The PA-PB1 interface of the influenza polymerase is an attractive site for antiviral drug design. In this study, we designed and synthesized a mini-library of indazole-containing compounds based on rational structure-based design to target the PB1-binding interface on PA. Biological evaluation of these compounds through a viral yield reduction assay revealed that compounds 27 and 31 both had a low micromolar range of the half maximal effective concentration (EC₅₀) values against A/WSN/33 (H1N1) (8.03 μmol/L for 27; 14.6 μmol/L for 31), while the most potent candidate 24 had an EC₅₀ value of 690 nM. Compound 24 was effective against different influenza strains including a pandemic H1N1 strain and an influenza B strain. Mechanistic studies confirmed that compound 24 bound PA with a K _d which equals to 1.88 μmol/L and disrupted the binding of PB1 to PA. The compound also decreased the lung viral titre in mice. In summary, we have identified a potent anti-influenza candidate with potency comparable to existing drugs and is effective against different viral strains. The therapeutic options for influenza infection have been limited by the occurrence of antiviral resistance, owing to the high mutation rate of viral proteins targeted by available drugs. To alleviate the public health burden of this issue, novel anti-influenza drugs are desired. In this study, we present our discovery of a novel class of indazole-containing compounds which exhibited favourable potency against both influenza A and B viruses. The EC₅₀ of the most potent compounds were within low micromolar to nanomolar concentrations. Furthermore, we show that the mouse lung viral titre decreased due to treatment with compound 24. Thus our findings identify promising candidates for further development of anti-influenza drugs suitable for clinical use.

To scientifically evaluate the intervention effect of Chinese medicine preventive administration(combined use of Huo-xiang Zhengqi Oral Liquid and Jinhao Jiere Granules) on community population in the case of coronavirus disease 2019(COVID-19), a large cohort, prospective, randomized, and parallel-controlled clinical study was conducted. Total 22 065 subjects were included and randomly divided into 2 groups. The non-intervention group was given health guidance only, while the traditional Chinese medicine(TCM) intervention group was given two coordinated TCM in addition to health guidance. The medical instructions were as follows. Huoxiang Zhengqi Oral Liquid: oral before meals, 10 mL/time, 2 times/day, a course of 5 days. Jinhao Jiere Granules: dissolve in boiling water and take after meals, 8 g/time, 2 times/day, a course of 5 days, followed up for 14 days, respectively. The study found that with the intake of medication, the incidence rate of TCM intervention group was basically maintained at a low and continuous stable level(0.01%-0.02%), while the non-intervention group showed an overall trend of continuous growth(0.02%-0.18%) from 3 to 14 days. No suspected or confirmed COVID-19 case occurred in either group. There were 2 cases of colds in the TCM intervention group and 26 cases in the non-intervention group. The incidence of colds in the TCM intervention group was significantly lower(P<0.05) than that in the non-intervention group. In the population of 16-60 years old, the incidence rate of non-intervention and intervention groups were 0.01% and 0.25%, respectively. The difference of colds incidence between the two groups was statistically significant(P<0.05). In the population older than 60 years old, they were 0.04% and 0.21%, respectively. The incidence of colds in the non-intervention group was higher than that in the intervention group, but not reaching statistical difference. The protection rate of TCM for the whole population was 91.8%, especially for the population of age 16-60(95.0%). It was suggested that TCM intervention(combined use of Huoxiang Zhengqi Oral Liquid and Jinhao Jiere Granules) could effectively protect community residents against respiratory diseases, such as colds, which was worthy of promotion in the community. In addition, in terms of safety, the incidence of adverse events and adverse reactions in the TCM intervention group was relatively low, which was basically consistent with the drug instructions.
Adolescent ; Adult ; Betacoronavirus ; Coronavirus Infections ; drug therapy ; Drugs, Chinese Herbal ; Humans ; Medicine, Chinese Traditional ; Middle Aged ; Pandemics ; Pneumonia, Viral ; drug therapy ; Prospective Studies ; Young Adult

