Curcumin-laden exosomes target ischemic brain tissue and alleviate cerebral ischemia-reperfusion injury by inhibiting ROS-mediated mitochondrial apoptosis.

The pathogenesis of ischemic cerebrovascular disease has revealed that ischemia-reperfusion (I/R) injury often leads to aggravation of metabolic oxidative stress and blood-brain barrier (BBB) destruction, eventually causing secondary brain tissue damage. Accumulated reactive oxygen species (ROS) in focal ischemia activate mitochondria-mediated apoptosis and damage the BBB by degrading tight junction proteins (TJPs). Herein, we report macrophage-derived exosomes (Ex) loaded with curcumin (cur) as a multifunctional biomimetic delivery vehicle (Ex-cur) for targeting ischemic brain tissue and alleviating cerebral I/R injury by inhibiting ROS-mediated mitochondrial apoptosis in a transient cerebral ischemia rat model. The design principle relies on unique features of macrophage-derived exosomes and the natural ingredient cur. Specifically, cur can be entrapped within exosomes when incubated with murine macrophage RAW264.7 cells, and its stability is subsequently significantly improved. The resultant Ex-cur can target ischemic regions by leveraging the targeting migration capability of Ex driven by inflammation. Accumulated Ex-cur in ischemic regions is experimentally proven to be highly effective at reducing ROS accumulation by virtue of the antioxidant properties of cur. Using Ex-cur to down-regulate ROS accumulation in lesions, we alleviate BBB damage and suppress mitochondria-mediated neuronal apoptosis, which is confirmed by a series of relevant protein analysis. These findings demonstrate good therapeutic efficacy of Ex-cur for treating I/R injury, providing experimental evidence for the potential clinical benefits of Ex-cur for other modes of neuroprotection.

Plasma exosomes protect against cerebral ischemia/reperfusion injury via exosomal HSP70 mediated suppression of ROS.

AIMS: Ischemic stroke is the leading cause of severe disability and death worldwide. As the pathogenesis of stroke has not been clearly elucidated and the ability of current therapeutic drugs on crossing the blood-brain barrier (BBB) is extremely low, there is no effective strategy to treat stroke. We aim at investigating the specific advantages of using plasma exosomes (Pla-Exo) for targeting ischemic brain and exploring its underlying mechanism in neuroprotection. MAIN METHODS: Pla-Exo was obtained by a gradient ultracentrifugation of fresh plasma. The quantification of penetrated Pla-Exo through BBB was investigated in vitro BBB model, furthermore, the effects of Pla-Exo and exosomal HSP70 on cerebral ischemia/reperfusion injury were evaluated. KEY FINDINGS: Pla-Exo enhanced BBB crossing by specific interaction between Pla-Exo inherited heat shock protein 70 (HSP70) and endothelial Toll-like receptor 4 (TLR4). As expected, Pla-Exo increased HSP70 expression in the ischemic region through the transfer of HSP70, and led to HSP70 mediated suppression of ROS, thus alleviating cerebral ischemia/reperfusion (I/R) injury by attenuating the deterioration of BBB and preventing mitochondria damage. SIGNIFICANCE: These findings indicated that Pla-Exo can provide protection against ischemia-reperfusion injury via the regulation of HSP70 and it should be further studied as a potential candidate for protection against ischemic injury.

Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles.

It is reported that quercetin (Que) can prevent tau pathology and induce neuroprotection by improving cognitive and functional symptoms in the treatment of Alzheimer's disease (AD). However, its clinical application has been limited due to its poor brain targeting and bioavailability. Exosomes are considered as cargo carriers for intercellular communication and especially serve as a natural and important drug brain delivery platform for achieving better treatment of central neurological diseases. Here, we developed plasma exosomes (Exo) loaded with Que (Exo-Que) to improve the drug bioavailability, enhance the brain targeting of Que and potently ameliorate cognitive dysfunction in okadaic acid (OA)-induced AD mice. Our results showed that Exo-Que improved brain targeting of Que as well as significantly enhanced bioavailability of Que. Furthermore, compared with free Que, Exo-Que better relieved the symptoms of AD by inhibiting cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles (NFTs), suggesting its therapeutic potential for better treatment of AD.

