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Efficacy and safety of the injection of the traditional Chinese medicine salviae miltiorrhizae and ligustrazine hydrochloride for the treatment of perioperative period of fracture: A meta-analysis of randomized controlled trials.
Xie, J, Chen, S, Ding, S
Medicine. 2020;(16):e19777
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Abstract
BACKGROUND The injection of the traditional Chinese patent medicine salviae miltiorrhizae and ligustrazine hydrochloride injection (SMLHI) has been widely used in treatment of various diseases such as angina pectoris or ischemic stroke in China. We aim to evaluate the efficacy and safety of SMLHI for the treatment of perioperative period of fracture. METHODS A systematic literature search was performed in seven medical databases from their inception until February 2019. 16 studies with randomized controlled trials, totaling 1589 patients, were included in this meta-analysis. The included studies were assessed by the cochrane risk of bias and analyzed by Review Manager 5.3 software. RESULTS The meta-analysis showed that SMLHI for the treatment of perioperative period of fracture was significantly better compared with the control group in terms of the total effective rate. The result showed that SMLHI could significantly reduce the risk of deep vein thrombosis and inflammatory cytokines. Furthermore, the result showed that SMLHI could significantly improve the coagulation function indexes such as prothrombin time, plasma fibrinogen and D-Dimer (P < .0001). CONCLUSIONS This meta-analysis demonstrated that SMLHI may be more effective and safe for the treatment of perioperative period of fracture. However, further and higher quality randomized controlled trials are required to prove treatment outcome.
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Coelenterazine-Dependent Luciferases as a Powerful Analytical Tool for Research and Biomedical Applications.
Krasitskaya, VV, Bashmakova, EE, Frank, LA
International journal of molecular sciences. 2020;(20)
Abstract
: The functioning of bioluminescent systems in most of the known marine organisms is based on the oxidation reaction of the same substrate-coelenterazine (CTZ), catalyzed by luciferase. Despite the diversity in structures and the functioning mechanisms, these enzymes can be united into a common group called CTZ-dependent luciferases. Among these, there are two sharply different types of the system organization-Ca2+-regulated photoproteins and luciferases themselves that function in accordance with the classical enzyme-substrate kinetics. Along with deep and comprehensive fundamental research on these systems, approaches and methods of their practical use as highly sensitive reporters in analytics have been developed. The research aiming at the creation of artificial luciferases and synthetic CTZ analogues with new unique properties has led to the development of new experimental analytical methods based on them. The commercial availability of many ready-to-use assay systems based on CTZ-dependent luciferases is also important when choosing them by first-time-users. The development of analytical methods based on these bioluminescent systems is currently booming. The bioluminescent systems under consideration were successfully applied in various biological research areas, which confirms them to be a powerful analytical tool. In this review, we consider the main directions, results, and achievements in research involving these luciferases.
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Pulcherrimin formation controls growth arrest of the Bacillus subtilis biofilm.
Arnaouteli, S, Matoz-Fernandez, DA, Porter, M, Kalamara, M, Abbott, J, MacPhee, CE, Davidson, FA, Stanley-Wall, NR
Proceedings of the National Academy of Sciences of the United States of America. 2019;(27):13553-13562
Abstract
Biofilm formation by Bacillus subtilis is a communal process that culminates in the formation of architecturally complex multicellular communities. Here we reveal that the transition of the biofilm into a nonexpanding phase constitutes a distinct step in the process of biofilm development. Using genetic analysis we show that B. subtilis strains lacking the ability to synthesize pulcherriminic acid form biofilms that sustain the expansion phase, thereby linking pulcherriminic acid to growth arrest. However, production of pulcherriminic acid is not sufficient to block expansion of the biofilm. It needs to be secreted into the extracellular environment where it chelates Fe3+ from the growth medium in a nonenzymatic reaction. Utilizing mathematical modeling and a series of experimental methodologies we show that when the level of freely available iron in the environment drops below a critical threshold, expansion of the biofilm stops. Bioinformatics analysis allows us to identify the genes required for pulcherriminic acid synthesis in other Firmicutes but the patchwork presence both within and across closely related species suggests loss of these genes through multiple independent recombination events. The seemingly counterintuitive self-restriction of growth led us to explore if there were any benefits associated with pulcherriminic acid production. We identified that pulcherriminic acid producers can prevent invasion by neighboring communities through the generation of an "iron-free" zone, thereby addressing the paradox of pulcherriminic acid production by B. subtilis.
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Rational magnetic modification of N,N-dioxidized pyrazine ring expanded adenine and thymine: a diradical character induced by base pairing and double protonation.
