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Febrifugine, a natural alkaloid, exhibits specific anti-phytophthora activity; however, its mode of action is unclear. In this study, halofuginone, a synthetic derivative of febrifugine, showed significantly higher anti-phytophthora activities than those of febrifugine and the commercial drug metalaxyl against

Galactosylated chitosan-coated liposome improved the therapeutic efficacy of oleanolic acid for the treatment of hepatocellular carcinoma through hepatocyte-targeted delivery, as demonstrated by using an axillary tumor xenograft mouse model.

Ischemic stroke can induce neurogenesis. However, most stroke-generated newborn neurons cannot survive. It has been shown that MR-409, a potent synthetic agonistic analog of growth hormone–releasing hormone (GHRH), can protect against some life-threatening pathological conditions by promoting cell proliferation and survival. The present study shows that long-term treatment with MR-409 (5 or 10 μg/mouse/d) by subcutaneous (s.c.) injection significantly reduces the mortality, ischemic insult, and hippocampal atrophy, and improves neurological functional recovery in mice operated on for transient middle cerebral artery occlusion (tMCAO). Besides, MR-409 can stimulate endogenous neurogenesis and improve the tMCAO-induced loss of neuroplasticity. MR-409 also enhances the proliferation and inhibits apoptosis of neural stem cells treated with oxygen and glucose deprivation–reperfusion. The neuroprotective effects of MR-409 are closely related to the activation of AKT/CREB and BDNF/TrkB pathways. In conclusion, the present study demonstrates that GHRH agonist MR-409 has remarkable neuroprotective effects through enhancing endogenous neurogenesis in cerebral ischemic mice.

Tumor-associated macrophages (TAMs) are a type of functionally plastic immune cell population in tumor microenvironment (TME) and mainly polarized into two phenotypes: M2 and M1-like TAMs. The M2-like TAMs could stimulate tumor growth and metastasis, tissue remodeling and immune-suppression, whereas M1-like TAMs could initiate immune response to dampen tumor progression. TAMs with different polarization phenotypes can produce various kinds of cytokines, chemokines and growth factors to regulate immunity and inflammatory responses. It is an effective method to treat cancer through ameliorating TME and modulating TAMs by converting M2 into M1-like phenotype. However, intracellular signaling mechanisms underlying TAMs polarization are largely undefined. Phosphoinositide 3-kinase (PI3K)/Akt is an important signaling pathway participating in M2-like TAMs polarization, survival, growth, proliferation, differentiation, apoptosis and cytoskeleton rearrangement. In the present review, we analyzed the mechanism of TAMs polarization focusing on PI3K/Akt and its downstream mitogen‑activated protein kinase (MAPK) as well as nuclear factor kappa B (NF-κB) signaling pathways, thus provides the first evidence of intracellular targets for cancer immunotherapy.

The degradation of phenol in Cl−-rich water by Fe(VI) was investigated using both chromatographic methods (HPLC and IC) and an on-line direct mass spectrometry (MS) analysis technique. Participation of Cl− during phenol degradation was observed through the formation of p-chlorophenol and coupled species with phenol. Though only a small concentration of Cl− was involved in the reaction, the presence of Cl− could affect the behavior of phenol substantially. With the increase of the Cl− concentration, generation of p-benzoquinone and p-chlorophenol was increased. Meanwhile, phenol in the bulk solution displayed a sharp decline followed by a gradual increase. The developed on-line MS analysis facilitated real-time monitoring of phenol changes in the reaction system. The results showed that phenol degradation by Fe(VI) with the presence of a high concentration of Cl− followed a second-order reaction process. The degradation pathway of phenol was also identified, with p-chlorophenol, p-benzoquinone, maleic acid and formic acid as the main byproducts.

Citri reticulatae pericarpium (CRP) shows multiple bioactivities, including antioxidant, anti-tumor, and anti-inflammation. The folk proverb “CRP, the older, the better” means storing for longer time would improve its quality, which attributed to the influence of bioactive compounds. The aim of this work was to study which compounds are the factors that long storage would influence the quality of CRP. 161 compounds, including 65 flavonoids, 51 phenolic acids, 27 fatty acids, and 18 amino acids were identified through derivatization and non-derivatization liquid chromatography mass spectrometry approaches. Their dynamic changes indicated phenolic acids, which were reported to have various activities, were the main increased components. Furthermore, the representative phenolic acids were quantified and correlation analysis between their contents and antioxidant activity implicated they were the possible indicators that long storage would improve CRP quality. The results would provide basis for quality control of CRP during storage.

