The innovative design of a delivery and real-time tracer system for anti-encephalitis drugs that can penetrate the blood-brain barrier.

As a "wall" between blood flow and brain cells, the blood-brain barrier (BBB) makes it really difficult for drugs to cross this barrier and work. This is particularly the case for pharmaceuticals of acute encephalitis therapies, largely excluded from the brain following systemic administration. Herein we report an advanced drug delivery system that can cross the BBB and target acute inflammation based on the controlled release of macrophage-camouflaged glow nanoparticles via a Trojan horse strategy. Benefiting from afterglow imaging that eliminates background interference and RAW 264.7 cells (RAW) with special immune homing and long-term tracking capabilities, polydopamine (PDA)-modified afterglow nanoparticles (ANPs) as near-infrared photo-responsive drug carriers in a controlled delivery system camouflaged by macrophages can penetrate the BBB by crossing the intercellular space and trigger the anti-inflammatory drug by photothermal conversion in the brain parenchyma dexamethasone (Dex) release, exhibiting good acute inflammation recognition and healing ability. APD@RAW was monitored to cross the BBB and image deep brain inflamed areas in a model of acute brain inflammation. Meanwhile, the delivered Dex mitigated the brain damage caused by inflammatory cytokines secretion (IL-6, TNF-α, and IL-1ß). Overall, this drug delivery system holds excellent potential for BBB penetrating and acute encephalitis therapies.

Co-overexpression of TRAIL and Smac sensitizes MDA-MB-231 cells to radiation through apoptosis depending on mitochondrial pathway.

Pro-apoptosis in cancer cells has been proposed as a beneficial therapeutic strategy for potentiating the anticancer effects of radiotherapy. TNF-related apoptosis inducing ligand (TRAIL) and Second mitochondria derived activator of caspase (Smac) can induce cell apoptosis. Herein, we designed a conditionally replicating adenoviral co-overexpression vector of TRAIL and Smac regulated by the Egr1 promoter, in which hTERT, E1A-E1B and E1B55K genes were inserted to achieve enhanced tumor targeting characteristics. After breast cancer MDA-MB-231 cells were infected and irradiated, cellular proliferation and colony formation were measured, apoptotic rate was detected by FCM after AnnexinV-FITC/PI staining. To explore the molecular mechanisms of apoptosis, mRNA and protein levels of TRAIL, Smac, Cytochrome c (Cyt c), death receptor 5 (DR5), caspase-8, -9 and -3 were measured by quantitative real-time PCR, ELISA and Western blot, and caspase-3 activity was detected using caspase-3 activity kits. The results showed that TRAIL and/or Smac overexpression enhanced proliferation inhibition and radio-sensitivity through apoptosis. In addition, the combination of IR and overexpression of TRAIL and/or Smac can activate more apoptosis in tumor cells, and the transcriptional levels and protein expressions of Cyt c, DR5, caspase-8, -9 and -3 had similar regularity with apoptotic changes, indicating the molecular mechanisms of TRAIL and Smac involves the mitochondrial pathway. Our findings may have implications for novel radiotherapy plans for breast tumor treatment.

Research progress of natural products interfering with cell signaling pathway in liver fibrosis.

Liver cirrhosis and hepatocellular carcinoma are the late stage of liver fibrosis. How to early use drugs to intervene in liver fibrosis is a prerequisite for the reversal of liver fibrosis. This paper mainly introduces a cell signaling transduction pathway in liver fibrosis and the intervention of natural products in order to provide theoretical basis for the treatment of liver fibrosis.

Pink1/PARK2/mROS-Dependent Mitophagy Initiates the Sensitization of Cancer Cells to Radiation.

Autophagy plays a double-edged sword for cancer; particularly, mitophagy plays important roles in the selective degradation of damaged mitochondria. However, whether mitophagy is involved in killing effects of tumor cells by ionizing radiation (IR) and its underlying mechanism remain elusive. The purpose is to evaluate the effects of mitochondrial ROS (mROS) on autophagy after IR; furthermore, we hypothesized that KillerRed (KR) targeting mitochondria could induce mROS generation, subsequent mitochondrial depolarization, accumulation of Pink1, and recruitment of PARK2 to promote the mitophagy. Thereby, we would achieve a new strategy to enhance mROS accumulation and clarify the roles and mechanisms of radiosensitization by KR and IR. Our data demonstrated that IR might cause autophagy of both MCF-7 and HeLa cells, which is related to mitochondria and mROS, and the ROS scavenger N-acetylcysteine (NAC) could reduce the effects. Based on the theory, mitochondrial targeting vector sterile α- and HEAT/armadillo motif-containing protein 1- (Sarm1-) mtKR has been successfully constructed, and we found that ROS levels have significantly increased after light exposure. Furthermore, mitochondrial depolarization of HeLa cells was triggered, such as the decrease of Na+K+ ATPase, Ca2+Mg2+ ATPase, and mitochondrial respiratory complex I and III activities, and mitochondrial membrane potential (MMP) has significantly decreased, and voltage-dependent anion channel 1 (VDAC1) protein has significantly increased in the mitochondria. Additionally, HeLa cell proliferation was obviously inhibited, and the cell autophagic rates dramatically increased, which referred to the regulation of the Pink1/PARK2 pathway. These results indicated that mitophagy induced by mROS can initiate the sensitization of cancer cells to IR and might be regulated by the Pink1/PARK2 pathway.