Design and synthesis of guaianolide-germacranolide heterodimers as novel anticancer agents against hepatocellular carcinoma.

Inspired by our previous finding that disesquiterpenoids showed more potent antihepatoma cytotoxicity than their corresponding parent monomers, natural product-like guaianolide-germacranolide heterodimers were designed and synthesized from guaianolide diene and germacranolides via a biomimetic Diels-Alder reaction to provide three antihepatoma active dimers with novel scaffolds. To explore the structure-activity relationship, 31 derivatives containing ester, carbamate, ether, urea, amide, and triazole functional groups at C-14' were synthesized and evaluated for their cytotoxic activities against HepG2, Huh7, and SK-Hep-1 cell lines. Among them, 25 compounds were more potent than sorafenib against HepG2 cells, 15 compounds were stronger than sorafenib against Huh7 cells, and 17 compounds were stronger than sorafenib against SK-Hep-1 cells. Compound 23 showed the most potent cytotoxicity against three hepatoma cell lines with IC50 values of 4.4 µM (HepG2), 3.7 µM (Huh7), and 3.1 µM (SK-Hep-1), which were 2.7-, 2.2-, and 2.8-fold more potent than sorafenib, respectively. The underlying mechanism study demonstrated that compound 23 could induce cell apoptosis, prevent cell migration and invasion, cause G2/M phase arrest in SK-Hep-1 cells. Network pharmacology analyses predicted PDGFRA was one of the potential targets of compound 23, and surface plasmon resonance (SPR) assay verified that 23 had strong affinity with PDGFRA with a dissociatin constant (KD) value of 90.2 nM. These promising findings revealed that structurally novel guaianolide-germacranolide heterodimers might provide a new inspiration for the discovery of antihepatoma agents.

Drift of sparse and dense spiral waves under joint external forces.

Many methods have been employed to investigate the drift behaviors of spiral waves in an effort to understand and control their dynamics. Drift behaviors of sparse and dense spirals induced by external forces have been investigated, yet they remain incompletely understood. Here we employ joint external forces to study and control the drift dynamics. First, sparse and dense spiral waves are synchronized by the suitable external current. Then, under another weak current or heterogeneity, the synchronized spirals undergo a directional drift, and the dependence of their drift velocity on the strength and frequency of the joint external force is studied.

Control of spiral waves in optogenetically modified cardiac tissue by periodic optical stimulation.

Resonant drift of nonlinear spiral waves occurs in various types of excitable media under periodic stimulation. Recently a novel methodology of optogenetics has emerged, which allows to affect excitability of cardiac cells and tissues by optical stimuli. In this paper we study if resonant drift of spiral waves in the heart can be induced by a homogeneous weak periodic optical stimulation of cardiac tissue. We use a two-variable and a detailed model of cardiac tissue and add description of depolarizing and hyperpolarizing optogenetic ionic currents. We show that weak periodic optical stimulation at a frequency equal to the natural rotation frequency of the spiral wave induces resonant drift for both depolarizing and hyperpolarizing optogenetic currents. We quantify these effects and study how the speed of the drift and its direction depend on the initial conditions. We also derive analytical formulas based on the response function theory which correctly predict the drift velocity and its trajectory. We conclude that optogenetic methodology can be used for control of spiral waves in cardiac tissue and discuss its possible applications.

Topological charge-density method of identifying phase singularities in cardiac fibrillation.

Spiral waves represent the key motifs of typical self-sustained dynamical patterns in excitable systems such as cardiac tissue. The motion of phase singularities (PSs) that lies at the center of spiral waves captures many qualitative and, in some cases, quantitative features of their complex dynamics. Recent clinical studies suggested that ablating the tissue at PS locations may cure atrial fibrillation. Here, we propose a different method to determine the location of PSs. Starting from the definition of the topological charge of spiral waves, we obtain the expression of the topological charge density in a discrete case. With this expression, we can calculate the topological charge at each grid in the space directly, so as to accurately identify the position of PSs.

Finding type and location of the source of cardiac arrhythmias from the averaged flow velocity field using the determinant-trace method.

Life threatening cardiac arrhythmias result from abnormal propagation of nonlinear electrical excitation waves in the heart. Finding the locations of the sources of these waves remains a challenging problem. This is mainly due to the low spatial resolution of electrode recordings of these waves. Also, these recordings are subjected to noise. In this paper, we develop a different approach: the AFV-DT method based on an averaged flow velocity (AFV) technique adopted from the analysis of optical flows and the determinant-trace (DT) method used for vector field analysis of dynamical systems. This method can find the location and determine all important types of sources found in excitable media such as focal activity, spiral waves, and waves rotating around obstacles. We test this method on in silico data of various wave excitation patterns obtained using the Luo-Rudy model for cardiac tissue. We show that the method works well for data with low spatial resolutions (up to 8×8) and is stable against noise. Finally, we apply it to two clinical cases and show that it can correctly identify the arrhythmia type and location. We discuss further steps on the development and improvement of this approach.

Resonance of scroll rings with periodic external fields in excitable media.

By direct numerical simulations of a chemical reaction-diffusion system coupled to a periodic external AC electric field with frequency equal to double frequency of the scroll wave rotation, we find that scroll rings resonate with the electric field and exhibit various dynamical behaviors, for example, their reversals, collapses, or growths, depending both on the initial phase of AC electric fields and on the initial phase of scroll rings. A kinematical model characterizing the drift velocity of the scroll rings along their radial directions as well as that of the scroll rings along their symmetry axes is proposed, which can effectively account for the numerical observations and predict the behaviors of the scroll rings. Besides, the existence of the equilibrium state of a scroll ring under the AC electric fields is predicted by the kinematical model and the predictions agree well with the simulations.

