Shenxian-Shengmai Oral Liquid Reduces Myocardial Oxidative Stress and Protects Myocardium from Ischemia-Reperfusion Injury

Background/Aims: Shenxian-shengmai (SXSM) oral liquid, a Chinese patent compound medicine, has been used to treat sinus bradyarrhythmias induced by mild sick sinus syndrome in clinical practice. Myocardial ischemia, in particular in serious or right coronary-related heart diseases, can cause bradyarrhythmias and cardiac dysfunction. Moreover, reperfusion of ischemic myocardium is associated with additional myocardial damage known as myocardial ischemia-reperfusion (I/R) injury. This study was designed to evaluate the effects of SXSM on bradyarrhythmias and cardiac dysfunction induced by myocardial I/R injury, and to explore the underlying mechanisms. Methods: Administration of SXSM to adult male Sprague Dawley (SD) rats was achieved orally by gavage and control rats were given equivalent deionized water every day for 14 days. After the last administration, the heart was connected with the Langendorff perfusion apparatus and both groups were subjected to ischemia for 20 min followed by reperfusion for 40 min to induce myocardial I/R injury. Heart rate (HR), left ventricular developed pressure (LVDP), the maximal increase rate of left ventricular pressure (+dp/dtmax) and the maximal decrease rate of left ventricular pressure (-dp/dtmax) were recorded by a physiological signal acquisition system. The heart treated with ischemic preconditioning (IPC) for 3 times at a range of 5 min/time before ischemia served as a positive control group. The hearts without I/R injury served as control group. After reperfusion, superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) activities in the myocardium were determined by appropriate assay kits. Myocardial SOD1 and glutamate cysteine ligase catalytic subunit (GCLC) expression were assessed by western blot analysis. For the in vitro study, SXSM serum was prepared according to the serum pharmacological method and neonatal rat cardiomyocytes were isolated from the heart of new born SD rats. Neonatal rat cardiomyocytes were pretreated with SXSM serum and subjected to H2O2 or anoxia/ reoxygenation (A/R) treatment to induce oxidative damage. Cell viability was evaluated using a Cell Counting Kit-8 (CCK8) assay. Levels of reactive oxygen species (ROS), SOD, GSH and GSH-Px in cardiomyocytes were determined by appropriate assay kits. SOD1 and GCLC expression were assessed by western blot analysis. Buthionine-[S, R]-sulfoximine (BSO), a GCLC inhibitor, and SOD1 siRNA were also used for identifying the cardiac protective targets of SXSM. Results: SXSM and ischemic preconditioning (IPC) significantly increased heart rate during myocardial reperfusion and protected cardiac function against myocardial I/R injury, including an increase in left ventricular diastolic pressure (LVDP), the maximal increase rate of left ventricular pressure (+dp/dtmax) and the maximal decrease rate of left ventricular pressure (-dp/dtmax). We also found that SXSM and IPC improved the expansion of myocardial interstitium, the structural abnormality and morphological changes of cardiomyocytes induced by I/R injury. Meanwhile, SXSM protected cardiomyocytes against the oxidative damage induced by H2O2 and A/R injury through reducing intracellular ROS levels. Moreover, SXSM increased SOD activity through enhancing SOD1 expression and increased GSH content through promoting GCLC expression as well as GSH-Px activity. BSO and SOD1 siRNA counteracted anti-arrhythmic and cardiac protective effect of SXSM, suggesting that the therapeutic targets of SXSM might be SOD1 and GCLC. Conclusion: SXSM is effective in protecting the myocardium from I/R injury, with myocardial SOD1 and GCLC being the potential therapeutic targets

Intraspecific variation in cadmium accumulation in Arabidopsis halleri: a comparative study between a hyperaccumulator and an excluder