There is growing evidence that uridine may act as an endogenous neuromodulator with a potential signaling role in the central nervous system in addition to its function in pyrimidine metabolism. We previously found that acute morphine treatment significantly increased uridine release in the dorsal striatum of mice, indicating that uridine may contribute to morphine-induced neurobehavioral changes. In the present study, we analyzed the mechanism involved in morphine-induced uridine release and the role of uridine in morphine-induced neurobehavioral changes. Uridine release in the dorsal striatum of mice was assessed by in vivo microdialysis coupled with high performance liquid chromatography (HPLC) after morphine treatment. Western blotting and immunofluorescence were used to evaluate the expression of uridine-related proteins. Morphine-induced neurobehavioral changes were assessed by locomotor activity, behavioral sensitization and conditioned place preference (CPP) test. The expression of NT5E, an extracellular enzyme involved in formation of nucleosides, including uridine, was specifically knocked down in the dorsal striatum of mice using adeno-associated virus (AAV)-mediated short hairpin RNA (shRNA). The results indicated that both acute and chronic morphine administration significantly increased uridine release in the dorsal striatum, and this was associated with upregulation of NT5E but not other uridine-related proteins. Inhibition of NT5E with APCP or shRNA markedly inhibited morphine-induced uridine release in the dorsal striatum and related neurobehavioral changes, including hyperlocomotor activity, behavioral sensitization and CPP. Our data give a better understanding of the contribution of NT5E to morphine-induced uridine release and neurobehavioral changes, and identify NT5E as a potential target for treating morphine abuse.

Propensity to relapse, even after long-term abstinence, is a crucial feature of methamphetamine (METH) abuse. We and other laboratories have reported that acute treatment of oxytocin (OXT), a hormone and neuropeptide, could inhibit reinstatement of METH seeking in animal studies. However, the effects of repeated OXT treatment on METH reinstatement as well as underlying mechanisms are still unclear. In the present study, the effects of repeated OXT treatment during abstinence on context- or restraint stress-induced reinstatement were investigated using the mice conditioned place preference (CPP) paradigm. After three intermittent injections of METH (2 mg/kg, i.p.) to induce CPP, mice received a daily bilateral intra-hippocampus injection of OXT (0.625, 1.25 or 2.5 μg) for 8 consecutive days before the context- or restraint stress-induced reinstatement test. Meanwhile, adult hippocampal neurogenesis (AHN) level was detected using immunostaining. To further clarify the role of AHN underlying OXT's effects on METH-CPP reinstatement, temozolomide (TMZ, 25 mg/kg, i.p.) was employed to deplete AHN prior to OXT treatment. The data showed that repeated OXT treatment (1.25 and 2.5 μg, intra-hippocampus) significantly inhibited both context- and restraint stress-induced METH-CPP reinstatement and concomitantly promoted AHN in a dose-dependent manner. Notably, TMZ pre-treatment markedly abolished all the above-mentioned effects of OXT, suggesting that AHN was closely involved in OXT's inhibition on reinstatement induced by both triggers. Taken together, the present study indicated that repeated OXT treatment during abstinence could inhibit both context- and restraint stress-induced METH-CPP reinstatement possibly by promoting AHN in mice, which provided a better understanding for OXT's beneficial effects on METH addiction.

