Simultaneous Determination of Six Immunosuppressants in Human Whole Blood by HPLC-MS/MS Using a Modified QuEChERS Method

A high-performance liquid chromatography-tandem mass spectrometry method was established for the simultaneous determination of mycophenolic acid, mycophenolate mofetil, tacrolimus, rapamycin, everolimus and pimecrolimus in human whole blood by optimizing the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) preparation method. Whole blood was extracted into ethyl acetate, salted out with anhydrous magnesium sulfate, and purified with ethylenediamine-N-propyl silane adsorbent. The supernatant was evaporated under nitrogen until dry and finally reconstituted in methanol. Chromatographic separation was performed on an Agilent Poroshell 120 EC-C18 column in methanol (mobile phase A)-water (optimized for 0.1% acetic acid and 10 mM ammonium acetate, mobile phase B) at a 0.3 mL·min⁻¹ flow rate. Electrospray ionization and positive ion multiple reaction monitoring were used for detection. The time for of analysis was 13 min. The calibration curves range of tacrolimus, rapamycin, everolimus and pimecrolimus were in the range of 1–100 ng·mL⁻¹, mycophenolate mofetil in the range of 0.1–10 ng·mL⁻¹ and mycophenolic acid at 10–1000 ng·mL⁻¹. All correlation coefficients were >0.993. The coefficients of variation (CV, %) for inter-day and intra-day precision were less than 10%, while the spiked recoveries were in the range of 92.1% to 116%. Our method was rapid, sensitive, specific, and reproducible for the simultaneous determination of six immunosuppressants in human whole blood. Importantly, our approach can be used to monitor drug concentrations in the blood to facilitate disease treatment.     

Cardiac-specific overexpression of Ndufs1 ameliorates cardiac dysfunction after myocardial infarction by alleviating mitochondrial dysfunction and apoptosis

Myocardial infarction (MI) is the leading cause of premature death among adults. Cardiomyocyte death and dysfunction of the remaining viable cardiomyocytes are the main pathological factors of heart failure after MI. Mitochondrial complexes are emerging as critical mediators for the regulation of cardiomyocyte function. However, the precise roles of mitochondrial complex subunits in heart failure after MI remain unclear. Here, we show that NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) expression is decreased in the hearts of heart failure patients and mice with myocardial infarction. Furthermore, we found that cardiac-specific Ndufs1 overexpression alleviates cardiac dysfunction and myocardial fibrosis in the healing phase of MI. Our results demonstrated that Ndufs1 overexpression alleviates MI/hypoxia-induced ROS production and ROS-related apoptosis. Moreover, upregulation of Ndufs1 expression improved the reduced activity of complex I and impaired mitochondrial respiratory function caused by MI/hypoxia. Given that mitochondrial function and cardiomyocyte apoptosis are closely related to heart failure after MI, the results of this study suggest that targeting Ndufs1 may be a potential therapeutic strategy to improve cardiac function in patients with heart failure.Subject terms: Heart failure, Myocardial infarction, Myocardial infarction     

Green Tea (Camellia sinensis): A Review of Its Phytochemistry,Pharmacology, and Toxicology

Objectives Green tea (Camellia sinensis) is a kind of unfermented tea that retains the natural substance in fresh leaves to a great extent. It is regarded as the second most popular drink in the world besides water. In this paper, the phytochemistry, pharmacology, and toxicology of green tea are reviewed systematically and comprehensively. Key findings Green tea has been demonstrated to be good for human health. Nowadays, multiple pharmacologically active components have been isolated and identified from green tea, including tea polyphenols, alkaloids, amino acids, polysaccharides, and volatile components. Recent studies have demonstrated that green tea shows versatile pharmacological activities, such as antioxidant, anticancer, hypoglycemic, antibacterial, antiviral, and neuroprotective. Studies on the toxic effects of green tea extract and its main ingredients have also raised concerns including hepatotoxicity and DNA damage. Summary Green tea can be used to assist the treatment of diabetes, Alzheimer’s disease, oral cancer, and dermatitis. Consequently, green tea has shown promising practical prospects in health care and disease prevention.     

Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease

Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identifying new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC₅₀ value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mammals and decreased in vivo fat accumulation.     

Mesoporous sodium four-coordinate aluminosilicate nanoparticles modulate dendritic cell pyroptosis and activate innate and adaptive immunity

Pyroptosis is a programmed cell death widely studied in cancer cells for tumour inhibition, but rarely in dendritic cell (DC) activation for vaccine development. Here, we report the synthesis of sodium stabilized mesoporous aluminosilicate nanoparticles as DC pyroptosis modulators and antigen carriers. By surface modification of sodium-stabilized four-coordinate aluminium species on dendritic mesoporous silica nanoparticles, the resultant Na-^IVAl-DMSN significantly activated DC through caspase-1 dependent pyroptosis via pH responsive intracellular ion exchange. The released proinflammatory cellular contents further mediated DC hyperactivation with prolonged cytokine release. In vivo studies showed that Na-^IVAl-DMSN induced enhanced cellular immunity mediated by natural killer (NK) cells, cytotoxic T cells, and memory T cells as well as humoral immune response. Our results provide a new principle for the design of next-generation nanoadjuvants for vaccine applications.

Na-^IVAl-DMSN acts as both antigen carriers and modulators to “hyperactivate” dendritic cells (DCs) via potassium (K⁺) efflux dependent pyroptosis, eventually leading to enhanced adaptive and innate immunity.     

Water Status and Predictive Models of Moisture Content during Drying of Soybean Dregs Based on LF-NMR

To explore the drying characteristics of soybean dregs and a nondestructive moisture content test method, in this study, soybean dregs were dried with hot air (80 °C), the moisture content was measured using the drying method, water status was analyzed using low-field nuclear magnetic resonance (LF-NMR) and the moisture content prediction models were built and validated. The results revealed that the moisture contents of the soybean dregs were 0.57 and 0.01 g/g(w.b.), respectively, after drying for 5 and 7 h. The effective moisture diffusivity increased with the decrease in moisture content; it ranged from 5.27 × 10⁻⁹ to 6.96 × 10⁻⁸ m²·s⁻¹. Soybean dregs contained bound water (T₂₁), immobilized water (T₂₂) and free water (T₂₃ and T₂₃’). With the proceeding of drying, all of the relaxation peaks shifted left until a new peak (T₂₃’) appeared; then, the structure of soybean dregs changed, and the relaxation peaks reformed, and the peak shifted left again. The peak area may predict the moisture content of soybean dregs, and the gray values of images predict the moisture contents mainly composed of free water or immobilized water. The results may provide a reference for drying of soybean dregs and a new moisture detection method.     

Tomatidine-stimulated maturation of human embryonic stem cell-derived cardiomyocytes for modeling mitochondrial dysfunction

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have been reported to exhibit immature embryonic or fetal cardiomyocyte-like phenotypes. To enhance the maturation of hESC-CMs, we identified a natural steroidal alkaloid, tomatidine, as a new substance that stimulates the maturation of hESC-CMs. Treatment of human embryonic stem cells with tomatidine during cardiomyocyte differentiation stimulated the expression of several cardiomyocyte-specific markers and increased the density of T-tubules. Furthermore, tomatidine treatment augmented the number and size of mitochondria and enhanced the formation of mitochondrial lamellar cristae. Tomatidine treatment stimulated mitochondrial functions, including mitochondrial membrane potential, oxidative phosphorylation, and ATP production, in hESC-CMs. Tomatidine-treated hESC-CMs were more sensitive to doxorubicin-induced cardiotoxicity than the control cells. In conclusion, the present study suggests that tomatidine promotes the differentiation of stem cells to adult cardiomyocytes by accelerating mitochondrial biogenesis and maturation and that tomatidine-treated mature hESC-CMs can be used for cardiotoxicity screening and cardiac disease modeling.Subject terms: Heart failure, Embryonic stem cells, Stem-cell differentiation     