Clinical evaluation of oral levofloxacin 500 mg once-daily dosage for treatment of lower respiratory tract infections and urinary tract infections: a prospective multicenter study in China.

Levofloxacin (LVFX), a fluoroquinolone agent, has a broad spectrum that covers Gram-positive and -negative bacteria and atypical pathogens. It demonstrates good clinical efficacy in the treatment of various infections, including lower respiratory tract infections (LRTIs) and urinary tract infections (UTIs). To evaluate the efficacy and safety of oral LVFX 500 mg once daily, a large open-label clinical trial was conducted in 1266 patients (899 with LRTIs and 367 with UTIs) at 32 centers in China. In the per-protocol population, the clinical efficacy rate (cure or improvement) at 7 to 14 days after the end of treatment was 96.4% (666/691) for LRTIs and 95.7% (267/279) for UTIs. In 53 patients diagnosed with atypical pneumonia the treatment was effective. The bacteriological efficacy rate was 96.6% (256/265) for LRTIs and 93.3% (126/135) for UTIs. The eradication rate of the causative pathogens was 100% (33/33) for Haemophilus influenzae and 96.0% (24/25) for Streptococcus pneumoniae in LRTIs, and 94.1% (80/85) for Escherichia coli in UTIs. The overall efficacy rates were 89.3% (617/691) for LRTIs and 87.8% (245/279) for UTIs. The incidence of drug-related adverse events (ADRs) was 17.3% (215/1245), and the incidence of drug-related laboratory abnormalities was 15.7% (191/1213). Common ADRs were dizziness, nausea, and insomnia. Common laboratory abnormalities included "WBC decreased", "alanine aminotransferase (ALT) increased", "aspartate aminotransferase (AST) increased", and "lactate dehydrogenase (LDH) increased". All of these events were mentioned in the package inserts of fluoroquinolones including LVFX, and most events were mild and transient. Thirty-four patients (2.7%) were withdrawn from the study because of the ADRs. No new ADRs were found. This study concluded that the dosage regimen of LVFX 500 mg once daily was effective and tolerable for the treatment of LRTIs and UTIs.

[The protective effects and mechanism of hypercapnia on acute lung injury].

OBJECTIVE: To explore the protective effects of hypercapnia on acute lung injury (ALI) and the possible mechanisms. METHODS: Twenty-four healthy New Zealand white rabbits were involved in this study, and randomly divided to three groups, a control group, a therapeutic group, and a prophylactic group (n=8, each). Lipopolysaccharide (1 mg/kg) was injected intravenously to establish the ALI model. Blood gas analysis and artery pressure were monitored. IL-8 and TNF-alpha in the serum and bronchoalveolar lavage fluid (BALF), wet weight/dry weigh (W/D), index of quantitative assessment of histological lung injury (IQA), myeloperoxidase (MPO) and malondialdehyde (MDA) activity in the lung tissue were measured. Apoptosis index of neutrophils were determined. RESULTS: (1) The mean artery pressure, heart rate, PaCO2, and PaO2/FiO2 changed in the ALI model of the therapeutic group and the prophylactic group [(79+/-6) mm Hg (1 mm Hg=0.133 kPa), (180+/-10)/min, (99+/-13) mm Hg, 250+/-26, (80+/-9) mm Hg, (181+/-12)/min, (95+/-11) mm Hg, 241+/-56, respectively]. In the control group, they were (66+/-10) mm Hg, (139+/-13)/min, (31+/-4) mm Hg, 182+/-35, respectively. The differences were significant compared with the control group (t=4.05, 26.32, 5.36, 28.15, 12.54, 11.07, 16.13, 12.36, P<0.05, 0.01). (2) The levels of W/D, MPO, and MDA in the therapeutic group and the prophylactic group were 1.98+/-0.28, 1.87+/-0.30, (6.1+/-1.6) U/g, (5.8+/-1.5) U/g, (20+/-5) mg/L, (19+/-4) mg/L; while in the control group, they were [2.43+/-0.26, (9.0+/-1.3) U/g, (36+/-8) mg/L] respectively. The difference was significant (t=11.07, 24.46, 2.35, 9.63, 12.34, 25.32, P<0.05, 0.01). (3) The levels of IL-8 and TNF-alpha in the serum and BALF and the apoptosis index in the three groups were (50+/-8) ng/ml, (103+/-49) ng/ml, (94+/-16) ng/ml, (44+/-9) ng/ml, (38+/-9)%, (56+/-5)%, (49+/-7) ng/ml, (96+/-50) ng/ml, (91+/-14) ng/ml, (39+/-6) ng/ml, (39+/-10)%, (55+/-10)%, (91+/-43) ng/ml, (177+/-60) ng/ml, (162+/-15) ng/ml, (67+/-7) ng/ml, (19+/-7)%, (43+/-7)%, respectively. The difference was significant among the three groups (t=7.12, 5.55, 7.30, 3.93, 13.08, 8.00, P<0.05, 0.01 respectively). (4) The apoptosis index of neutrophils was negatively correlated with the levels of IL-8 in the serum and BALF (r=-0.73, -0.72, -0.52, -0.64, -0.73, -0.56, all P<0.05), and the levels of TNF-alpha in the serum and BALF (r=-0.57, -0.78, -0.69, -0.75, -0.82, -0.84, all P<0.05). CONCLUSION: Hypercapnia does not affect hemodynamics and has protective effects on ALI.