Arabidopsis halleri is one of the best plant models to study metal homeostasis and adaptation to extreme metallic environments. We took advantage of the existence of several non-metallicolous (NM) and metallicolous (M) populations to investigate the molecular and biochemical mechanisms underlying the large intraspecific variation of cadmium (Cd) accumulation and to contribute to a better understanding of Cd tolerance and adaptation to Cd contaminated soils. The A. halleri I16 population is considered as a Cd excluder limiting the translocation of Cd from the root to the shoot. Two genetically close A. halleri populations within the same genetic unit were compared: I30 NM population and I16 M population. The molecular mechanisms linked to the adaptation of I16 to metalliferous soil were investigated as part of my PhD project. The results supported that both alteration of cell wall (CW) composition and regulation of transporter genes played a role in limiting accumulation of metals in A. halleri I16. I16 (M) also compared to another metallicolous population from another genetic unit, the Cd hyperaccumulator PL22 (M) in a work before this PhD. Many differentially expressed genes between I16 and PL22 belonged to i) the CW category and ii) the metal transporter category, as the iron-regulated transporter (IRT1) which can transport iron (Fe), but also Cd, zinc (Zn), manganese (Mn), nickel (Ni) in A. thaliana and is believed to be a main pathway of Cd entry into the plants. Therefore, my PhD work focused on the role of CW and the role of IRT1 in the intraspecific variation of Cd accumulation between I16 and PL22. To analyse the CW part, Cd absorption capacity of CW polysaccharides, CW mono- and poly- saccharides contents and CW glycan profiles were compared between PL22 and I16. Results highlighted that pectin played a major role in the Cd adsorption in CW, and supported an indirect role for β-1,4-galactan (side chain of Rhamnogalacturonan I) in Cd translocation from the root to the shoot, possibly by a joint effect of regulating the length of Rhamnogalacturonan-I sidechains, the pectin structure and interactions between polysaccharides in the CW. In addition, GALACTAN SYNTHASE 1, BIIDXI and LEUNIG-HOMOLOG CW pectin modification-related genes were identified as new potential players involved in Zn translocation from roots to the shoots. To analyse the role of IRT1 in root Cd responses, the promoter and coding sequence of IRT1 from A. halleri PL22 and I16 A. halleri and from A. thaliana Col-0 were cloned, and their promoter activities were further studied via the GUS report in Fe deficient and/or Cd treatment conditions. The results highlighted that the IRT1 promoter sequences from A. halleri PL22 and I16 showed high similarity but were different from the IRT1 promoter of A. thaliana Col-0. Their activities were strongly induced by Fe deficient condition but sharply decreased when Cd was added to the Fe deficient medium or control medium. Moreover, a Fe/Cd competition experiment supported that Cd uptake and transport in PL22 and I16 are not affected by the Fe status. Finally, Cd tolerance and accumulation were also studied in seven (M and NM) A. halleri and A. arenosa populations. This thesis deepens our knowledge of Cd tolerance and Cd accumulation in the model species A. halleri and provides novel tools to manipulate Cd-accumulating in plants.Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

The list linear arboricity of planar graphs

The linear arboricity la(G) of a graph G is the minimum number of linear forests which partition the edges of G. An and Wu introduce the notion of list linear arboricity lla(G) of a graph G and conjecture that lla(G) = la(G) for any graph G. We confirm that this conjecture is true for any planar graph having Δ ≥ 13, or for any planar graph with Δ ≥ 7 and without i-cycles for some i ∈ {3,4,5}. We also prove that ⌈½Δ(G)⌉ ≤ lla(G) ≤ ⌈½(Δ(G)+1)⌉ for any planar graph having Δ ≥ 9

Hamiltonicity of 3tEC Graphs with α=κ+1

A set S of vertices in a graph G is a total dominating set of G if every vertex of G is adjacent to some vertex in S. The minimum cardinality of a total dominating set of G is the total domination number γtG of G. The graph G is total domination edge-critical, or γtEC, if for every edge e in the complement of G, γtG+e<γtG. If G is γtEC and γtG=k, we say that G is ktEC. In this paper, we show that every 3tEC graph with δG≥2 and αG=κG+1 has a Hamilton cycle

Intermittent Fasting Alleviates the Increase of Lipoprotein Lipase Expression in Brain of a Mouse Model of Alzheimer's Disease: Possibly Mediated by β-hydroxybutyrate