Chen, D, Bu, Y
Physical chemistry chemical physics : PCCP. 2019;(36):20095-20106
Abstract
Rational modification of biomolecules especially DNA base pairs for the theoretical design of molecular magnets has attracted extensive interest. In this work, we report a modification strategy for adenine/thymine-based magnets through introducing a N,N-dioxidized pyrazine ring to either adenine or thymine to form ring-expanded bases (noA/noT) based on their experimentally synthesized derivatives. Further functionalization is conducted by double protonation and pairing with a normal complementary base (nohA-T/nohT-A), respectively. The diversity of protonation sites in noA generates totally six nohA-Ts, together with nohT-A forming seven two-step modified topic base pairs. DFT calculations are performed to characterize the magnetic properties and the diradical character, which indicate three diamagnetic (DM) nohA-Ts and three antiferromagnetic (AFM) nohA-Ts with extremely large magnetic coupling constants J ranging from -1279.7 to -2807.4 cm-1, while a relatively mild AFM nohT-A with a J of -194.6 cm-1. The electron separation effect induced by attraction of positive charges originating from protonation is proposed to explain the diradicalization, which is different from the traditional radical-coupler-radical coupling mode. In addition, atomic natural charges and spin densities, and H-bond and molecular orbital analyses are further discussed for verification and deep understanding of the observed unique phenomena. It should be noted that our designed seven topic base pairs have excellent characters including a good synthetic basis, a large scope of the |J| values, and the AFM-DM magnetic conversion or AFM strength modulation controlled by protonation/deprotonation, prototropic tautomerization, base pairing/dissociation, single proton transfer, and even the applied electric field. All these indicate the promising applications in the field of magnetic information storage or switch control. This work highlights the magnetic modification schemes and possible modulation methods of double positive charge doped DNA base pairs by utilizing their potential spin coupling modes.
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Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: safety and efficacy.
Massaro, F, Colafigli, G, Molica, M, Breccia, M
Expert review of hematology. 2018;(4):301-306
Abstract
Chronic myeloid leukemia (CML) is characterized by a pathognomonic chromosomal translocation, which leads to the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus 1 (ABL1) genes, generating an oncoprotein with deregulated tyrosine kinase activity. Areas covered: In the last two decades, BCR/ABL1 kinase has become the molecular target for tyrosine kinase inhibitors (TKIs), a class of drugs that impressively improved overall survival. Despite these results, a proportion of patients experiences resistance to TKIs and need to change treatment. Furthermore, TKIs are unable to eradicate leukemic stem cells, allowing the persistence of neoplastic clones. Therefore, there is still clinical need for new agents to overcome common resistance mechanisms to available drugs. This review explores the horizon of drugs actually under investigation for CML patients resistant to conventional treatment. Expert commentary: Radotinib is an ATP-competitive TKI that showed significant activity also in front-line setting and could find employment indications in CML. Asciminib, an allosteric ABL1 inhibitor, could demonstrate a higher capacity in overcoming common TKIs resistant mutations, including T315I, but clinical findings are needed. CML stem cell target will probably require new therapeutic strategies: combinations of several compounds acting with different mechanisms of action are actually under investigation.
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Adipose tissue lipolytic inhibition enhances the glucoregulatory properties of exercise in type 2 diabetes patients.
Hansen, D, Verboven, K, van Dijk, JW, Zorenc, A, Minten, L, Smeets, K, Verdijk, LB, van Loon, LJC
European journal of sport science. 2018;(9):1245-1254
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Abstract
AIMS: Exercise combined with adipose tissue lipolytic inhibition augments intramuscular lipid and glycogen use in type 2 diabetes patients. The present study investigates the impact of adipose tissue lipolytic inhibition during exercise on subsequent postprandial glycemic control in type 2 diabetes patients. METHODS Fourteen male type 2 diabetes patients (age 65 ± 2 years, HbA1c 6.7 ± 0.1% (50 ± 2 mmol/mol)) participated in a double-blind placebo-controlled randomized cross-over study in which subjects performed endurance-type exercise after being administered 250 mg of a nicotinic acid analogue (acipimox; ACP) or a placebo (PLA). A control experiment was included in which no exercise was performed (CON). RESULTS Sixty minutes of endurance-type exercise (at 45% Wpeak) did not significantly lower circulating plasma glucose and insulin excursions in PLA when compared with CON (P = .300). Acipimox administration strongly reduced circulating plasma FFA concentrations during exercise (P < .001). Circulating plasma glucose and insulin excursions were substantially lower during 7.5 h of recovery from exercise (i.e. postprandial) in ACP when compared with either CON (P = .041 and P = .002, respectively) or PLA (P = .009 and P = .001, respectively). CONCLUSIONS Collectively, exercise with adipose tissue lipolytic inhibition reduces postprandial blood glucose and insulin excursions and, as such, further improves glycemic control in male type 2 diabetes patients.
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[The effects and mechanisms of ligustrazine injection on pulmonary arterial hypertension in COPD patients].
