Synthesis and biological evaluation of triazolones/oxadiazolones as novel urease inhibitors.

Urease is the main virulence factor of infectious gastritis and gastric ulcers. Urease inhibitors are regarded as the first choice for the treatment of such diseases. Based on the triazolone/oxadiazolone skeleton, a urea-like fragment being able to specifically bind the urease activity pocket and prevent urea from hydrolysis, we designed and synthesized 45 triazolones/oxadiazolones as urease inhibitors. Eight compounds were proved to show excellent inhibitory activity against Helicobacter pylori urease, being more potency than the clinically used urease inhibitor acetohydroxamic acid. The most active inhibitor with IC50 value of 1.2 µM was over 20-fold higher potent than the positive control. Enzymatic kinetic assays showed that these novel inhibitors reversibly inhibited urease with a mixed competitive mechanism. Molecular dockings provided evidence for the observations in enzyme assays. Furthermore, these novel inhibitors were proved as drug-like compounds with very low cytotoxicity to mammalian cells and favorable water solubility. These results suggested that triazolone and oxadiazolone were promising scaffolds for the design and discovery of novel urease inhibitors, and were expected as good candidates for further drug development.

Association of magnesium sulfate use with mortality in critically ill patients with sepsis: a retrospective propensity score-matched cohort study.

BACKGROUND: Trials have demonstrated lower rates of acute kidney injury in critically ill patients receiving magnesium supplementation, but they have yielded conflicting results regarding mortality. METHODS: This is a retrospective cohort study based on the MIMIC-IV (Medical Information Mart in Intensive Care-IV) database. Adult critically ill patients with sepsis were included in the analysis. The exposure was magnesium sulfate use during ICU stay. The primary outcome was 28-day all-cause mortality. Propensity score matching (PSM) was conducted at a 1:1 ratio. Multivariable analyses were used to adjust for confounders. RESULTS: The pre-matched and propensity score-matched cohorts included 10 999 and 6052 patients, respectively. In the PSM analysis, 28-day all-cause mortality rate was 20.2% (611/3026) in the magnesium sulfate use group and 25.0% (757/3026) in the no use group. Magnesium sulfate use was associated with lower 28-day all-cause mortality (hazard ratio [HR], 0.70; 95% CI, 0.61-0.79; P<0.001). Lower mortality was observed regardless of baseline serum magnesium status: for hypomagnesaemia, HR, 0.64; 95% confidence interval (CI), 0.45-0.93; P=0.020; for normomagnesaemia, HR, 0.70; 95% CI, 0.61-0.80; P<0.001. Magnesium sulfate use was also associated with lower ICU mortality (odds ratio [OR], 0.52; 95% CI, 0.42-0.64; P<0.001), lower in-hospital mortality (OR, 0.65; 95% CI, 0.55-0.77; P<0.001), and renal replacement therapy (OR, 0.67; 95% CI, 0.52-0.87; P=0.002). A sensitivity analysis using the entire cohort also demonstrated lower 28-day all-cause mortality (HR, 0.62; 95% CI, 0.56-0.69; P<0.001). CONCLUSIONS: Magnesium sulfate use was associated with lower mortality in critically ill patients with sepsis. Prospective studies are needed to verify this finding.

Identification of (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids as novel urease inhibitors and the mechanism exploration.

Thirty-three (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids were synthesized in an effort to develop novel urease inhibitors. Among these compounds, 2-(N-(3-nitrophenyl)-N-(4-tert-butylphenylsulfonyl))aminoacetohydroxamic acid (e2) exhibited excellent inhibitory activity against Helicobacter pylori urease with no perceptible cytotoxicity to mammalian cells. Compound e2 showed over 690-fold higher potency than the clinical used urease inhibitor acetohydroxamic acid, reversibly inhibiting urease with a mixed mechanism. Molecular modeling revealed that (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids may possibly bind Ni ions and two hydrophobic regions with a 'Y'-like shape.

A situational analysis of human resource and non-communicable diseases management for community health workers in Chengdu, China: a cross-sectional study.

