ABSTRACT
Introduction: Atopic dermatitis (AD) is one of the most prevalent intractable chronic itch diseases worldwide. In recent years, new molecular-targeted drugs have emerged, but side effects and economic challenges remain. Therefore, since it is important for AD patients to have a wider range of treatment options, it is important to explore new therapeutic agents. Gabapentinoids, gabapentin and pregabalin, have been shown to be effective for the clinical treatment of several chronic itch. Recently, mirogabalin (MGB) was developed as a novel gabapentinoid. MGB is a drug for neuropathic pain and has a margin of safety between its side effects and the analgesic effect for animal experiments. Herein, we showed that MGB exhibited an antipruritic effect in a mouse model of AD using NC/Nga mice. Methods and results: The oral administration of MGB (10 mg/kg) inhibited spontaneous scratching behavior in AD mice and its effect was dose dependently. Then, when MGB (10 mg/kg) was orally administrated to healthy mice, it did not affect motor function, including locomotor activity, wheel activity, and coordinated movement. Moreover, gabapentin (100 mg/kg) and pregabalin (30 mg/kg), inhibited spontaneous scratching behavior in AD mice and decreased motor function in healthy mice. Furthermore, intracisternal injection of MGB (10 µg/site) significantly suppressed spontaneous scratching behavior in AD mice. Discussion: In summary, our results suggest that MGB exerts an antipruritic effect via the spinal dorsal horn using NC/Nga mice. We hope that MGB is a candidate for a novel therapeutic agent for AD with relatively few side effects.
ABSTRACT
The therapeutic benefits of photobiomodulation (PBM) in pain management, although well documented, are accompanied by concerns about potential risks, including pain, particularly at higher laser intensities. This study investigated the effects of laser intensity on pain perception using behavioral and electrophysiological evaluations in rats. Our results show that direct laser irradiation of 1000 mW/cm2 to the sciatic nerve transiently increases the frequency of spontaneous firing in the superficial layer without affecting the deep layer of the spinal dorsal horn, and this effect reverses to pre-irradiation levels after irradiation. Interestingly, laser irradiation at 1000 mW/cm2, which led to an increase in spontaneous firing, did not prompt escape behavior. Furthermore, a significant reduction in the time to initiate escape behavior was observed only at 9500 mW/cm2 compared to 15, 510, 1000, and 4300 mW/cm2. This suggests that 1000 mW/cm2, the laser intensity at which an increase in spontaneous firing was observed, corresponds to a stimulus that did not cause pain. It is expected that a detailed understanding of the risks and mechanisms of PBM from a neurophysiological perspective will lead to safer and more effective use of PBM.
Subject(s)
Low-Level Light Therapy , Rats, Sprague-Dawley , Spinal Cord Dorsal Horn , Animals , Low-Level Light Therapy/methods , Male , Rats , Spinal Cord Dorsal Horn/radiation effects , Sciatic Nerve/radiation effects , Sciatic Nerve/physiology , Action Potentials/radiation effectsABSTRACT
Photobiomodulation (PBM) has attracted attention as a treatment for chronic pain. Previous studies have reported that PBM of the sciatic nerve inhibits neuronal firing in the superficial layers (lamina I-II) of the spinal dorsal horn of rats, which is evoked by mechanical stimulation that corresponds to noxious stimuli. However, the effects of PBM on the deep layers (lamina III-IV) of the spinal dorsal horn, which receive inputs from innocuous stimuli, remain poorly understood. In this study, we examined the effect of PBM of the sciatic nerve on firing in the deep layers of the spinal dorsal horn evoked by mechanical stimulation. Before and after PBM, mechanical stimulation was administered to the cutaneous receptive field using 0.6-26.0 g von Frey filaments (vFFs), and vFF-evoked firing in the deep layers of the spinal dorsal horn was recorded. The vFF-evoked firing frequencies were not altered after the PBM for any of the vFFs. The inhibition rate for 26.0 g vFF-evoked firing was approximately 13 % in the deep layers and 70 % in the superficial layers. This suggests that PBM selectively inhibits the transmission of pain information without affecting the sense of touch. PBM has the potential to alleviate pain while preserving the sense of touch.