Curcumin-primed exosomes potently ameliorate cognitive function in AD mice by inhibiting hyperphosphorylation of the Tau protein through the AKT/GSK-3ß pathway.

Alzheimer's disease (AD) is the progressive development of fatal neurodegenerative diseases. Owing to the unclearness of the pathogenesis of AD and the failure of the drug to cross the blood-brain barrier (BBB), there is currently a lack of effective diagnostic and therapeutic approaches in the treatment of AD. The aim of this study was to design exosomes (Exo) as a specifically designed carrier able to carry curcumin (cur) to prevent neuronal death in vitro and in vivo to alleviate the AD symptoms. Our results demonstrated that Exo improved the solubility and bioavailability of cur and increased drug penetration across the BBB by specific active targeting between Exo, inheriting the lymphocyte function-associated antigen 1 (LFA-1) and endothelial intercellular adhesion molecule 1 (ICAM-1). Exosomes derived from curcumin-treated (primed) cells (Exo-cur) can better prevent the death of neurons in vitro and in vivo to relieve the symptoms of AD by inhibiting phosphorylation of the Tau protein through activating the AKT/GSK-3ß pathway. Our results suggested that Exo-cur featured highly effective BBB-crossing via receptor-mediated transcytosis to access brain tissues and inhibited Tau phosphorylation, holding great potential in improving targeted drug delivery and the recovery of neuronal function in AD therapy.

Chitosan nanoparticles induced the antitumor effect in hepatocellular carcinoma cells by regulating ROS-mediated mitochondrial damage and endoplasmic reticulum stress.

In recent years, numerous studies have confirmed the role of chitosan nanoparticles (CS NPs) as a promising drug delivery carrier for improving the efficiency of anticancer drug in the treatment of cancer. However, the possible biological effects of CS NPs on tumour cells and underlying mechanisms are still unclear. Recently, reactive oxygen species (ROS)-mediated cell apoptosis has been implicated in the regulation of cell death. In this study, we found that CS NPs induced the massive generation of ROS and resulted in apoptosis of hepatocellular carcinoma cells (SMMC-7721) through activating the mitochondrial pathway and endoplasmic reticulum stress. These results suggest an important role of ROS in CS NPs-induced cancer cell death.

Clinical application of 13C-Hiolein breath test in assessing pancreatic exocrine insufficiency.

OBJECTIVE: To examine the feasibility and significance of 13C-Hiolein breath test in evaluating chronic pancreatitis-related exocrine insufficiency and efficacy of enzyme treatment. METHODS: The 13C-Hiolein breath test was used in 8 healthy volunteers (group 1), 8 chronic pancreatitis (CP) patients without steatorrhea (group 2), and 8 CP patients with steatorrhea (group 3). To evaluate the function of pancreatic exocrine, 13CO2 was determined following 13C-Hiolein diet. The 13C-Hiolein test was repeated in group 3 after enzyme supplement therapy. RESULTS: Administration of 13C-Hiolein diet resulted in significantly higher cumulative percent dose of 13C recovery per 6 h (cPDR/6 h) and maximal PDR (PDR(peak)) in the healthy controls (group 1) than the CP patients with steatorrhea (group 3) (11.22%+/-1.22% and 6.11%+/-0.59% vs 2.87%+/-0.73% and 1.53%+/-0.36%, respectively, both P<0.01). In the CP patients with steatorrhea (group 3), a repeated test after enzyme supplementation therapy showed a significant elevation of both cPDR/6 h and PDR(peak) (9.03%+/-0.84% and 2.33%+/-0.47%, both P<0.01 compared with those before enzyme treatment), but cPDR/6 h remained significantly lower than that in the healthy volunteers (group 1, P<0.05). Both cPDR and PDR(peak) in the CP patients without steatorrhea (group 2) were similar to those in the healthy controls (group 1, both P>0.05). CONCLUSION: The results of 13C-Hiolein breath test well reflect fat metabolism status in CP patients, and the test can be used to monitor the efficacy of pancreatic enzymes therapy.