass (BM) were measured after 2 weeks of treatment. Following euthanasia, quadriceps femoris were dissected and myofiber and mitochondrial morphology were observed by transmission electron microscopy (TEM). Mitochondrial membrane potential (MMP), adenosine triphosphatase (ATP) and reactive oxygen species (ROS) levels were determined using colorimetric methods, and immunoblot analysis of Microtubule-associated protein light chain 3 (LC3) and Sequestosome 1 (p62) was performed to monitor mitophagy and AMPK/ULK1 signaling. RESULTS: Compared with control (C) group rats, in the S group, HP was reduced, the myofiber Z line was disordered, mitochondria were scattered, and numerous vacuoles and mitophagy were observed. MMP and ATP levels were reduced, ROS levels were elevated, and LC3B expression, and p-AMPKα (Thr172)/AMPKα, p-ULK1 (Ser555)/ULK1, and p-Raptor (Ser792)/Raptor ratios were increased, while p62 expression and p-mTOR (Ser2448)/mTOR and p-ULK1 (Ser757)/ULK1 ratios were decreased. After treatment, compared with the S group, HP was improved in M and H groups but not in the L group. Mitophagy was reduced in M, H and L groups but the Z line was disordered and vacuolization remained in the L group. ATP levels were elevated in M, H and L groups, and MMPs were elevat-ed in M and H groups but not in the L group. ROS levels were decreased in M, H and L groups, as were LC3B expression and p-Raptor (Ser792)/Raptor ratios, while p62 expression and p-mTOR (Ser2448)/mTOR and p-ULK1 (Ser757)/ULK1 ratios were increased in M and H groups but not in the L group. p-AMPKα (Thr172)/AMPKα and p-ULK1 (Ser555)/ULK1 ratios were decreased in M, H and L groups. CONCLUSIONS: Sijunzi decoction improved HP, possibly by inhibiting mitophagy via suppression of AMPK/ULK1 signaling. This restored mitochondrial morphology and improved oxidative phosphorylation, which contributed to recovery of limb weakness in SQD model rats.