Subject(s)
Low-Level Light Therapy , Rats , Animals , Rats, Sprague-Dawley , Spinal Cord Dorsal Horn , Neurons , Sciatic Nerve , Pain , Spinal Cord/physiologyABSTRACT
The pain matrix, which includes several brain regions that respond to pain sensation, contribute to the development of chronic pain. Thus, it is essential to understand the mechanism of causing chronic pain in the pain matrix such as anterior cingulate (ACC), or primary somatosensory (S1) cortex. Recently, combined experiment with the behavior tests and in vivo calcium imaging using fiber photometry revealed the interaction between the neuronal function in deep brain regions of the pain matrix including ACC and the phenotype of chronic pain. However, it remains unclear whether this combined experiment can identify the interaction between neuronal activity in S1, which receive pain sensation, and pain behaviors such as hyperalgesia or allodynia. In this study, to examine whether the interaction between change of neuronal activity in S1 and hyperalgesia in hind paw before and after causing inflammatory pain was detected from same animal, the combined experiment of in vivo fiber photometry system and von Frey hairs test was applied. This combined experiment detected that amplitude of calcium responses in S1 neurons increased and the mechanical threshold of hind paw decreased from same animals which have an inflammatory pain. Moreover, we found that the values between amplitude of calcium responses and mechanical thresholds were shifted to negative correlation after causing inflammatory pain. Thus, the combined experiment with fiber photometry and the behavior tests has a possibility that can simultaneously consider the interaction between neuronal activity in pain matrix and pain induced behaviors and the effects of analgesics or pain treatments.
Subject(s)
Chronic Pain , Hyperalgesia , Animals , Mice , Behavior Rating Scale , Calcium , Somatosensory Cortex , Calcium, Dietary , Disease Models, Animal , Neurons , PhotometryABSTRACT
Purpose. The aim of this study was to assess the repeatability of the SUV normalized by liver volume (SUVL) between two liver receptor SPECT/CT studies performed on different days in patients with ICG-R15 values within normal range.Methods. 935 patients who underwent liver receptor scintigraphy between January 2010 and August 2018 were included. Patients who underwent liver resection, hepatic arterial embolization or had ICG-R15 >10% between scans were excluded, and 38 patients were finally included in the analysis. The repeatability of SUVL between scans was assessed using the intraclass correlation coefficient (ICC) (1.1) between SUVLmax, SUVLpeak and SUVLmean at the first and second scan and the additive and proportional errors from the Bland-Altman analysis.Results. In ICC (1,1), SUVLmax, SUVLpeak and SUVLmean were all greater than 0.8, indicating almost perfect repeatability; neither additive nor proportional errors were observed in the Bland-Altman analysis.Conclusions. In patients with ICG-R15 values within the normal range, the SUV Liver (SUVL) between two liver receptor SPECT/CT studies performed on different days was repeatability over time. It was suggested that the SUVL of liver receptor scintigraphy could be an indicator that could be used for follow-up over time in the assessment of liver fibrosis.
Subject(s)
Liver , Single Photon Emission Computed Tomography Computed Tomography , Humans , Liver/diagnostic imagingABSTRACT
Chinese artichoke tuber (Stachys sieboldii Miq.) is used as an herbal medicine as well as edible food. This study examined the effect of the Chinese artichoke extracts on the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway that induces the expression of antioxidant enzymes to explore its novel characteristics. Hot water extracts exhibited relatively high ARE activity. ARE activity was observed in two fractions when the hot water extracts were separated in the presence of trifluoroacetic acid using HPLC. Conversely, the highly active fraction disappeared when the hot water extracts were separated in the absence of trifluoroacetic acid. These results indicate that acidic degradation produces active ingredients. The structural analysis of the two active fractions identified harpagide, which is an iridoid glucoside, and harpagogenin. In vitro experiments revealed that harpagide was converted into harpagogenin under acidic conditions and that harpagogenin, but not harpagide, had potent ARE activity. Therefore, this study identified harpagogenin, which is an acid hydrolysate of harpagide, as an ARE activator and suggests that Nrf2-ARE pathway activation by Chinese artichoke contributes to the antioxidative effect.
Subject(s)
Stachys , Antioxidant Response Elements , Antioxidants/pharmacology , NF-E2-Related Factor 2 , Plant Extracts/pharmacology , Plant Extracts/chemistry , Stachys/chemistry , Trifluoroacetic Acid , WaterABSTRACT
Amyloid ß-protein (Aß42) aggregates have been demonstrated to induce cognitive decline and neurodegeneration in Alzheimer's disease (AD). Thus, functional food ingredients that inhibit Aß42 aggregation are valuable for AD prevention. Although several food ingredients have been studied for their anti-aggregation activity, information on their bioavailability in the brain, incorporated forms, and relevance to AD etiology is limited. Here, we first detected the sulfate- and glucuronic-acid-conjugated forms of green perilla-derived chalcone (1) and taxifolin (2), which inhibit Aß42 aggregation, in the brain, small intestine, and plasma of mice (1 and 2 were administered orally) using ultra-performance liquid chromatography-tandem mass spectrometry. We observed that the conjugated metabolites (sulfate (4) and glucuronide (5)) of 1 prevented the fibrillization and oligomerization of Aß42. These findings imply that the conjugated metabolites of 1 can prove beneficial for AD treatment.
