Inhibition of MMP-2 and MMP-9 attenuates surgery-induced cognitive impairment in aged mice.

BACKGROUND: The inhibition of matrix metalloproteinases (MMPs) has shown potential in the treatment of various neurodegenerative diseases, and perioperative neurocognitive disorders (PND) is accompanied by the increased expression of MMP-2 and MMP-9 in the hippocampus. However, the effect of inhibiting MMP-2 and MMP-9 on PND is not clear. In this study we aimed to evaluate the effects of inhibiting MMP-2 and MMP-9 on cognitive function in the aged mice after surgery, in order to find a possible target for the prevention and treatment of PND METHODS: In this study, 14-month-old C57BL/6 mice were used to establish a PND model by tibial fracture surgery and sevoflurane anesthesia. Three days later, part of the mice were subjected to cognitive assessment and the other was sacrificed for biochemical analysis. We used the Novel object recognition test and Fear conditioning test to evaluate the postoperative cognitive function of mice. The expression of mmp-2 and MMP-9 was detected by western blotting. We also examined the expression of claudin-5 and occludin using Western blotting, and the activation of microglia and astrocytes using immunofluorescence. RESULTS: The results showed that surgery increased the expression of MMP-2 and MMP-9 in the hippocampus of mice, accompanied by cognitive impairment, decreased expression of claudin-5 and occludin, and increased activation of microglia and astrocytes. However, inhibition of MMP-2 and MMP-9 expression by SB-3CT reversed these changes. CONCLUSIONS: Our study shows that inhibition of MMP-2 and MMP-9 alleviates anesthesia/surgery-induced cognitive decline by increasing BBB integrity and inhibiting glial cell activation.

Sugammadex Is Associated With Reduced Pulmonary Complications in Patients With Respiratory Dysfunction.

INTRODUCTION: Use of sugammadex is associated with fewer postoperative pulmonary complications (PPCs). This study investigated the relationship between sugammadex and PPCs in specific patients with respiratory dysfunction. MATERIALS AND METHODS: We reviewed the electronic medical and anesthesia records of patients with respiratory dysfunction who underwent laparoscopic gastric or intestinal surgery at a single center between May 1, 2018 and December 31, 2019. The patients were divided into the sugammadex group and the nonsugammadex group, based on whether they received sugammadex or neostigmine. Binary logistic regression analyses were used to characterize the differences in incidence of PPC. RESULTS: A total of 112 patients were included, of which 46 patients (41.1%) received sugammadex. In the logistic regression analysis, the incidences of PPC were fewer in the sugammadex group. Postoperative fever (odds ratio [OR] 0.330; 95% confidence interval [CI] 0.137-0.793, P = 0.0213), postoperative intensive care unit admission (OR 0.204; 95% CI 0.065-0.644, P = 0.007), cough (OR 0.143; 95% CI 0.061- 0.333, P < 0.001), pleural effusion (all) (OR: 0.280; 95% CI 0.104- 0.759, P = 0.012), pleural effusion (massive) (OR: 0.142; 95% CI 0.031- 0.653, P = 0.012), and difficulty in breathing (OR: 0.111; 95% CI 0.014-0.849, P = 0.039) showed significant differences between the two groups. CONCLUSIONS: Sugammadex is associated with a reduction in PPC in patients with respiratory dysfunction.

Anti-Inflammatory and Antioxidant Effects of Acetyl-L-Carnitine on Atherosclerotic Rats.

BACKGROUND The purpose of the present study was to evaluate the regulatory effects of acetyl-L-carnitine (ALCAR) on atherosclerosis in Wister rats and to explore its anti-atherosclerotic mechanism. MATERIAL AND METHODS We randomly divided 32 Wister rats into 4 groups: a normal diet group (control group, n=8), a normal diet+ALCAR group (ALCAR group, n=8), an atherosclerosis group (AS group, n=8), and an atherosclerosis+ALCAR group (AS+ALCAR group, n=8). The serum lipid distribution, oxidative stress, inflammatory factors and adiponectin (APN) in the blood, and heart and aortic tissues were determined using the standard assay kits, xanthine oxidase method, and ELISA, respectively. HE staining was performed to observe aortic pathology structure change, and the level of angiotensin II (AngII) in the aorta was assessed using radioimmunoassay. In addition, real-time quantitative PCR and Western blot analysis were applied to detect the expression of iNOS, IL-1ß, TNF-alpha, and CRP in the aortic and heart tissues. RESULTS Compared with the AS group, the levels of serum TC, TG, LDL, and VLDL in rats decreased significantly, while HDL level significantly increased in the AS+ALCAR group. ALCAR administration enhanced the SOD and GSH-Px activities and decreased MDA activity. APN level was significantly elevated in the AS group, but ALCAR had no significant effect on APN. Further, ALCAR reduced the expressions of inflammation factors TNF-alpha, IL-1ß, iNOS, and CRP, and the concentration of AngII in serum, aortic, and heart tissues. CONCLUSIONS ALCAR can inhibit the expressions of inflammatory factors and antioxidation to suppress the development of atherosclerosis by adjusting blood lipid in the myocardium of AS rats.

ADAR1p150 Forms a Complex with Dicer to Promote miRNA-222 Activity and Regulate PTEN Expression in CVB3-Induced Viral Myocarditis.