Drugs of abuse, including morphine and cocaine, can reduce hippocampal neurogenesis (HN). Whereas promotion of HN is being increasingly recognized as a promising strategy for treating morphine and cocaine addiction. The present study is focused on exploring the changes of HN during methamphetamine (METH) administration and further clarify if HN is involved in METH-associated reward memory. After successfully establishing the conditioned place preference (CPP) paradigm to simulate the METH-associated reward memory in C57BL/6 mice, we observed that HN was significantly inhibited during METH (2 mg/kg, i. p.) administration and returned to normal after the extinction of METH CPP, as indicated by the immunostaining of bromodeoxyuridine (BrdU) and doublecortin (DCX) in the hippocampus. To promote/inhibit HN levels, 7,8-dihydroxyflavone (DHF), a small tyrosine kinase receptor B (TrkB) agonist and temozolomide (TMZ), an alkylating agent, were administered intraperitoneally (i.p.), respectively. The data showed that either DHF (5 mg/kg, i. p.) or TMZ (25 mg/kg, i. p.) pre-treatment before METH administration could significantly prolong extinction and enhance reinstatement of the reward memory. Notably, DHF treatment after METH administration significantly facilitated extinction and inhibited METH reinstatement, while TMZ treatment resulted in opposite effects. The present study indicated that METH administration could induce a temporal inhibitory effect on HN. More importantly, promotion of HN after the acquisition of METH-associated reward memory, but not inhibition of HN or promotion of HN before the acquisition of reward memory, could facilitate METH extinction and inhibit METH reinstatement, indicating the beneficial effect of HN on METH addiction by erasing the according reward memory.

Drug addiction is one of the leading causes of mortality worldwide. Despite great advances were achieved in understanding the neurobiology of drug addiction, the therapeutic options are severely limited, with poor effectiveness and serious side effects. The neuropeptide oxytocin (OXT) is well known for its effects on uterine contraction, sexual/maternal behaviors, social affiliation, stress and learning/memory by interacting with the OXT receptor and other neuromodulators. Emerging evidence suggests that the acute or chronic exposure to drugs can affect the OXT system. Additionally, OXT administration can ameliorate a wide range of abused drug-induced neurobehavioral changes. Overall, OXT not only suppresses drug reward in the binge stage of drug addiction, but also reduces stress responses and social impairments during the withdrawal stage and, finally, prevents drug/cue/stress-induced reinstatement. More importantly, clinical studies have also shown that OXT can exert beneficial effects on reducing substance use disorders of a series of drugs, such as heroin, cocaine, alcohol, cannabis and nicotine. Thus, the present review focuses on the role of OXT in treating drug addiction, including the preclinical and clinical therapeutic potential of OXT and its analogs on the neurobiological perspectives of drugs, to provide a better insight of the efficacy of OXT as a clinical addiction therapeutic agent.

Thienopyridines and related heterocycles were prepared in a straightforward manner in moderate to good yields and under mild conditions by palladium-catalysed cross-coupling of ortho-fluorinated iodopyridines and terminal alkynes, followed by a reagent-capsule-assisted thiolation cyclization process. By applying paraffin wax capsules to prevent catalyst poisoning and undesired side reactions, the separation and purification processes were reduced.

The copper-catalyzed cycloamination reaction of 1,1-dibromoalkenes with amidines affords a diverse set of polysubstituted haloimidazole derivatives. By using this strategy, high regio- and chemoselectivity has been achieved, using 4,7-diphenyl-1,10-phenanthroline as ligand without the addition of expensive catalysts to provide moderate to good yields.

Glyphosate is one of the most commonly used herbicides worldwide due to its broad spectrum of activity and reported low toxicity to humans. Glyphosate has an amino acid-like structure that is highly polar and shows low bioavailability following oral ingestion and low systemic toxicity following intravenous exposures. Spray applications of glyphosate in agricultural or residential settings can result in topical or inhalation exposures to the herbicide. Limited systemic exposure to glyphosate occurs following skin contact, and pulmonary exposure has also been reported to be low. The results of nasal inhalation exposures, however, have not been evaluated. To investigate the mechanisms of glyphosate absorption across epithelial tissues, the permeation of glyphosate across Caco-2 cells, a gastrointestinal epithelium model, was compared with permeation across nasal respiratory and olfactory tissues excised from cows. Saturable glyphosate uptake was seen in all three tissues, indicating the activity of epithelial transporters. The uptake was shown to be ATP and Na(+) independent, and glyphosate permeability could be significantly reduced by the inclusion of competitive amino acids or specific LAT1/LAT2 transporter inhibitors. The pattern of inhibition of glyphosate permeability across Caco-2 and nasal mucosal tissues suggests that LAT1/2 play major roles in the transport of this amino-acid-like herbicide. Enhanced uptake into the epithelial cells at barrier mucosae, including the respiratory and gastrointestinal tracts, may result in more significant local and systemic effects than predicted from glyphosate's passive permeability, and enhanced uptake by the olfactory mucosa may result in further CNS disposition, potentially increasing the risk for brain-related toxicities.