Zhao, MP, Miu, CL, Zhang, CC, Zheng, MX, Huang, LJ, Wu, CY, Wang, WT
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology. 2016;(5):408-412
Abstract
OBJECTIVE To observe the effects of ligustrazine hydrochloride injection(LHI) on pulmonary arterial hypertension in chronic obstructive pulmonary disease(COPD) patients and to investigate its possible mechanisms. METHODS Twenty-two cases of patients with COPD were randomly divided into conventional treatmentgroup (group C) and ligustrazine treatment group(group L), 11 persons were randomly selected from healthy subjects without lung disease served as normal control group(group N). Group C was given bed rest, low flow oxygen inhalation, bronchial diastolic agent, glucocorticoid and antibiotics and other conventional treatment, and group L was added with ligustrazine hydrochloride injection on the above mentioned basis treatment, group N was given no treatment. After 2 weeks, lung function, blood gas analysis and pulmonary arterial pressure were compared among the three groups, and the content of H2S in plasma was tested with sensitive sulfur electrode method. RESULTS ①After two weeks treatment, in group L and group C pulmonary function, blood gas analysis, pulmonary artery pressure were obviously improved, and group L was better than group C (P<0.05); ② In group L the content of H2S was increased (P<0.01), group C had no significant difference (P>0.05), and there was a significant difference between the two groups (P<0.01). CONCLUSIONS Combination with LHI can effectively improve lung function. LHI mayrelieve hypoxic hypercapnia pulmonary hypertension induced by COPD through raising the content of H2S.
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Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial.
Makimura, H, Stanley, TL, Suresh, C, De Sousa-Coelho, AL, Frontera, WR, Syu, S, Braun, LR, Looby, SE, Feldpausch, MN, Torriani, M, et al
The Journal of clinical endocrinology and metabolism. 2016;(3):1123-33
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CONTEXT Increased circulating free fatty acids (FFAs) have been proposed to contribute to insulin resistance in obesity. Short-term studies have investigated the effects of acipimox, an inhibitor of hormone-sensitive lipase, on glucose homeostasis, but longer-term studies have not been performed. OBJECTIVE To test the hypothesis that long-term treatment with acipimox would reduce FFA and improve insulin sensitivity among nondiabetic, insulin-resistant, obese subjects. DESIGN, SETTING, PATIENTS, AND INTERVENTION At an academic medical center, 39 obese men and women were randomized to acipimox 250 mg thrice-daily vs identical placebo for 6 months. MAIN OUTCOME MEASURES Plasma lipids, insulin sensitivity, adiponectin, and mitochondrial function via assessment of the rate of post-exercise phosphocreatine recovery on (31)P-magnetic resonance spectroscopy as well as muscle mitochondrial density and relevant muscle gene expression. RESULTS Fasting glucose decreased significantly in acipimox-treated individuals (effect size, -6 mg/dL; P = .02), in parallel with trends for reduced fasting insulin (effect size, -6.8 μU/mL; P = .07) and HOMA-IR (effect size, -1.96; P = .06), and significantly increased adiponectin (effect size, +668 ng/mL; P = .02). Acipimox did not affect insulin-stimulated glucose uptake, as assessed by euglycemic, hyperinsulinemic clamp. Effects on muscle mitochondrial function and density and on relevant gene expression were not seen. CONCLUSION These data shed light on the long-term effects of FFA reduction on insulin sensitivity, other metabolic parameters, and muscle mitochondrial function in obesity. Reduced FFA achieved by acipimox improved fasting measures of glucose homeostasis, lipids, and adiponectin but had no effect on mitochondrial function, mitochondrial density, or muscle insulin sensitivity.
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Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.
van de Weijer, T, Phielix, E, Bilet, L, Williams, EG, Ropelle, ER, Bierwagen, A, Livingstone, R, Nowotny, P, Sparks, LM, Paglialunga, S, et al
Diabetes. 2015;(4):1193-201
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Abstract
Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 ± 1.1 years, BMI 33.4 ± 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 ± 44 vs. 1,135 ± 97 μmol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans.
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How Does the Local Electrostatic Field Influence Emitted Wavelengths and Bioluminescent Intensities of Modified Heteroaromatic Luciferins?
Zhou, JG, Williams, QL, Walters, W, Deng, ZY
The journal of physical chemistry. B. 2015;(33):10399-405
Abstract
The firefly chromophore, oxyluciferin, is in the pocket of the firefly luciferase and is surrounded by the side-chains of some amino acid residues. The charged residues produce the local electrostatic field (LEF) around the oxyluciferin. The emitted wavelengths and intensities of the oxyluciferin and its heterocyclic analogs under the LEF are examined. The common overlapping volumes of the HOMO and LUMO explain why the oscillator strengths vary under the LEF. Three average Ex change rates of the first excited energy are introduced to measure what luciferins are more sensitive to the LEF. The first excited energies and intensities in two enzymatic-like microenvironments are simulated via the LEF. The oscillator strengths and the net electric charges of the O6' and the O4 are applied to explain the experimental bioluminescent intensities.