Adenosine deaminases acting on RNA (ADAR) are enzymes that regulate RNA metabolism through post-transcriptional mechanisms. ADAR1 is involved in a variety of pathological conditions including inflammation, cancer, and the host defense against viral infections. However, the role of ADAR1p150 in vascular disease remains unclear. In this study, we examined the expression of ADAR1p150 and its role in viral myocarditis (VMC) in a mouse model. VMC mouse cardiomyocytes showed significantly higher expression of ADAR1p150 compared to the control samples. Coimmunoprecipitation verified that ADAR1p150 forms a complex with Dicer in VMC. miRNA-222, which is involved in many cardiac diseases, is highly expressed in cardiomyocytes in VMC. In addition, the expression of miRNA-222 was promoted by ADAR1p150/Dicer. Among the target genes of miRNA-222, the expression of phosphatase-and-tensin (PTEN) protein was significantly reduced in VMC. By using a bioinformatics tool, we found a potential binding site of miRNA-222 on the PTEN gene's 3'-UTR, suggesting that miRNA-222 might play a regulatory role. In cultured cells, miR-222 suppressed PTEN expression. Our findings suggest that ADAR1p150 plays a key role in complexing with Dicer and promoting the expression of miRNA-222, the latter of which suppresses the expression of the target gene PTEN during VMC. Our work reveals a previously unknown role of ADAR1p150 in gene expression in VMC.

Aconitine induces apoptosis in H9c2 cardiac cells via mitochondria­mediated pathway.

Aconitine, a diterpenoid alkaloids derived from Aconitum plants, is widely employed to treat various diseases. The aim of the present study was to investigate the apoptotic effect of aconitine in H9c2 cardiac cells. H9c2 cell apoptosis induced by aconitine was detected by a Cell Counting kit­8 assay, DAPI staining, Annexin V­FITC/propidium iodide double staining and western blotting. The effects of aconitine on reactive oxygen species levels and mitochondrial membrane potential were confirmed by fluorescence microscopy and flow cytometry. In addition, ATP contents were determined using a ATP­dependent bioluminescence assay kit. The levels of peroxisome proliferator activated receptor Î³ co­activator 1α (PGC­1α) expression and apoptosis­associated proteins including Caspase­3, B­cell lymphoma 2 (Bcl­2), Bcl­2­associated X protein (Bax) and Cytochrome c were also assessed. Taken together, the results indicated that aconitine may inhibit cell viability, decrease PGC­1α expression, induce mitochondrial dysfunctions, upregulate Cytochrome c, Bax and Caspase­3, and downregulate Bcl­2, suggesting that aconitine may induce apoptosis through mitochondria­mediated signaling pathways in H9c2 cells.

Serum Amyloid a Promotes Visfatin Expression in Macrophages.

Visfatin has been reported to exert an important role in the development of atherosclerosis. However, the mechanism that regulated the expression of Visfatin has not been elucidated yet. This study aimed to investigate the effect of SAA on the regulation of Visfatin, as well as the potential pathway. After RAW264.7 macrophages and primary monocytes were stimulated with SAA, the mRNA and protein expression of Visfatin was detected with real-time PCR and western blot, respectively. The concentration of Visfatin in the supernatant was measured with ELISA. Formyl peptide receptor 2 (FPR2) agonist (WKYMVm) and inhibitor (WRW(4)), extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor (PD98059), and peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist (Rosiglitazone) and inhibitor (GW9662) were used to investigate the mechanism of regulation of Visfatin. The results demonstrated that SAA upregulated Visfatin expression in cultured RAW264.7 macrophages and in the primary monocytes. WRW(4) decreased SAA-induced Visfatin production, while WKYMVm could induce Visfatin expression. PD98059 reduced SAA-induced Visfatin production. What is more, GW9662 inhibited SAA-induced Visfatin production, while Rosiglitazone promoted Visfatin expression. These results demonstrate that SAA upregulates Visfatin expression via a FPR2/ERK1/2/PPAR-γ signaling pathway.

Salvianolic acid A suppresses CCL-20 expression in TNF-α-treated macrophages and ApoE-deficient mice.

OBJECTIVES: The CC chemokine ligand-20 (CCL-20)/macrophage inflammatory protein-3α has been seen as one of the most important chemokines and played a key role in atherogenesis, but the mechanism that underlies the regulation of CCL-20 has not been established clearly yet. The aim of this study was to investigate the influence of salvianolic acid A (SAA) on the expression of CCL-20 in macrophages and ApoE-deficient (ApoE) mice. METHODS: The expression of CCL-20 was detected both at protein and messenger RNA levels in RAW264.7 cells. We validated the result in ApoE mice that were intraperitoneally injected with SAA. Phosphorylation of p38 mitogen-activated protein kinase was detected with Western blot, and inhibitor of p38 was used to investigate the mechanism of regulation of CCL-20. Hematoxylin and eosin and Oil-Red-O staining were used to evaluate the atherosclerotic lesions and lipid accumulation in ApoE mice. Immunohistochemical analysis was used to detect the expressions of CCL-20 and CCR6 in the atherosclerotic lesions. Immunofluorescent analysis was used to certify the origination of CCL-20. RESULTS: Recombinant tumor necrosis factor-α (TNF-α) upregulated CCL-20 production in dose- and time-dependent manners in RAW264.7 cells. The activity of TNF-α-induced CCL-20 production seemed to be significantly suppressed by SAA. Using p38 mitogen-activated protein kinase inhibitor, we found that p38 mediated the effects of TNF-α- and SAA-induced CCL-20 expression changes. In addition, immunohistochemical analysis of aortic root of ApoE mice also demonstrated that the expressions of CCL-20 and CCR6 were both downregulated significantly with SAA treatment. Furthermore, treatment of SAA inhibited the progression of the atherosclerotic plaques and lipid accumulation. CONCLUSIONS: These results demonstrate that TNF-α increased but SAA suppressed CCL-20 production significantly via a novel mechanism.