BACKGROUND: Non-communicable diseases (NCDs) pose a major challenge to health economic cost and residents' health status. Community health workers (CHWs) are the gatekeeper of primary health care. OBJECTIVE: This study aimed to conduct a situational analysis of current human resource and requirements of NCDs-related training among CHWs in Chengdu with regard to address to understand the suggestions for improvement of challenges and barriers. METHODS: A descriptive online cross-sectional survey was conducted among CHWs (doctors and nurses) from 23 districts and counties in Chengdu. Sociodemographic and NCDs-related variables were collected. Univariate analysis and multiple response analysis were used to describe the characteristics of these variables. RESULTS: 711 doctors and 637 nurses completely responded. There were significant differences among gender, age, educational levels, professional title, working year, type of institution, urban circle and registration in general practice between doctors and nurses (P < 0.001). 60.6% of doctors were female, compared to 98.0% for nurses. 58.2% of doctors held a bachelor's degree compared with 45.4% of nurses, while 48.3% of nurses held a junior college degree compared with 25.7% of doctors. Higher levels of professional title and registration in general practice were found in doctors compared with nurses. The proportions of NCDs' category, NCDs-related roles and tasks, NCDs-related training contents and forms that CHWs have attend and hoped to gain more were significantly different between doctors and nurses (P < 0.001). In general, the proportions in nurses were much lower than those of doctors (P < 0.05). The top five diseases managed by CHWs were hypertension, diabetes, cerebrovascular disease, chronic respiratory diseases and mental diseases. The five most reported roles performed among doctors included the distribution of health education (91.4%), following up (85.9%), establishing archives (71.3%), medicine adjustment (64.7%) and treatment implementation (52.0%). The top three diseases managed by nurses were same with doctors. The top four and five tasks were contact with patients or health services (39.6%) and referral (16.6%) in nurses. Most CHWs had received primary and common diseases-related trainings, but they had few opportunities to study in a tertiary hospital (40.4% in doctors and 20.9% in nurses, respectively), attend domestic academic conferences (26.9% in doctors vs. 9.7% in nurses), and take part in training courses (44.9% in nurses). CHWs hoped that the above-discussed training contents and forms could be provided more in the future. Besides basic skills related trainings, some specific skills related trainings should be strengthened. CONCLUSION: The qualifications in doctors were much better than those of nurses. The roles performed by CHWs in NCDs management are varied form common and frequent disease management to subsequent follow up and supervision. CHWs hope to receive more desired and oriented trainings. There is a need for building capacity of CHWs, optimizing and defining CHWs' role, facilitating postgraduate medical education support and strengthening multidisciplinary collaboration would be effective in NCDs management.

Evolution of cephalic structures in extreme myrmecophiles: a lesson from Clavigeritae (Coleoptera: Staphylinidae: Pselaphinae).

Pselaphinae is a large subfamily, comprising over 10 000 species of the megadiverse Staphylinidae (rove beetles). A remarkable feature of this group is the extreme structural diversity of different body regions, especially the head and its appendages. Within Pselaphinae, Clavigeritae stand out as a clade of highly specialized myrmecophiles. We examined internal and external head structures of the clavigerite species Diartiger kubotai Nomura, using state-of-the-art techniques. The cephalic morphology indicates in a phylogenetic context that the loss of eyes in some Clavigeritae was the latest of major evolutionary changes. We compiled the largest set of morphological data ever scored for the subfamily, comprising 155 characters of the head. Parsimony analyses and Bayesian inference yielded a similar phylogenetic pattern, largely congruent with results published previously. We retrieved Pselaphinae as a clade, and Faronitae as sister to all remaining groups of the subfamily. Faronitae are followed by a "Euplectitae grade" and non-monophyletic Goniaceritae, Batrisitae and Pselaphitae. Clavigeritae are monophyletic, but have evolved within the pselaphite grade. The enigmatic Colilodion Besuchet, recently shifted from Clavigeritae to a paraphyletic Pselaphitae, was placed as sister to extant clavigerites based on an array of cephalic synapomorphies. The current classification of Pselaphinae is unstable and deep changes should be made maintaining only monophyletic units, whereas most of the supertribes are paraphyletic. Characters of the head, with a concentration of mouthparts and sensory structures, and essential parts of the digestive tract and the nervous system, are highly informative phylogenetically. Study of internal structures, presently still at a very preliminary stage, obviously is essential for understanding the evolution of Pselaphinae. Future genetic investigations may reveal mechanisms behind the unique structural megadiversity in this exceptional group of rove beetles.

Synthesis, evaluation and mechanism exploration of 2-(N-(3-nitrophenyl)-N-phenylsulfonyl)aminoacetohydroxamic acids as novel urease inhibitors.

