Study on the Mechanism of Probucol Nanosuspension on Hyperlipidemic Pancreatitis and Regulation of Blood Lipid Function.

High-fat pancreatitis and hyperlipidemia refer to disorders of blood lipid metabolism caused by abnormally elevated blood lipids, and are risk factors for high-risk diseases such as atherosclerosis, coronary heart disease, and cerebral infarction. Hyperlipidemia is also a common disease that is common in modern people, and has a tendency to become younger. In this paper, probucol is made into a self-assembled probucol loaded nanosuspensions (SPN) using molecular selfassembly technology for research on improving its oral absorption. The main research contents include: preparation, prescription screening and characterization of physicochemical properties of SPN nanosuspensions; study of SPN intestinal cell uptake and in vivo dynamic behavior; research on the mechanism of SPN improving oral absorption of probucol and its gastrointestinal Preliminary Evaluation of Physiological Safety. And by using the method of intraperitoneal injection of SPN to interfere with the retrograde bile duct injection of SPN in the hyperlipidemia model, to make hyperlipidemia combined with severe acute pancreatitis to observe the severity of pancreatitis and lung injury; discuss the protective effect of SPN on hyperlipidemia combined with severe acute pancreatitis with lung injury and its mechanism.

Salinomycin Exerts Anticancer Effects on PC-3 Cells and PC-3-Derived Cancer Stem Cells In Vitro and In Vivo.

Salinomycin is an antibiotic isolated from Streptomyces albus that selectively kills cancer stem cells (CSCs). However, the antitumor mechanism of salinomycin is unclear. This study investigated the chemotherapeutic efficacy of salinomycin in human prostate cancer PC-3 cells. We found that cytotoxicity of salinomycin to PC-3 cells was stronger than to nonmalignant prostate cell RWPE-1, and exposure to salinomycin induced G2/M phage arrest and apoptosis of PC-3 cells. A mechanistic study found salinomycin suppressed Wnt/ß-catenin pathway to induce apoptosis of PC-3 cells. An in vivo experiment confirmed that salinomycin suppressed tumorigenesis in a NOD/SCID mice xenograft model generated from implanted PC-3 cells by inhibiting the Wnt/ß-catenin pathway, since the total ß-catenin protein level was reduced and the downstream target c-Myc level was significantly downregulated. We also showed that salinomycin, but not paclitaxel, triggered more apoptosis in aldehyde dehydrogenase- (ALDH-) positive PC-3 cells, which were considered as the prostate cancer stem cells, suggesting that salinomycin may be a promising chemotherapeutic to target CSCs. In conclusion, this study suggests that salinomycin reduces resistance and relapse of prostate tumor by killing cancer cells as well as CSCs.

Electrical stimulation influences chronic intermittent hypoxia-hypercapnia induction of muscle fibre transformation by regulating the microRNA/Sox6 pathway.

Chronic obstructive pulmonary disease can cause muscle fibre transformation due to chronic intermittent hypoxia-hypercapnia (CIHH). Studies have shown that high expression of Sox6 in muscle could suppress type-I fibres through downregulating the PPARß (peroxisome proliferator-activated receptor ß)/ERRγ (oestrogen-related receptor γ)/microRNA pathway. However, whether this pathway is involved in CIHH-induced muscle fibre transformation is unknown. Electrical stimulation (ES) is an effective approach to ameliorate muscle dysfunction. Here, we explored the effects of ES on CIHH-induced muscle fibre transformation and the microRNA/Sox6 pathway. After CIHH exposure, both the soleus (SOL) and gastrocnemius (GC) muscles showed decreased type-I fibres. The PPARß/ERRγ/mir-499&208b (PEM, for GC) and PPARß/mir-499&208b (PM, for SOL) signalling cascades were suppressed, followed by elevated Sox6 expression. Low frequency electrical stimulation (LFES) activated the PEM/PM pathway and enhanced type-I fibre numbers through suppressing Sox6 in SOL and GC. High frequency electrical stimulation (HFES) promoted type-I fibre expression through activating the PEM pathway in GC. Although PPARß expression and type-I fibres were suppressed in SOL after HFES, no significant change was found in mir-499&208b/Sox6 expression. These results suggest that the microRNA/Sox6 pathway is disturbed after CIHH. Both low and high frequency electrical stimulations induce muscle fibre transformation partly through regulating the microRNA/Sox6 pathway.

Electrical Stimulation Improves Rat Muscle Dysfunction Caused by Chronic Intermittent Hypoxia-Hypercapnia via Regulation of miRNA-Related Signaling Pathways.

Skeletal muscle dysfunction in chronic obstructive pulmonary disease (COPD) patients is common. Neuromuscular Electrical Stimulation (NMES) is a powerful exercise training that may relieve muscle dysfunction in COPD. This study investigated whether electrical stimulation may have atypical adaptations via activation of miRNA related pathways in counteracting COPD muscle dysfunction. Forty-eight male Sprague-Dawley rats were randomly assigned to 3 groups. With the exception of the rats in the control group, the experimental rats were exposed to chronic intermittent hypoxia-hypercapnia (CIHH) (9∼11%O2,5.5∼6.5%CO2) for 2 or 4 weeks. Electrical stimulation was performed immediately after each CIHH session. Following assessment of the running capacity, biopsy samples were obtained from the gastrocnemius of the rats. The miR-1, miR-133a and miR-133b levels were measured, as well as their related proteins: phosphorylation of Akt (p-AKT), PGC-1alpha (PGC-1α), histone deacetylase 4 (HDAC4) and serum response factor (SRF). Myosin heavy chainIIa (MHCIIa) and myosin heavy chainIIb (MHCIIb) were also measured to assess fiber type changes. After 2 weeks, compared with the controls, only miR-1 and miR-133a were significantly increased (p<0.05) in the exposure group. After 4 weeks, the exposure group exhibited a decreased running distance (p = 0.054) and MHCIIa-to-MHCIIb shift (p<0.05). PGC-1α (p = 0.051), nuclear HDAC4 (p = 0.058), HDAC4, p-AKT, PGC-1α and SRF was also significantly decreased (p<0.05). In contrast, miR-1 and miR-133a were significantly increased (p<0.05). Four weeks of electrical stimulation can partly reversed those changes, and miR-133b exhibited a transient increase after 2 weeks electrical stimulation. Our study indicate miRNAs may have roles in the response of CIHH-impaired muscle to changes during electrical stimulation.