Polyoxometalate/Cellulose Nanofibrils Aerogels for Highly Efficient Oxidative Desulfurization

Polyoxometalate (POM) presents great potential in oxidative desulfurization (ODS) reaction. However, the high dissolubility of POM in common solvents makes it difficult to recycle. Besides, the small specific surface area of POM also limits the interaction between them and the substrate. Depositing polyoxometalates onto three-dimensional (3D) network structured materials could largely expand the application of POM. Here, the surfaces of cellulose nanofibrils (CNFs) were modified with very few (3-Aminopropyl) trimethoxysilane (APTS) to endow positive charges on the surfaces of CNFs, and then phosphotungstic acid (PTA) was loaded to obtain the aerogel A-CNF/PTA as the ODS catalyst. FT-IR indicated the successful deposition of PTA onto aminosilane modified CNF surfaces. UV-VIS further suggested the stability of PTA in the aerogels. BET and SEM results suggested the increased specific surface area and the relatively uniform 3D network structure of the prepared aerogels. TGA analysis indicated that the thermal stability of the aerogel A-CNF/PTA50% was a little higher than that of the pure CNF aerogel. Most importantly, the aerogel A-CNF/PTA50% showed good catalytic performance for ODS. Catalysis results showed that the substrate conversion rate of the aerogel A-CNF/PTA50% reached 100% within 120 min at room temperature. Even after five cycles, the substrate conversion rate of the aerogel A-CNF/PTA50% still reached 91.2% during the dynamic catalytic process. This work provides a scalable and facile way to stably deposit POM onto 3D structured materials.     

Improvement of Biological Effects of Root-Filling Materials for Primary Teeth by Incorporating Sodium Iodide

Therapeutic iodoform (CHI₃) is commonly used as a root-filling material for primary teeth; however, the side effects of iodoform-containing materials, including early root resorption, have been reported. To overcome this problem, a water-soluble iodide (NaI)-incorporated root-filling material was developed. Calcium hydroxide, silicone oil, and NaI were incorporated in different weight proportions (30:30:X), and the resulting material was denoted DX (D5~D30), indicating the NaI content. As a control, iodoform instead of NaI was incorporated at a ratio of 30:30:30, and the material was denoted I30. The physicochemical (flow, film thickness, radiopacity, viscosity, water absorption, solubility, and ion releases) and biological (cytotoxicity, TRAP, ARS, and analysis of osteoclastic markers) properties were determined. The amount of iodine, sodium, and calcium ion releases and the pH were higher in D30 than I30, and the highest level of unknown extracted molecules was detected in I30. In the cell viability test, all groups except 100% D30 showed no cytotoxicity. In the 50% nontoxic extract, D30 showed decreased osteoclast formation compared with I30. In summary, NaI-incorporated materials showed adequate physicochemical properties and low osteoclast formation compared to their iodoform-counterpart. Thus, NaI-incorporated materials may be used as a substitute for iodoform-counterparts in root-filling materials after further (pre)clinical investigation.     

大模场面积光子晶体光纤激光器展宽脉冲锁模域的束缚态运转

实验研究了大模面积光子晶体光纤飞秒激光器在近零色散点展宽脉冲锁模的束缚态运转.获得了双脉冲束缚态锁模,以及脉冲间隔不相等的多脉冲束缚态锁模,实验发现束缚态的子脉冲间距具有随机性.通过建立光纤锁模激光器的数值模型,分析了激光器束缚态锁模建立的动力学过程,在一定抽运强度下,激光器存在多个稳态,或者单脉冲运转,或者子脉冲间隔不相等的束缚态运转,这取决于锁模建立阶段半导体可饱和吸收镜(SESAM)对噪声信号的随机提取.并提出了抑制束缚态的方法,模拟得出此项技术可直接获得的最大单脉冲能量为19.6 nJ,考虑到40%左右的压缩损耗,可得到压缩至76 fs的最短脉冲,单脉冲能量为11.8 nJ.数值模拟结果能很好的与实验相符合.