Thirteen 2-(N-(3-nitrophenyl)-N-phenylsulfonyl)aminoacetohydroxamic acids which were reported for the first time were designed and synthesized as novel urease inhibitors. Most of them showed higher potency than the positive control acetohydroxamic acid, with 2-(N-(3-nitrophenyl)-N-(4-bromophenylsulfonyl)aminoacetohydroxamic acid (d7) being the most active (IC50 = 0.13 ± 0.01 µM). Compound d7 reversibly inhibits urease with mixed mechanism showing excellent binding affinity to urease active site (KD = 0.34 nM, Ki=0.065 ± 0.003 µM andKi' = 1.20 ± 0.09 µM) and very low cytotoxicity against mammalian cells (cell viability of 91.4 % against HepG2 at 250 µg/mL). These positive results indicated that d7 may be used as the lead for further research to develop urease inhibitors with promising properties.

Analysis on the relationship between effort-reward imbalance and job satisfaction among family doctors in China: a cross-sectional study.

BACKGROUND: Family doctor contract services was launched in Sichuan province in 2016. The focus was mainly on developing primary health care services but paying less attention to the work stress and job satisfaction of in-service family doctors. OBJECTIVE: This study aims to explore the influencing factors of job satisfaction, and the relation between work stress indicators and job satisfaction among family physicians. METHODS: An analytical online cross-sectional survey was performed among 1,105 family doctors from 23 districts and counties in Chengdu. Self-administered questionnaire was completed. Sociodemographic factors, work stress measured by Effort-Reward Imbalance (ERI)scale, and job satisfaction assessed by the short Chinese version of the Minnesota Satisfaction Questionnaire (MSQ) were collected in this study. A statistical analysis and hierarchical linear regression analysis were performed to explore the influencing factors and the correlations among related variables. RESULTS: The overall mean MSQ score was 52.01 ± 13.23. Analysis of doctor satisfaction indicated that age, education, job rank, type of institution, years of working and monthly income were statistically significant (P < 0.05). There were negative correlation coefficients between general job satisfaction and effort/reward ratio (ERR) (r = -0.130, P < 0.001) and overcommitment (r = -0.615, P < 0.001). CONCLUSION: The level of job satisfaction among family doctors was considerable low. Age, education, job rank, type of institution, years of working and monthly income were influencing factors of job satisfaction. ERI and overcommitment had a negative correlation with general job satisfaction.

Study on the effects of different postprandial positions on blood pressure and heart rate in older adults with primary hypertension and postprandial hypotension.

This randomized controlled trial explored the effects of a supine position or a semi-fowler position on postprandial blood pressure (BP) of older adults with primary hypertension and postprandial hypotension (PPH). Ninety-six participants were divided into the supine group, the semi-fowler group, and the control group with block-randomization. After a meal, the patients were placed in a supine position, a 45° semi-fowler position, or allowed daily activities, respectively. BP, heart rate and PPH symptoms were measured 5 times in 120 minutes after the meal. Repeated measurement analysis showed no statistical difference in BP, heart rate and PPH symptom scores among the three groups. BP in all groups decreased rapidly at the 30-minute point, and then moved steadily downward. Taking a supine position or semi-fowler position after meals had no effect on postprandial BP and heart rate after meals in older adults with hypertension and PPH.

N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation.

A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10-3 s-1) from the catalytic domain.

Efficacy and safety of ceritinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-resistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC. METHODS: We searched articles published from January 1980 to March 2019 in PubMed, EMBASE, Cochrane Library and Web of Science. The pooled estimate and 95% CI were calculated with DerSimonian-Laird method and the random effect model. RESULTS AND DISCUSSION: From 15 articles, 2,598 patients were included in the meta-analysis. Eleven studies reported the ORR, and the DCR was presented in 10 studies. The ORR and DCR of ceritinib were 0.48 (95% CI, 0.39-0.57) and 0.76 (95% CI, 0.69-0.82), respectively. The PFS and OS were presented in nine and three eligible studies, respectively. The PFS and OS of ceritinib were 7.26 months (95% CI, 5.10-9.43) and 18.73 months (95% CI; 14.59-22.87). These results suggested that ceritinib can effectively treat patients with ALK-rearranged NSCLC. Diarrhoea, nausea and vomiting were the three most common AEs and occurred in 69% (95% CI 51.7-87.1%), 66% (95% CI 47.0-85.8%) and 51% (95% CI 35.9-66.8%) of patients, respectively. Considering serious gastrointestinal AEs, antiemetic and antidiarrhoeal drugs should be considered to improve a patient's tolerance to ceritinib. WHAT IS NEW AND CONCLUSION: Ceritinib is effective in the treatment of patients with ALK-rearranged NSCLC with crizotinib resistance. The DCR was up to 76%, and PFS was extended to 7.6 months. The AEs were acceptable.

