To discover novel fluoroquinolone lead compounds as possible anti-infective or/and antitumor chemotherapies, combination principle of pharmacophore-based drug design, a series of novel tricyclic fluoroquinolone title compounds, [1,2,4]triazino[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives ( 5a-5p), were designed and synthesized with a fused [1,2,4]-triazine ring unit. Their structures were characterized by spectral data and elemental analysis and the in vitro antibacterial and anti-cell proliferation activities were also evaluated. The results showed that the titled compounds exhibited more significant inhibitory activities against drug-resistant bacteria (Methicillin-resistant Staphylococcus aureus and multi drug-resistant Escherichia coli strains) and three tested cancer cell lines (human hepatoma SMMC-7721, murine leukemia L1210 and human murine leukemia HL60 cells). Interestingly, SAR showed that compounds with electron-donating groups attached to benzene ring had stronger antibacterial activity than antitumor activity, but electron-withdrawing compounds displayed more potential antitumor activity than antibacterial activity, especially antitumor activity of nitro compounds was comparable to comparison doxorubicin. Thus, novel triazine-fused tricyclic fluoroquinolones as potent anti-infective or/and antitumor lead compounds are valuable to pay attention and for further development.
Animals ; Anti-Bacterial Agents ; chemical synthesis ; chemistry ; Antineoplastic Agents ; chemical synthesis ; chemistry ; Carboxylic Acids ; Carcinoma, Hepatocellular ; Cell Line ; Cell Proliferation ; Drug Design ; Escherichia coli ; drug effects ; Fluoroquinolones ; chemical synthesis ; chemistry ; HL-60 Cells ; Humans ; Leukemia L1210 ; Liver Neoplasms ; Methicillin-Resistant Staphylococcus aureus ; drug effects ; Mice ; Naphthyridines ; Triazines

To explore an efficient strategy for the conversion of antibacterial fluoroquinolones into antitumor fluoroquinolones, an azole heterocyclic ring of oxadiazole instead of the C-3 carboxylic acid group with a functionalized hydrazone group as a modified side-chain, fifteen novel 2-(fluoroquinolon-3-yl)-oxadiazole-5- sulfanylacetylhydrazone derivatives 7a-7o were designed and synthesized on the basis of the pharmacophore hybridization principle from pefloxacin, separately. The structures for fifteen title compounds were characterized by elemental analysis, 1H NMR and MS, and their in vitro antitumor activity against Hep-3B cell line was evaluated by a MTT assay. The results showed that the title compounds exhibited more significantly inhibitory activity than that of the parent pefloxacin, in which compounds with electron-withdrawing group attached on aryl ring had more potency than that of compounds with electron donating group, especially compounds with a carboxylic substituent were comparable to comparison doxorubicin. It suggests that it is favorable for an improvement of antitumor activity to remain a carboxylic acid unit at the aromatic ring.
Antineoplastic Agents ; chemical synthesis ; chemistry ; Cell Line, Tumor ; Fluoroquinolones ; chemistry ; Humans ; Oxadiazoles ; chemistry ; Structure-Activity Relationship

Adult ; Burnout, Professional ; Female ; Humans ; Life Change Events ; Middle Aged ; Occupations ; Professional Competence ; Work ; psychology ; Young Adult

Objective To investigate the hypoglycemic effects of Laminaria japonica (L. japonica) on diabetic model induced by alloxan in rats. Methods Sixty healthy female rats were used to establish diabetic models by injecting alloxan peritoneally, and L.japonica was applied as raw materials for potential marine drugs.The levels of fasting blood glucose (FBG) were detected by automatic blood glucose device. Enzyme linkedimmunoabsorbant assay was applied to determine the insulin level in serum. The shape and structure of isletcells were observed with histopathological staining, and the expression of superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) in islet cells were detected by immunohistochemical technique. Results After the treatment, the levels of FBG of L.japonica treated group B [(9.37±1.70) mmol/LandC (9.18±1.65 ) mmol/L, F= 32.81, q=6.35～11.72, P<0.05 ] reduced, while the serum levels of insulin in treated group A, Band C (0.0378±0.0026, 0.0378±0.0027, 0.0367±0.0035) increased(F= 11.40, q=4.28～8.47, P<0.05) significantly than those of diabetic model group (0.0456 ±0.0057) . The shape and structure of islet cells improved with the up-expressing SOD(t=4.73～4.76, P<0.05)and down-expressing iNOS (t=4.81～5.30, P<0.05) in L.japonica treated group B and C than those in diabetic model group. Conclusion L.japonica might decrease the serum level of FBG through promoting the islet cell recovery by an anti-oxide effect.