This study was performed to investigate the effect of a concentrate of fermented wild ginseng root culture (HLJG0701) on memory improvement in the scopolamine (SPL)-induced memory-deficient mouse model. Eight-week-old male ICR mice were used to evaluate the protective effect of HLJG0701 against the SPL-induced memory loss animal model. The Morris water maze test, which measures hippocampus-dependent learning ability, and the Y-maze test, a short-term memory assessment test, were performed and related markers were analyzed. HLJG0701-treated groups displayed significantly reduced acetylcholinesterase activity and increased acetylcholine level compared with the SPL-administered group (SPL-G) (P < 0.05). In the Y-maze test, the spontaneous alternation in al HLJG0711-treated groups was significantly increased compared with that in SPL-G (P < 0.05). In the Morris water maze test, the escape latency and time spent in the target quadrant in all HLJG0701-treated groups were significantly decreased and increased, respectively, compared with those in SPL-G (P < 0.05). In addition, the brain-derived neurotrophic factor level in groups treated with HLJG0701 300 and 600 mg/kg body weight was significantly increased compared with that in SPL-G (P < 0.05). These results suggest that the HLJG0701 may protect against memory loss by inhibiting acetylcholinesterase activity and preventing acetylcholine deficiency.
Acetylcholine ; Acetylcholinesterase ; Animals ; Body Weight ; Brain-Derived Neurotrophic Factor ; Ginsenosides ; Humans ; Learning ; Male ; Memory Disorders* ; Memory* ; Memory, Short-Term ; Mice* ; Mice, Inbred ICR ; Models, Animal ; Panax* ; Scopolamine Hydrobromide ; United Nations ; Water

This study investigated the anti-cancer potential of a near-infrared fluorescence (NIRF) molecule conjugated with Cetuximab (Cetuximab-NIRF) in six-week-old female BALB/c athymic (nu+/nu+) nude mice. A431 cells were cultured and injected into the animals to induce solid tumors. Paclitaxel (30 mg/kg body weight (BW)), Cetuximab (1 mg/kg BW), and Cetuximab-NIRF (0.25, 0.5 and 1.0 mg/kg BW) were intraperitoneally injected twice a week into the A431 cell xenografts of the nude mice. Changes in BW, tumor volume and weight, fat and lean mass, and diameter of the peri-tumoral blood vessel were determined after two weeks. Tumor volumes and weights were significantly decreased in the Cetuximab-NIRF (1 mg/kg BW) group compared with the control group (P < 0.001). Lean mass and total body water content were also conspicuously reduced in the Cetuximab-NIRF (1 mg/kg BW) group compared with the vehicle control group. Peri-tumoral blood vessel diameters were very thin in the Cetuximab-NIRF groups compared with those of the paclitaxel group. These results indicate that the conjugation of Cetuximab with NIRF does not affect the anti-cancer potential of Cetuximab and NIRF can be used for molecular imaging in cancer treatments.
Animals ; Blood Vessels ; Body Water ; Body Weight ; Cetuximab* ; Female ; Fluorescence* ; Heterografts ; Humans ; Mice ; Mice, Nude ; Molecular Imaging ; Paclitaxel ; Tumor Burden ; Weights and Measures

In the Materials and Methods section, material supply source is incorrectly cited and has been changed upon request of authors.

The reason why the author withdraw the paper is a controversy on intellectual property rights between JIBiopharm Inc. and Hoseo University.

BACKGROUND AND OBJECTIVES: Cigarette smoking is a risk significant factor in coronary artery disease (CAD) and vasospastic angina (VSA). However, it is largely unknown whether smoking adds to any long-term clinical risk in VSA patients. SUBJECTS AND METHODS: A total of 2797 patients without significant CAD underwent acetylcholine (Ach) provocation test between November 2004 and October 2010. Patients were divided into three groups, based on the presence of coronary artery spasm (CAS) and smoking habits (non-CAS group: n=1188, non-smoking CAS group: n=1214, smoking CAS group: n=395). All CAS patients were prescribed with anti-anginal medications for at least 6 months. The incidence of major clinical outcomes and recurrent angina of these groups were compared up to 3 years. RESULTS: There were considerable differences in the baseline clinical and angiographic characteristics among the three groups, but there was no difference in the endpoints among the three groups (including individual and composite hard endpoints) such as death, myocardial infarction, de novo percutaneous coronary intervention, cerebrovascular accident, and major adverse cardiac events. However, there was a higher incidence of recurrent angina in both the non-smoking CAS group and smoking CAS group, as compared to the non-CAS group. In multivariable adjusted Cox-proportional hazards regression analysis, smoking CAS group exhibited a higher incidence of recurrent angina compared with the non-CAS group (hazard ratio [HR]; 2.46, 95% confidence interval [CI]; 1.46-4.14, p=0.001) and non-smoking CAS group (HR; 1.76, 95% CI; 1.08-2.87, p=0.021). CONCLUSION: Cigarette smoking CAS group exhibited higher incidence of recurrent angina during the 3-year clinical follow-up compared with both the non-CAS group and non-smoking CAS group. Quitting of smoking, paired with intensive medical therapy and close clinical follow-up, can help to prevent recurrent angina.
Acetylcholine ; Coronary Artery Disease ; Coronary Vessels ; Follow-Up Studies ; Humans ; Incidence ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Smoke ; Smoking* ; Spasm ; Stroke ; Tobacco Products*