Local intra-gestational sac methotrexate injection followed by dilation and curettage in treating cesarean scar pregnancy.

PURPOSE: To assess the safety and efficacy of local intra-gestational sac methotrexate injection followed by dilation and curettage (D&C) in treating cesarean scar pregnancies (CSP). METHOD: Medical records of CSP patients treated with local intra-gestational sac methotrexate injection followed by dilation and curettage were analyzed at the Maternal and Child Hospital of Guangxi Zhuang Autonomous Region, China. RESULTS: Thirty-one patients were included in this study. The mean gestational age, sac diameter and thickness of the uterine scar were 49.6 ± 7.7 days, 1.8 ± 0.6 cm and 0.30 ± 0.15 cm, respectively. The median pretreatment serum ß-human chorionic gonadotropin (ß-HCG) level was 40,887 mIU/mL, with the 25th and 75th percentiles at 19,852 and 74,552, respectively. The median blood loss during D&C was 20 mL with the 25th and 75th percentiles at 10 mL and 50 mL. Following D&C, a Foley's balloon catheter compression was implanted in 26 (83.9%) patients due to active uterine bleeding. All patients had a ß-HCG regression time of ≤ 4 weeks after D&C. While 30 patients (96.8%) had a uterine recovery time of ≤ 4 weeks, and 29 patients (93.5%) had resumption of menstruation of less than 6 weeks. Three patients (9.7%) had complications. One of them suffered from massive vaginal bleeding and underwent s blood transfusion. There were no other complications, such as pelvic infection and uterine rupture during the procedures. And no patient was converted to surgical resection or uterine artery embolization. Overall, 30 patients (96.8%) were treated successfully. CONCLUSION: Local intra-gestational sac methotrexate injection followed by D&C with the aid of a Foley's balloon catheter compression appears to be a safe and effective treatment for CSP. Further randomized controlled trials are suggested to confirm these findings.

A Hyperspectral Image Classification Approach Based on Feature Fusion and Multi-Layered Gradient Boosting Decision Trees.

At present, many Deep Neural Network (DNN) methods have been widely used for hyperspectral image classification. Promising classification results have been obtained by utilizing such models. However, due to the complexity and depth of the model, increasing the number of model parameters may lead to an overfitting of the model, especially when training data are insufficient. As the performance of the model mainly depends on sufficient data and a large network with reasonably optimized hyperparameters, using DNNs for classification requires better hardware conditions and sufficient training time. This paper proposes a feature fusion and multi-layered gradient boosting decision tree model (FF-DT) for hyperspectral image classification. First, we fuse extended morphology profiles (EMPs), linear multi-scale spatial characteristics, and nonlinear multi-scale spatial characteristics as final features to extract both special and spectral features. Furthermore, a multi-layered gradient boosting decision tree model is constructed for classification. We conduct experiments based on three datasets, which in this paper are referred to as the Pavia University, Indiana Pines, and Salinas datasets. It is shown that the proposed FF-DT achieves better performance in classification accuracy, training conditions, and time consumption than other current classical hyperspectral image classification methods.

[Clinical cases and experimental evaluation of liver injury related to anti-psoriasis Keyin Pills].

Keyin Pills is a kind of traditional Chinese medicine for the treatment of psoriasis, but it has been reported that it can cause serious liver injury. In this paper, we used the integrated evidence chain method to retrieve and reevaluate the adverse drug reaction database, CNKI literature and cases of liver injury relating to Keyin Pills in specialist hepatology hospitals. We screened out 23 cases with the causal relationship of the possible grade and above. Among them, 11 cases showed the positive causal relationship only with Keyin Pills, accounting for 47.83%, suggesting that there was objective liver injury caused by Keyin Pills. The incubation period of liver injury caused by Keyin Pills is 1-90 days, and the cumulative dosage span is 20-1 800 g. There were obvious individual diffe-rences. There was no relationship between liver injury as well as dose and course of treatment, suggesting that Keyin Pills could induce immune idiosyncratic liver injury. Furthermore, based on the liver injury model induced by immunological stress, it was confirmed that Keyin Pills could induce acute liver injury in a dose-dependent manner in rats with immunological stress. The toxic dose(14 g·kg~(-1)) of a single dose was 6.7 times of the clinical equivalent dose, and had no significant effect on the biochemical index of liver function and histopathology in normal rats. Decomposition experiments showed that Dictamnus dasycarpus in Keyin Pills is the main medicinal flavor that causes special liver injury, and the other three medicines had neither liver injury nor compatibility attenuation effect. The results suggest that clinical medication shall pay attention to the risk of liver injury caused by Keyin Pills in patients with immunological stress.