Objective To evaluate the effects of serum procalcitonin (PCT)-guided antibiotic therapy in elderly patients with early-onset stroke-associated pneumonia (EOP).Methods Totally 179 eligible elderly patients with EOP were randomly devided into 2 groups:standard therapy group (standard group,n=88) and PCT-guided group (PCT group,n=91).Patients in standard group received antibiotics according to antibiotics guidelines in China by the treating physicians.Patients in PCT group were treated with antibiotics for 5 days,then the antibiotic treatment was based on serum PCT levels as follows:discouraged if PCT＜0.25 μg/L and encouraged if PCT≥0.25 μg/L.Length of hospitalization,duration of antibiotics,costs of hospitalization and antibiotics,clinical efficacy,andmortality,National Institutes of Health Stroke Scale (NIHSS) score and Barthel index (BI) on the 28th day were observed.Results There were no significant differences in clinical efficacy,mortality,NIHSS score and BI between the two groups on the 28th day [(85.7％ vs.86.3％),(8.8％ vs.7.9％),10.1 (7.8,16.2) vs.9.8 (6.0,15.5),60.1(42.5,82.3) vs.57.9 (39.2,84.8),respectively,all P＞ 0.05].The length of hospitalization,antibiotic duration,costs of hospitalization and antibiotics were lower in PCT group than in standard group [19 (10,38) d vs.26(17,42) d,10 (7,14) dvs.15 (6,21) d,3350 (2052,6163) yuanvs.10355 (6877,15421) yuan,7532 (4810,12116) yuan vs.5358 (3089,8144) yuan,respectively,all P＜0.05].Conclusions PCT guidance of antibiotic therapy is effective and safe for the treatment of early-onset stroke associated pneumonia in elderly patients.It can reduce the antibiotic duration and costs of hospitalization.

BACKGROUND:Fibrin glue introduced into calcium phosphate cement has not been confirmed whether this way could overcome the compressive limits and the low degradation of calcium phosphate cement and to modify the biological properties of calcium phosphate cement. OBJECTIVE:To explore the mechanical and biological properties of calcium phosphate cement/fibrin glue at different powder/liquid ratio for bone regeneration in vitro. METHODS:Calcium phosphate cement and fibrin glue were mixed at ratios of 1:1, 3:1, 5:1 (mL/g), and the pure calcium phosphate cement served as controls. Setting time, scanning electron microscope and the biomechanical test were used to analyze the composite scaffold structure, physical performance and the mechanical properties. Passage 3 osteoblasts were respectively inoculated on the material surface of the four groups, and pure cells served as blank controls. celladhesion, proliferation and alkaline phosphatase activity were observed. RESULTS AND CONCLUSION:The initial and final setting time of calcium phosphate cement/fibrin glue at 1:1 and 3:1 (mL/g) was higher than that in the control group (P<0.05), while the initial and final setting time of calcium phosphate cement/fibrin glue at 5:1 (mL/g) was lower than that of the control group (P<0.05). Scanning electron microscope showed smoother and denser surface of composite scaffolds compared with the pure calcium phosphate cement. The aperture of the composite scaffolds was decreased with the increasing concentration of fibrin glue. The compressive strength of composite scaffolds at 3:1 and 5:1 was higher than that of the control group (P<0.05), while the modulus of the composite scaffolds at 1:1, 3:1, 5:1 was higher than that of the control group (P<0.05). celladhesion, proliferation and alkaline phosphatase activity showed no difference among the three composite scaffold and control groups, but al higher than the blank control group (P<0.05). These findings indicate that fibrin glue introduced into calcium phosphate cement can overcome the low-strength limits of calcium phosphate cement, and maintain the good biological properties of calcium phosphate cement for bone regeneration.

Objective To investigate the efficacy of spectral entropy measurement in reflection of depth of anesthesia and noxious stimulation. Methods Forty-five patients of ASAⅠorⅡ were randomly divided into three groups(n=15).Group A,B and C received fentanyl 1,3 and 5 ?g/kg,respectively,3 min before target controlled infusion(TCI) of propofol.Intubation was performed when the effect-site concentration(CE)reached 3.5 ?g/mL,which was maintained until 5 min after incision.Response entropy(RE),State entropy(SE) as well as heart rate(HR),mean arterial pressure(MAP) were measured at the time points of before fentanyl and 2,3 min after fentanyl,every CE of propofol steps,before intubation,immediately and 1,3,5 min after intubation,before skin incision,and 0.5,1,3,5 min after skin incision,respectively. Results Three minutes after receiving fentanyl,the values of RE and SE in the three groups decreased significantly in a dose-dependent manner,and increased obviously at the same degree during intubation and after skin incision.The values recovered to the level before stress stimulation 1 min after intubation and 5 min after skin incision.There were no differences in the fluctuation of RE and SE among the three groups when the CE of propofol reached 1.0 ?g/mL.Conclusion Spectral entropy may effectively reflect the depth of anesthesia,but not analgesia during anesthesia.