Strategic management for economic development has been the hallmark of the Singapore ‘success story.’ State-led, market-driven intervention underscored the city-state's development strategies. This paper revisits this development blueprint in the context of Singapore's efforts at regionalization. The paper takes a closer look at Singapore's state enterprise strategy, and the ‘portability’ of the strat-egy–in the framework of Regionalization 2000–beyond the city-state. It concludes that the calculated, schematised efforts, though remarkable, have been overly optimistic and have failed to engender equally compelling results, more often than not frustrated by the intricacies of socio-political realities in the host economies.

Purpose: We present a validation study of CT and PET lung image registration and fusion based on the chamfer-matching method. Methods and Materials: The contours of the lung surfaces from CT and PET transmission images were automatically segmented by the thresholding technique. The chamfer-matching technique was then used to register the extracted lung surfaces. Arithmetic means of distance between the two data sets of the pleural surfaces were used as the cost function. Matching was then achieved by iteratively minimizing the cost function through three-dimensional (3D) translation and rotation with an optimization method. Results: Both anatomic thoracic phantom images and clinical patient images were used to evaluate the performance of our registration system. Quantitative analysis from five patients indicates that the registration error in translation was 2–3 mm in the transverse plane, 3–4 mm in the longitudinal direction, and about 1.5 degree in rotation. Typical computing time for chamfer matching is about 1 min. The total time required to register a set of CT and PET lung images, including contour extraction, was generally less than 30 min. Conclusion: We have implemented and validated the chamfer-matching method for CT and PET lung image registration and fusion. Our preliminary results show that the chamfer-matching method for CT and PET images in the lung area is feasible. The described registration system has been used to facilitate target definition and treatment planning in radiotherapy.

A simple algorithm is presented for planar image registration and the method is applied to the simulator and portal image registration for patient setup verification in radiation therapy. Basically, the algorithm follows the concept proposed by Balter et al. [Med. Phys. 19, 329-334 (1992)], which converts the problem of open curve registration into matching a series of points along the curves. Balter's algorithm consists of three steps: (1) to determine a common starting point for each curve pair, (2) acquire two corresponding point sets along each curve, and (3) obtain a global transform matrix by matching two point sets. We integrate all three steps into one simple procedure which fits the sampled points along the intended curve pair by taking the relative path length shift as an independent fitting parameter. After being modified, the algorithm is able to take the different magnification factors of images into account, and it avoids curvature calculations. Numerical simulation as well as clinical and phantom images have been utilized to test the accuracy of the algorithm. The typical errors are less than 1 mm in translation and 1 degree in rotation. We also made a comparison study with the chamfer method. The results of the two methods agree to within 0.5 mm in translation and 0.5 degree in rotation.

The conventional method for source localization in an interstitial ribbon implant by means of biplane radiographs can be difficult, especially when a large number of seeds are involved. We present a new algorithm for more efficient source localization with the same conventional biplane radiographs. The method does not require a one-to-one source correspondence between two radiographs. The user needs only to digitize several points, following the shape of each ribbon from both films. The points that are digitized do not need to be the location of the seeds, and they do not have to correspond to the same points on both films. The algorithm uses the multidimensional minimization method to reconstruct the three-dimensional locus of the ribbon. The location of each seed is then determined by its pathlength relative to the corresponding starting point. We have used phantom experiments and clinical cases to test the reliability of the algorithm. The results show that the errors in the determination of seed locations are less than 2 mm, and the efficiency in source digitization for data entry can be increased by a factor up to 5.

A least square fitting algorithm for alignment of multi-open-curved segments and point pairs of anatomical features obtained from both portal images and simulation radiographs has been developed for patient position verification in radiation therapy. A coordinate system associated with each curved segment pair is constructed so that the discrepancies of each segment pair can be obtained easily. The algorithm allows users to select not only multiple curve pairs but also individual point pairs on the important anatomic landmarks. The misregistration is measured by the sum of the position deviation of individual point pairs and ordinate discrepancies of all segment pairs from their corresponding coordinate systems. A mathematical minimization method is applied to seek an optimal transformation for matching of all segment and/or point pairs involved. The reliability of the algorithm has been tested with both phantom and clinical images. The test results indicate that the typical errors are less than 1 mm and 1 degrees in translation and rotation, respectively.