To investigate kinetics of free 177Lu and 177Lu-labeled thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION), suspensions were intravenously injected into the tail vein of mice at a dose of 5 microCi/mouse or 15 mg/kg body weight, respectively. Free 177Lu radioactivity levels were highest in kidney followed by liver and lung 1 day post-injection. 177Lu-labeled TCL-SPION radioactivity in liver and spleen was significantly higher compared to that of other organs throughout the experimental period (p < 0.05). Radioactivity in blood, brain, and epididymis rapidly declined until 28 days. Based on these results, TCL-SPION could be a safe carrier of therapeutics.
Animals ; Body Weight ; Brain ; Epididymis ; Iron* ; Kidney ; Kinetics ; Liver ; Lung ; Male ; Mice ; Mice, Inbred ICR* ; Nanoparticles* ; Radioactivity ; Spleen ; Suspensions ; Veins

This study was investigated the change of concentration and toxicity of thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) on tissues of Sprague-Dawley rats. TCL-SPION at the dose of 15 mg/kg body weight was intravenously injected into the tail vein of the male Sprague-Dawley rats. The fate of TCL-SPION in serum, urine and tissues was observed during 28 days. Serum iron level was maximal at 0.25 h post-injection and gradually declined thereafter. In addition, the sinusoids of liver and the red pulp area of spleen were mainly accumulated iron from 0.5 h to 28-day post-injection. In kidney, iron deposition was detected in the tubular area until 0.5 h after injection. Malondialdehyde concentration in the liver slightly increased with time and was not different with that at zero time. In the liver and spleen, TNF-alpha and IL-6 levels of TS treated with TCL-SPION were not different with those of the control during the experimental period. From the results, TCL-SPION could stay fairly long-time in certain tissues after intravenous injection without toxicity. The results indicated that TCL-SPION might be useful and safe as a contrast for the diagnosis of cancer or a carrier of therapeutic reagents to treat diseases.
Animals ; Body Weight ; Diagnosis ; Humans ; Indicators and Reagents ; Injections, Intravenous ; Interleukin-6 ; Iron* ; Kidney ; Liver ; Male ; Malondialdehyde ; Nanoparticles* ; Rats ; Rats, Sprague-Dawley* ; Spleen ; Tumor Necrosis Factor-alpha ; Veins

BACKGROUNDErythromycin-resistant Streptococcus pneumoniae isolates that causing invasive pneumococcal diseases (IPD) in Chinese children remain uncharacterized. This study aims to identify the resistance genes associated with erythromycin resistance and to determine the genetic relationships of IPD isolates in Chinese children.

METHODSA total of 171 S. pneumoniae strains were isolated from 11 medical centers in China from 2006 to 2008. All the isolates were characterized via serotyping and antibiotic susceptibility determination. The erythromycin-resistant isolates were further characterized via ermB and mefA gene detection, multi-locus sequence typing analysis, and pulsed-field gel electrophoresis.

RESULTSA total of 164 (95.9%) isolates showed resistance to erythromycin, of which 162 strains with high high-level resistance (MIC ≥ 256 µg/ml). A total of 104 (63.4%) isolates carry the ermB gene alone, whereas 59 (36.0%) harbor both ermB and mefA genes. Of the 59 strains, 54 were of serotypes 19A and 19F and were identified as highly clonal and related to the Taiwan(19F)-14 clone.

CONCLUSIONSThe erythromycin resistance rate in IPD isolates is significantly high and is predominantly mediated by the ermB gene. Isolates that carry both ermB and mefA genes are predominantly of serotypes 19A and 19F.

Adolescent ; Anti-Bacterial Agents ; pharmacology ; Child ; Child, Preschool ; Drug Resistance, Bacterial ; Electrophoresis, Gel, Pulsed-Field ; Erythromycin ; pharmacology ; Humans ; Infant ; Multilocus Sequence Typing ; Pneumococcal Infections ; microbiology ; Serotyping ; Streptococcus pneumoniae ; classification ; drug effects ; genetics ; isolation & purification