Intermittent fasting has been demonstrated to protect against Alzheimer's disease (AD), however, the mechanism is unclear. Histone acetylation and lipoprotein lipase (LPL) are involved in AD progression. Importantly, LPL has been documented to be regulated by histone deacetylases (HDACs) inhibitors (increase histone acetylation level) in adipocyte and mesenchymal stem cells, or by fasting in adipose and muscle tissues. In brain, however, whether histone acetylation or fasting regulates LPL expression is unknown. This study was designed to demonstrate intermittent fasting may protect against AD through increasing β-hydroxybutyrate, a HDACs inhibitor, to regulate LPL. We also investigated microRNA-29a expression associating with regulation of LPL and histone acetylation. The results showed LPL mRNA expression was increased and microRNA-29a expression was decreased in the cerebral cortex of AD model mice (APP/PS1), which were alleviated by intermittent fasting. No significant differences were found in the total expression of LPL protein (brain-derived and located in capillary endothelial cells from peripheral tissues) in the cerebral cortex of APP/PS1 mice. Further study indicated that LPL located in capillary endothelial cells was decreased in the cerebral cortex of APP/PS1 mice, which was alleviated by intermittent fasting. LPL and microRNA-29a expression were separately increased and down-regulated in 2 μM Aβ25−35-exposed SH-SY5Y cells, but respectively decreased and up-regulated in 10 μM Aβ25−35-exposed cells, which were all reversed by β-hydroxybutyrate. The increase of HDAC2/3 expression and the decrease of acetylated H3K9 and H4K12 levels were alleviated in APP/PS1 mice by intermittent fasting treatment, as well in 2 or 10 μM Aβ25−35-exposed cells by β-hydroxybutyrate treatment. These findings above suggested the results from APP/PS1 mice were consistent with those from cells treated with 2 μM Aβ25−35. Interestingly, LPL expression was reduced (0.2-folds) and microRNA-29a expression was up-regulated (1.7-folds) in HDAC2-silenced cells, but respectively increased (1.3-folds) and down-regulated (0.8-folds) in HDAC3-silenced cells. Furthermore, LPL expression was decreased in cells treated with microRNA-29a mimic and increased with inhibitor treatment. In conclusion, intermittent fasting inhibits the increase of brain-derived LPL expression in APP/PS1 mice partly through β-hydroxybutyrate-mediated down-regulation of microRNA-29a expression. HDAC2/3 may be implicated in the effect of β-hydroxybutyrate on microRNA-29a expression

Exploring the role and mechanism of Astragalus membranaceus and radix paeoniae rubra in idiopathic pulmonary fibrosis through network pharmacology and experimental validation

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic disease with an unclear etiology and no effective treatment. This study aims to elucidate the pathogenic mechanism networks involving multiple targets and pathways in IPF. Extracts and metabolites of Astragalus membranaceus (AM) and Radix paeoniae rubra (RPR), two well-known traditional Chinese medicines, have demonstrated therapeutic effects on IPF. However, the underlying mechanisms of AM and RPR remain unclear. Utilizing network pharmacology analysis, differentially expressed genes (DEGs) associated with IPF were obtained from the GEO database. Targets of AM and RPR were identified using the TCM Systems Pharmacology Database and Analysis Platform and SwissTargetPrediction. A protein–protein interaction (PPI) network was subsequently constructed and analyzed using the STRING database and Cytoscape software. Gene ontology enrichment analysis and kyoto encyclopedia of genes and genomes analysis were conducted using Metascape. Additionally, a component-target-pathway network and a Sankey diagram were employed to identify the main active components, and molecular docking was performed between these components and proteins encoded by key targets. Finally, in vivo studies were conducted based on network pharmacology. A total of 117 common targets between DEGs of IPF and drug targets were identified and included in the PPI network, in which AKT1, MAPK3, HSP90AA1, VEGFA, CASP3, JUN, HIF1A, CCND1, PTGS2, and MDM2 were predicted as key targets. These 117 targets were enriched in the PI3K-AKT pathway, HIF-1 signaling pathway, apoptosis, and microRNAs in cancer. Astragaloside III, (R)-Isomucronulatol, Astragaloside I, Paeoniflorin, and β-sitosterol were selected as the main active components. Docking scores ranged from − 4.7 to − 10.7 kcal/mol, indicating a strong binding affinity between the main active compounds and key targets. In vivo studies have indeed shown that AM and RPR can alleviate the pathological lung fibrotic damage caused by bleomycin treatment. The treatment with AM and RPR resulted in a reduction of mRNA levels for key targets AKT1, HSP90AA1, CASP3, MAPK3, and VEGFA. Additionally, the protein expression levels of AKT1, HSP90AA1, and VEGFA were also reduced. These results support the therapeutic potential of AM and RPR in ameliorating pulmonary fibrosis and provide insight into the molecular mechanisms involved in their therapeutic effects