BACKGROUND AND PURPOSE
Caffeic acid phenethyl ester (CAPE) is a component of honey bee propolis that can induce expression of haem oxygenase‐1 (HO‐1). Because HO‐1 induction has been suggested to ...protect dopaminergic neurons in the substantia nigra, we examined the effect of CAPE in experimental models of dopaminergic neurodegeneration.
EXPERIMENTAL APPROACH
Neuroprotective effect of CAPE was investigated in rat organotypic midbrain slice cultures and in vivo, using a mouse model of dopaminergic neurodegeneration induced by intranigral injection of LPS and intrastriatal injection of 6‐hydroxydopamine.
KEY RESULTS
CAPE protected dopaminergic neurons in slice cultures from IFN‐γ/LPS‐induced injury. The effect of CAPE was inhibited by zinc protoporphyrin IX, an HO‐1 inhibitor, and by neutralizing antibody against brain‐derived neurotrophic factor (BDNF). A p38 MAPK inhibitor SB203580 prevented activation of NF‐E2‐related factor 2, attenuated increased expression of HO‐1 and BDNF, and blocked the neuroprotective actions of CAPE. In the LPS‐injected mouse model, daily intraperitoneal administration of CAPE protected dopaminergic neurons, up‐regulated HO‐1 and BDNF, and reduced the increase of activated microglia/macrophages. Neuroprotective effects of CAPE against LPS‐induced injury was prevented by zinc protoporphyrin IX or anti‐BDNF antibody. CAPE protected dopaminergic neurons and alleviated methamphetamine‐induced rotational behaviour also in 6‐hydroxydopamine hemiparkinsonian mice.
CONCLUSION AND IMPLICATIONS
CAPE is a novel type of neuroprotective agent whose actions are mediated by both HO‐1 and BDNF. These findings may provide novel clues to develop neuroprotective agents for treatment of neurodegenerative disorders.
Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although ...increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated.
In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore.
ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity.
Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection.
JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).
Abstract
In a bulk solid, optical control of atomic motion provides a better understanding of its physical properties and functionalities. Such studies would benefit from active control and ...visualization of atomic motions in arbitrary directions, yet, so far, mostly only one-dimensional control has been shown. Here we demonstrate a novel method to optically control and visualize two-dimensional atomic motions in a bulk solid. We use a femtosecond laser pulse to coherently superpose two orthogonal atomic motions in crystalline bismuth. The relative amplitudes of those two motions are manipulated by modulating the intensity profile of the laser pulse, and these controlled motions are quantitatively visualized by density functional theory calculations. Our control-visualization scheme is based on the simple, robust and universal concept that in any physical system, two-dimensional particle motion is decomposed into two orthogonal one-dimensional motions, and thus it is applicable to a variety of condensed matter systems.
We addressed the role of nitric oxide (NO) in orexin neuron degeneration that has been observed under various pathological conditions. Administration of an NO donor NOC18 (50 nmol) into the third ...ventricle of mice resulted in a significant decrease of orexin-immunoreactive (-IR) neurons, in contrast to a modest change in melanin-concentrating hormone-IR neurons. In addition, NOC18 promoted formation of orexin-A-IR aggregates within orexin neurons. An endoplasmic reticulum stress inducer tunicamycin replicated the effect of NOC18 with regard to decrease of orexin-IR neurons and formation of aggregates. We also found that NOC18 caused an increase in S-nitrosation of protein disulfide isomerase (PDI) and a decrease in PDI activity in hypothalamic tissues. Moreover, PDI inhibitors, such as cystamine and securinine, caused a selective decrease of orexin neurons and promoted formation of orexin-A-IR aggregates. Aggregate formation in orexin-IR neurons was also induced by local injection of small interfering RNA targeting PDI. Interestingly, sleep deprivation for 7 consecutive days induced a selective decrease of orexin-IR neurons, which was preceded by aggregate formation in orexin-IR neurons and an increase in S-nitrosated PDI in the hypothalamus. Activity of neuronal NO synthase (nNOS)-positive neurons in the lateral hypothalamus as assessed by c-Fos expression was elevated in response to sleep deprivation. Finally, sleep deprivation-induced decrease of orexin-IR neurons, formation of aggregates, and S-nitrosation of PDI were not observed in nNOS knock-out mice. These results indicate that nNOS-derived NO may mediate specific pathological events in orexin neurons, including neuropeptide misfolding via S-nitrosation and inactivation of PDI.
Palygorskite-TiO2 nanocomposites were prepared by deposition of the anatase form of TiO2 on the clay surfaces using a sol-gel method with titanium isopropoxide as a precursor under hydrothermal ...treatment at 180 C. The same procedure was followed in the formation of halloysite-TiO2 nanocomposites using a halloysite sample. Phase composition, particle morphology and physical properties were characterised using XRD, SEM and microanalysis by EDS, TEM, attenuated total reflection using FTIR and N2 surface area analysis by BET. The photocatalytic activities of clay-titania nanocomposites in decomposing NOx gas were measured. After treatment with TiO2, the halloysite and palygorskite samples had mesopores of about 5.6 and 6.5 nm, respectively, while the macropores of halloysite disappeared. This is attributed to the covering of the central hole in halloysite tubes by TiO2 nanoparticles making the pore size of the TiO2-treated halloysite was significantly smaller. The clay-titania samples showed significantly higher activity in decomposing NOx gas under visible-light irradiation (wavelength > 510 nm) and UV light irradiation (wavelength > 290 nm) compared to that of the standard commercial titania, P25.