The synthesis and evaluation of phenoxyacylhydroxamic acids as potential agents for Helicobacter pylori infections.

Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC50 = 0.061 ±â€¯0.003 µM) and intact cell (IC50 = 0.89 ±â€¯0.05 µM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds.

Characterization of the novel protein KIAA0564 (Von Willebrand Domain-containing Protein 8).

The VWA8 gene was first identified by the Kazusa cDNA project and named KIAA0564. Based on the observation, by similarity, that the protein encoded by KIAA0564 contains a Von Willebrand Factor 8 domain, KIAA0564 was named Von Willebrand Domain-containing Protein 8 (VWA8). The function of VWA8 protein is almost unknown. The purpose of this study was to characterize the tissue distribution, cellular location, and function of VWA8. In mice VWA8 protein was mostly distributed in liver, kidney, heart, pancreas and skeletal muscle, and is present as a long isoform and a shorter splice variant (VWA8a and VWA8b). VWA8 protein and mRNA were elevated in mouse liver in response to high fat feeding. Sequence analysis suggests that VWA8 has a mitochondrial targeting sequence and domains responsible for ATPase activity. VWA8 protein was targeted exclusively to mitochondria in mouse AML12 liver cells, and this was prevented by deletion of the targeting sequence. Moreover, the VWA8 short isoform overexpressed in insect cells using a baculovirus construct had in vitro ATPase activity. Deletion of the Walker A motif or Walker B motif in VWA8 mostly blocked ATPase activity, suggesting Walker A motif or Walker B motif are essential to the ATPase activity of VWA8. Finally, homology modeling suggested that VWA8 may have a structure most confidently similar to dynein motor proteins.

Liver X receptors agonists suppress NLRP3 inflammasome activation.

Inflammasomes are multiprotein complexes that control the production of IL-1ß and IL-18. NLRP3 inflammasome, the most characterized inflammasome, plays prominent roles in defense against infection, however aberrant activation is deleterious and leads to diseases. Therefore, its tight control offers therapeutic promise. Liver X receptors (LXRs) have significant anti-inflammatory properties. Whether LXRs regulate inflammasome remains unresolved. We thus tested the hypothesis that LXR's anti-inflammatory properties may result from its ability to suppress inflammasome activation. In this study, LXRs agonists inhibited the induction of IL-1ß production, caspase-1 cleavage and ASC oligomerization by NLRP3 inflammasome. The agonists also inhibited inflammasome-associated mtROS production. Importantly, the agonists inhibited the priming of inflammasome activation. In vivo data also showed that LXRs agonist prevented NLRP3-dependent peritonitis. In conclusion, LXRs agonists are identified to potently suppress NLRP3 inflammasome and the regulation of LXRs signaling is a potential therapeutic for inflammasome-driven diseases.

Imaging the Transformation of Ipsilateral Internal Capsule Following Focal Cerebral Ischemia in Rat by Diffusion Kurtosis Imaging.

BACKGROUND: The purpose of our study is to explore the relationship between recovery of neural function and transformation of the internal capsule (IC) after transient middle cerebral artery occlusion (MCAO) by using diffusion kurtosis imaging (DKI). METHODS: Six male adult Sprague-Dawley rats implemented with transient MCAO were used in this study. Sensorimotor function was assessed according to repetitive behavioral testing on day 1, 3, 7, 14, and 28 after cerebral ischemia. Metrics of DKI were acquired, and the time course of the region-to-normal ratio was evaluated in IC. RESULTS: After cerebral ischemia, relative fractional anisotropy in IC decreased on day 3 (P < .01). Relative mean diffusivity (rMD) increased on day 28 (P < .05). Relative mean diffusional kurtosis (rMK) increased on day 3 (P < .01) and decreased on day 7 (P < .05). Relative axial diffusional kurtosis (rKa) increased on day 3 (P < .01) and declined on day 7 (P < .05). Relative radial diffusional kurtosis (rKr) was reduced on day 7 (P < .05). Changes in rMK were larger than changes in rMD on day 3 (P < .05). The factor of rKa and rKr revealed marked difference on day 7 (P < .05) and day 14 (P < .05). Neurological function score showed that rats exhibited functional recovery from day 7 (P < .01) post stroke. CONCLUSIONS: This longitudinal multiparametric magnetic resonance imaging study suggested that K metrics offers information complimentary to conventional diffusion metrics and revealed the procedure during the structural modification in the ipsilateral IC following focal cerebral ischemia. After transient MCAO, the neural transformation occurred in a time-dependent procedure.