Objective To investigate the expression and distribution of the downstream substrate of extracellular regulated protein kinase(ERK1/2) pathway, ternary complex factor phospho-Elk-1, in rat brains with chronic fluorosis, and reveal the mechanism of the impaired learning and memory ability caused by chronic fluorosis. Methods Seventy-two SD rats, weighing 100 - 120 g, were randomly divided into 3 groups, 24 in each group (half male and half female). The rats in control group were fed with tap water (fluoride < 0.5 mg/L); low- and high-dose fluoride groups were fed with tap water with different concentrations of NaF(5.0,50.0 mg/L F-, respectively). After 6 months, body weight was weighed, dental fluorosis was determined by observation and urinary fluoride and bone fluoride were detected by fluorine ion-selective electrode; the learning ability of rats was measured by navigation test of Morris water maze, and memory ability by spatial probe test in Morris water maze; the expression and distribution of phospho-Elk-1 in different brain regions were detected by immunohistochemistry method. Results In low- and high-fluoride groups, the body weight of rat[(449.2 ± 77.1), (312.8 ± 89.7)g] was significantly decreased than that of control [(635.5 ± 76.2 )g, all P< 0.05], the varying degrees of dental fluorosis were observed(x2 = 7.83, P<0.05), urinary fluoride[(2.56 ±0.91),(5.73 ±3.14)mg/L] and bone fluoride[(709.2 ± 37.4) ,(1306.3 ± 102.4) mg/kg] were significantly higher than those in controls[(0.92 ± 0.30)mg/L,(348.5 ± 89.2)mg/kg, all P< 0.05]. The escape latency of low- and high-fluoride groups[ (7.4 ± 4.1), (12.2 ± 5.7)s] was longer than that of control [(4.8 ± 2.7 )s, all P < 0.05] and the escape latency in high-fluoride group was significantly longer than that in other groups (all P < 0.05); in spatial probe test, the time of first crossing platform was longer in rats with fluorosis [(4.18 ± 1.10),(5.89 ± 0.56)s] as compared to control[(1.17 ± 0.75)s, all P< 0.05]. Expressions of phospho-Elk-1 in the hippocampus CA1(167.4 ± 8.3,163.2 ± 9.4), CA2(175.7 ± 5.0,183.3 ± 4.2), CA3(165.2 ± 11.6,162.9 ± 4.4), CA4(168.7± 6.9,169.5 ±5.3), fascia dentate (185.2 ±4.0,193.1 ±6.1) and caudate putamen( 181.4 ± 3.8, 179.8 ± 5.5) in low- and high-fluoride groups were higher than those of controls(142.4 ± 8.1,144.9 ± 8.4,143.6 ± 5.8, 116.8 ± 9.1,140.2 ± 7.8,163.1 ± 13.1, all P< 0.05). Conclusion Chronic fluorosis can cause increased expression of phospho-Elk-1 in the hippocampus and caudate putamen region of rat brains, which might be related to the mechanisms of decreased learning and memory ability of rats overexposed to fluoride.

The aim of this study is to develop a synthetic medium suitable for 13C metabolic flux analysis (13C-MFA) of Streptomyces rimosus. The cell growth rate and oxytetracycline production by S. rimosus M4018 were compared when M4018 cells were growth on the optimized chemically defined media with organic nitrogen sources or inorganic nitrogen sources. First, a synthetic medium contained KNO3 as the main nitrogen source was screened, then optimized by a response surface method. Using this new medium, the oxytetracycline yield was increased from 75.2 to 145.6 mg/L. Furthermore, based on the 13C-MFA, we identified that Entner-Doudoroff pathway does not exist in S. rimosus cells cultured in a chemically defined medium with feed of 100% 1-13C labeled glucose. This study is helpful for subsequent 13C-MFA application of S. rimosus.
Carbon Isotopes ; analysis ; Culture Media ; chemistry ; Metabolic Flux Analysis ; Nitrogen ; chemistry ; Oxytetracycline ; biosynthesis ; Streptomyces rimosus ; metabolism

Objective To analyze the ultrasonic features of thyroid microcarcinoma (TMC) and the causes of misdiagnosis. Methods The ultrasonic features including shape, margin, echogenecity, microcalcification, vascularity and lymphadenopathy were analyzed retrospectively in 26 pathologically-proven TMC patients. Results In 26 cases, 11 cases were diagnosed correctly before operation (11/26, 42.31%), 12 cases were misdiagnosed (12/26, 46.15%) as adenoma or benign nodule, and 3 cases were missed diagnosed (3/26, 11.54%). Among the 23 cases detected on ultrasound, 21 cases were solid and hypoechoic (21/23, 91.30%);19 cases were ill-defined (19/23, 82.61%);12 cases were taller than wide in shape (12/23, 52.17%); 14 cases had microcalcification (14/23, 60.87%); 7 cases showed central or peripheral blood flow signals (7/23,30.43%) with arterial resistance index>0.70 in 3 lesions and<0.70 in 4 lesions. Conclusions Several ultrasonographic features are helpful in identiifcation of TMC, including hypo/iso-echogenecity, ill-deifned margin, taller-than-wide shape, microcalciifcation, arterial signals with high resistance index, and abnormal lymphadenopathy. Moreover, for cases with multiple lesions, to the potential co-existence of benign and malignant lesions should be considered.