Highlights ► Effects of nicotinic receptor agonists on hemorrhagic injury were examined. ► α7 nicotinic receptor agonist PNU-282987 protected striatal neurons. ► PNU-282987 inhibited activation of ...microglia/macrophages in the perihematoma region. ► PNU-282987 had no effect on hematoma expansion and edema formation.
Highlights ► High K+ depolarization protects dopaminergic neurons from MPP+ cytotoxicity. ► The protective effect is dependent on nitric oxide and protein kinase G (PKG). ► 8-Nitro-cGMP is produced ...in response to high K+ depolarization. ► 8-Nitro-cGMP confers neuroprotection in a PKG-dependent manner. ► PKG-independent expression of heme oxygenase-1 is also involved in neuroprotection.
Abstract Intracerebral hemorrhage represents stroke characterized by formation and expansion of hematoma within brain parenchyma. Blood-derived factors released from hematoma are considered to be ...involved in poor prognosis of this disorder. We previously reported that thrombin, a blood-derived serine protease, induced cytotoxicity in the cerebral cortex and the striatum in organotypic slice cultures, which depended on mitogen-activated protein kinase (MAPK) pathways. Here we investigated the mechanisms of thrombin cytotoxicity in the striatum in vivo . Thrombin microinjected into the striatum of adult rats induced neuronal death and microglial activation around the injection site. Neuronal loss without any sign of nuclear fragmentation was observed as early as 4 h after thrombin injection, which was followed by gradual neuronal death exhibiting nuclear fragmentation. Thrombin-induced damage assessed at 72 h after injection was partially but significantly reduced by concomitant administration of inhibitors of MAPK pathways. Activation of extracellular signal-regulated kinase (ERK) and p38 MAPK in response to thrombin was verified by Western blot analysis. Moreover, phosphorylated ERK and p38 MAPK were localized prominently in reactive microglia, and inhibition of microglial activation by minocycline attenuated thrombin-induced damage, suggesting that reactive microglia were responsible for thrombin-induced neuronal death. Thus, MAPK pathways and microglial activation may serve as therapeutic targets of pathogenic conditions associated with hemorrhagic stroke.
In this paper we describe the synthesis and characterization of small-sized TiO2 particles supported on palygorskite (Pal) with Pal to TiO2 mass ratios of 10:90, 20:80, 30:70, 40:60 and 50:50. The ...above Pal–TiO2 nanocomposites were prepared by deposition of anatase form of TiO2 on the Pal surfaces using a sol-gel method with titanium isopropoxide as a precursor under hydrothermal treatment at 180°C. Phase composition, particle morphology and physical properties of these samples were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), attenuated total reflection using Fourier transform infrared spectroscopy (ATR-FTIR) and N2 surface area analysis by BET. In order to investigate the absorption properties of the catalysts, UV–vis reflection spectra were measured. Preparation of Pal–TiO2 nanocomposites led to good dispersion of TiO2 on Pal surfaces. By increasing the amount of TiO2, the deposited 3–10nm TiO2 particles were found to be aggregated on the surfaces of the Pal particles. However, by decreasing the amount of TiO2, the Pal particles were found to be aggregated. After treating with TiO2, Pal samples largely showed interparticle mesopores of about 5.8nm. It was observed that the commercial titania P25 showed no absorption in visible light region. In contrast, the prepared Pal–TiO2 samples showed gray color and absorption in visible light region.
•Increasing amount of TiO2 the deposited TiO2 particles aggregated on palygorskite•Decreasing the amount of TiO2 palygorskite particles were found to be aggregated.•TiO2–palygorskite samples showed gray color and absorption in visible light region.
Abstract Narcolepsy results from disruption of orexin neurons in the hypothalamus that play a key role in maintenance of the arousal state. Underlying mechanisms leading to selective loss of orexin ...neurons remain unknown. On the other hand, endoplasmic reticulum stress, namely, conditions associated with impairment of endoplasmic reticulum functions such as proper folding and sorting of newly synthesized proteins, is implicated in pathogenesis of several types of neurodegenerative disorders. Here we found that application of endoplasmic reticulum stress inducers such as tunicamycin (that prevents protein N-glycosylation) and thapsigargin (that inhibits Ca2+ -ATPase) to organotypic slice cultures of the hypothalamus caused preferential loss of orexin-immunoreactive neurons, as compared to melanin-concentrating hormone- or calcitonin gene-related peptide-immunoreactive neurons. The decrease in orexin-immunoreactive neurons at early time points (6–24 h) was not accompanied by induction of cell death as indicated by the absence of caspase-3 activation and no significant change in the number of NeuN-positive cells, whereas sustained treatment with tunicamycin for 72 h induced cell death. At 24- h treatment, tunicamycin and thapsigargin did not decrease expression of prepro-orexin mRNA, suggesting that post-transcriptional mechanisms were responsible for depletion of orexin peptides. In addition, inhibition of axonal transport by colchicine and inhibition of proteasomal activity by MG132 significantly prevented the decrease in orexin immunoreactivity by tunicamycin. Comparative examinations of expression of unfolded protein response-related proteins revealed that C/EBP-homologous protein (a transcription factor that promotes induction of apoptosis) as well as phosphorylated form of RNA-dependent protein kinase-like endoplasmic reticulum kinase (a protein kinase that mediates inhibition of protein translation) was expressed more prominently in orexin neurons than in melanin-concentrating hormone neurons, in response to tunicamycin. These results indicate that orexin neurons are particularly sensitive to endoplasmic reticulum stress, which may be relevant to pathogenic events in narcolepsy.
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