Combining systemic and stereotactic MEMRI to detect the correlation between gliosis and neuronal connective pathway at the chronic stage after stroke.

BACKGROUND: The early dysfunction and subsequent recovery after stroke, characterized by the destruction and remodeling of connective pathways between cortex and subcortical regions, is associated with neuroinflammation. As major components of the inflammatory process, reactive astrocytes have double-edged effects on pathological progression. The temporal patterns of astrocyte and neuronal pathway activity can be revealed by systemic and stereotactic manganese-enhanced magnetic resonance imaging (MEMRI), respectively. In the present study, we aimed to detect an association between astrocyte activity and recovery of neuronal connective pathways by combining systemic with stereotactic MEMRI. METHODS: Fifty adult rats, divided into two groups, underwent a 60-min occlusion of the middle cerebral artery. The groups were given either a systemic administration or stereotactic injection of MnCl2 at 1, 3, 7, and 14 days after stroke and underwent MRI 4 and 2 days later, respectively. Immunofluorescence (IF) of group 1 was conducted to corroborate the results. Repetitive behavioral testing was also performed with all rats at 1, 3, 7, and 14 days to obtain a functional score. RESULTS: Ring- or crescent-shaped enhancements formed in the striatal peri-infarct regions (STR) at 11 and 18 days. This was concurrent with the activity of glial fibrillary acidic protein (GFAP)-positive astrocytes, which mainly localized at the peri-infarct region and significantly increased in number at 11 and 18 days after stroke. Microglia/macrophages, detected by IF, mainly localized in the lesion core, rather than in the region of enhancement. The ipsilateral substantia nigra (SN) revealed Mn-related signal enhancement reduction and subsequent signs of the recovery process at 3 to 5 days and 9 to 16 days, respectively. Behavioral testing showed that sensorimotor functions were initially disturbed, but subsequently recovered at 7 and 14 days. CONCLUSIONS: We found a positive temporal correlation between astrogliosis and the recovery of neuronal connective pathways at the chronic stage by using the in vivo method of MEMRI. Our results highlighted the potential contribution of astrocytes to the neuronal recovery of these connective pathways.

3-Arylpropionylhydroxamic acid derivatives as Helicobacter pylori urease inhibitors: Synthesis, molecular docking and biological evaluation.

Helicobacter pylori urease is involved in several physiologic responses such as stomach and duodenal ulcers, adenocarcinomas and stomach lymphomas. Thus, inhibition of urease is taken for a good chance to treat H. pylori-caused infections, we have therefore focused our efforts on seeking novel urease inhibitors. Here, a series of arylpropionylhydroxamic acids were synthesized and evaluated for urease inhibition. Out of these compounds, 3-(2-benzyloxy-5-chlorophenyl)-3-hydroxypropionylhydroxamic acid (d24) was the most active inhibitor with IC50 of 0.15±0.05µM, showing a mixed inhibition with both competitive and uncompetitive aspects. Non-linear fitting of kinetic data gives kinetics parameters of 0.13 and 0.12µg·mL(-1) for Ki and Ki', respectively. The plasma protein binding assays suggested that d24 exhibited moderate binding to human and rabbit plasma proteins.

The development of dual-label time-resolved fluorescence immunoassay (TRFIA) for screening of ovarian cancer based on simultaneous detection of human epididymis protein-4 and cancer antigen 125.

A two-step dual-label TRFIA was developed for the simultaneous detection of human epididymis protein-4 and cancer antigen 125 in a single run. The performance of this assay was first evaluated using clinical serum samples, and then compared with commercialized kits. The sensitivity of this assay for cancer antigen 125 detection was 0.5 U/mL (dynamic range, 0-1400 U/L), and the sensitivity for human epididymis protein-4 detection was 1 pM (dynamic range, 1-900 pM). High correlation coefficients (R) were obtained between the present dual-label TRFIA and commercially available kits (R = 0.99). The present dual-label TRFIA has high sensitivity, specificity, and accuracy in clinical sample analysis. It is a good alternative to the single-label diagnostic methods.