Therapeutic Effects of Salvianolic Acid B on Angiotensin II-Induced Atrial Fibrosis by Regulating Atrium Metabolism via Targeting AMPK/FoxO1/miR-148a-3p Axis.

The present study highlights the effects of salvianolic acid B (Sal B) on angiotensin II (Ang II)-activated atrial fibroblasts as well as the associated potential mechanism from the metabonomics perspective. Metabolic profile analysis performed an optimal separation of the Ang II and control group, indicating a recovery impact of Sal B on Ang II-activated fibroblasts (FBs). We found that metabolite levels in the Ang II + Sal B group were reversed to normal. Moreover, 23 significant metabolites were identified. Metabolic network analysis indicated that these metabolites participated in purine metabolism and FoxO signaling pathway. We found that Sal B activated AMP-activated protein kinase (AMPK) phosphorylation, which further promoted FoxO1 activation and increased miR-148a-3p level. We further verified that Sal B modulate the abnormal AMP, phosphocreatine, glutathione (GSH), and reactive oxygen species (ROS) production in Ang II-stimulated FBs. Collectively, Sal B can protect the Ang II-activated FBs from fibrosis and oxidative stress via AMPK/FoxO1/miRNA-148a-3p axis.

MicroRNA­296­5p downregulated AKT2 to inhibit hepatocellular carcinoma cell proliferation, migration and invasion.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy in men, and the seventh in women worldwide. Despite development in the therapy of HCC, the prognosis of HCC patients remains poor. Therefore, it is of great significance to explore the molecular mechanism underlying HCC progression, and investigate novel therapeutic strategies for the treatments of HCC. MicroRNAs (miRs) are known to be involved in the pathogenesis of HCC. The present study aimed to investigate the expression patterns and potential roles of miR­296­5p in HCC. Results revealed that miR­296­5p was frequently downregulated in HCC tissue samples and cell lines. Additionally, reduced miR­296­5p expression levels were correlated with tumor size, TNM stage and metastasis in HCC. Gain­of­function demonstrated that miR­296­5p inhibited HCC cell proliferation, migration and invasion in vitro. Furthermore, AKT2 was identified as a novel direct and functional target of miR­296­5p in HCC. These findings indicated that miR­296­5p/AKT2 axis serves important roles in HCC carcinogenesis and progression, and miR­296­5p/AKT2 based target therapy hampers HCC tumor growth and metastasis.

Target deletion of complement component 9 attenuates antibody-mediated hemolysis and lipopolysaccharide (LPS)-induced acute shock in mice.

Terminal complement membrane attack complex (MAC) formation is induced initially by C5b, followed by the sequential condensation of the C6, C7, C8. Polymerization of C9 to the C5b-8 complex forms the C5b-9 (or MAC). The C5b-9 forms lytic or non lytic pores in the cell membrane destroys membrane integrity. The biological functionalities of MAC has been previously investigated by using either the mice deficient in C5 and C6, or MAC's regulator CD59. However, there is no available C9 deficient mice (mC9(-/-)) for directly dissecting the role of C5b-9 in the pathogenesis of human diseases. Further, since C5b-7 and C5b-8 complexes form non lytic pore, it may also plays biological functionality. To better understand the role of terminal complement cascades, here we report a successful generation of mC9(-/-). We demonstrated that lack of C9 attenuates anti-erythrocyte antibody-mediated hemolysis or LPS-induced acute shock. Further, the rescuing effect on the acute shock correlates with the less release of IL-1ß in mC9(-/-), which is associated with suppression of MAC-mediated inflammasome activation in mC9(-/-). Taken together, these results not only confirm the critical role of C5b-9 in complement-mediated hemolysis and but also highlight the critical role of C5b-9 in inflammasome activation.

Effects of intraperitoneal hydrogen injection on nitric oxide synthase mRNA and malondialdehyde following limb ischemia-reperfusion in rabbits.

OBJECTIVE: The purpose of this study was to investigate the effects of intraperitoneal hydrogen (H2) injection on the mRNA expression levels of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) as well as the serum malondialdehyde (MDA) level in a rabbit model of limb ischemia-reperfusion (I/R)-induced skeletal muscle injury. METHODS: To establish the hind limb I/R animal model, 30 rabbits were randomly assigned to one of 3 groups: sham, I/R, and ischemia-reperfusion + H2 (IRH). An intraperitoneal injection of H2 was given to the IRH group, while an equivalent amount of air was given to the sham and I/R groups. At 3, 6, 12, and 24 h after reperfusion, serum MDA level as well as skeletal muscle iNOS and eNOS mRNA expression levels were determined. RESULTS: Both iNOS mRNA expression and serum MDA levels were higher in the I/R group than the sham group (p<0.01) and lower in the IRH group than the I/R group (p<0.01, p<0.05, respectively) at various time points after reperfusion. The eNOS mRNA expression level exhibited no significant difference between the I/R and sham groups after reperfusion but was significantly higher in the IRH group than in the sham group (p<0.01, p<0.05, respectively). CONCLUSION: During the I/R process, the expression of iNOS mRNA was up-regulated along with an increase in MDA. Intraperitoneal injection of H2 can down-regulate iNOS mRNA expression and up-regulate eNOS mRNA expression in the I/R process, suggesting a protective effect of H2 in I/R-induced skeletal muscle injury.

Effects of 3,4-dihydroxyacetophenone on the hypercholesterolemia-induced atherosclerotic rabbits.

3,4-Dihydroxyacetophenone (3,4-DHAP) is one herbal extract from bald Mao-dong-qing leaves. We reported that 3,4-DHAP had anti-inflammatory function by decreasing tumor necrosis factor-α (TNF-α) secretion in macrophages. The aim of the study was to examine the effects of 3,4-DHAP on plasma and liver lipids, plasma alanine aminotranferase (ALT) and TNF-α level, vascular cell adhesion molecule-1 (VCAM-1) expression, plaque vulnerability and vascular inflammation in hypercholesterolemia-induced atherosclerotic rabbits. Male New Zealand white rabbits were randomized into negative control, positive control, 3,4-DHAP and simvastatin groups. From weeks 2 to 12, the rabbits were treated with 3,4-DHAP or simvastatin. At weeks 12, all the animals were sacrificed. Plasma lipids and ALT were measured using the enzymatic endpoint method. Plasma TNF-α was measured using enzyme-linked immuno sorbent assay (ELISA). Liver lipids concentrations were estimated using commercial kits. The expression of VCAM-1 was measured using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Histological analysis was used to evaluate the pathologic changes of rabbit aortas. The results showed that 3,4-DHAP markedly lowered plasma and liver lipids, lowered plasma ALT and TNF-α levels compared with the positive control group. VCAM-1 mRNA and protein were markedly inhibited by 3,4-DHAP. Decreased aortic plaque instability was evident in 3,4-DHAP-treated rabbits, as demonstrated by a thickened elastic layer, increased vascular smooth muscle cells (VSMCs) accumulation in the plaques, less neointima hyperplasia and macrophages recruitment. 3,4-DHAP may attenuate the progression of atherosclerotic lesions and stabilize plaques by lowering plasma lipids, the number of macrophages and the expression of VCAM-1, while increasing the number of VSMCs in the atherosclerotic plaques.