Subject(s)
Alzheimer Disease , Chalcones , Food Ingredients , Mice , Animals , Amyloid beta-Peptides/metabolism , Flavonoids , Tandem Mass Spectrometry , Chromatography, Liquid , Alzheimer Disease/metabolism , Sulfates , Peptide Fragments/chemistryABSTRACT
Photobiomodulation is an effective treatment for pain. We previously reported that the direct laser irradiation of the exposed sciatic nerve inhibited firing in the rat spinal dorsal horn evoked by mechanical stimulation, corresponding to the noxious stimulus. However, percutaneous laser irradiation is used in clinical practice, and it is unclear whether it can inhibit the firing of the dorsal horn. In this study, we investigated whether the percutaneous laser irradiation of the sciatic nerve inhibits firing. Electrodes were inserted into the lamina II of the dorsal horn, and mechanical stimulation was applied using von Frey filaments (vFFs) with both pre and post laser irradiation. Our findings show that percutaneous laser irradiation inhibited 26.0 g vFF-evoked firing, which corresponded to the noxious stimulus, but did not inhibit 0.6 g and 8.0 g vFF-evoked firing. The post- (15 min after) and pre-irradiation firing ratios were almost the same as those for direct and percutaneous irradiation. A photodiode sensor implanted in the sciatic nerve showed that the power density reaching the sciatic nerve percutaneously was attenuated to approximately 10% of that on the skin. The relationship between the laser intensity reaching the nerve and its effect could be potentially useful for a more appropriate setting of laser conditions in clinical practice.
ABSTRACT
Amyloid ß (Aß) plays a key role in the pathology of Alzheimer's disease (AD) and is toxic owing to its ability to aggregate into oligomers and fibrils. Aß has high aggregative ability and potent toxicity due to the "toxic turn" at positions 22 and 23. Furthermore, APP knock-in mice producing E22P-Aß with the toxic turn exhibited AD-related phenotypes such as cognitive impairment, Aß plaque accumulation, and tau hyperphosphorylation. In these mice, it is suggested that the activation of neuroinflammation and dysregulation of hypoxia-inducible factor (HIF) expression in the hippocampus contribute to the pathogenesis of AD-related phenotype. However, it remains unclear which cells are responsible for the dysregulation of HIF expression and the neuroinflammation which was induced by E22P-Aß with the toxic turn. Here, we investigated the effects of chronic treatment with E22P-Aß42 and lipopolysaccharides (LPS) on the inflammatory response in BV-2 microglia. Chronic treatment with E22P-Aß42 and LPS increased nitric oxide production and the expression of interleukin-6 (IL-6), whereas it reduced the expression of HIF-1α and HIF-3α in BV-2 microglia. The reduction of HIF-1α caused by E22P-Aß42 and LPS was milder than that caused by LPS. Furthermore, chronic treatment with E22P-Aß42 and LPS increased the nuclear translocation of nuclear factor-kappaB (NF-κB). E22P-Aß42 could enhance the inflammatory response of microglia with abnormal HIF signaling and contribute to the progression of AD pathology.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Mice , Animals , Amyloid beta-Peptides/metabolism , Microglia , Lipopolysaccharides/toxicity , Neuroinflammatory Diseases , Alzheimer Disease/metabolism , HypoxiaABSTRACT
Preoperative assessment of the degree of liver fibrosis is important to determine treatment strategies. In this study, galactosyl human serum albumin single-photon emission-computed tomography and ethoxybenzyl (EOB) contrast-enhanced magnetic resonance imaging (MRI) were used to assess the changes in hepatocyte function after liver fibrosis, and the standardized uptake value (SUV) was combined with gadolinium EOB-diethylenetriaminepentaacetic acid to evaluate its added value for liver fibrosis staging. A total of 484 patients diagnosed with hepatocellular carcinoma who underwent liver resection between January 2010 and August 2018 were included. Resected liver specimens were classified based on pathological findings into nonfibrotic and fibrotic groups (stratified according to the Ludwig scale). Galactosyl human serum albumin-single-photon emission-computed tomography and EOB contrast-enhanced MRI examinations were performed, and the mean SUVs (SUVmean) and contrast enhancement indices (CEIs) were obtained. The diagnostic value of the acquired SUV and CEIs for fibrosis was assessed by calculating the area under the receiver operating characteristic curve (AUC). In the receiver operating characteristic analysis, SUV + CEI showed the highest AUC in both fibrosis groups. In particular, in the comparison between fibrosis groups, SUV + CEI showed significantly higher AUCs than SUV and CEI alone in discriminating between fibrosis (F3 and 4) and no or mild fibrosis (F0 and 2) (AUC: 0.879, vs SUV [P = 0.008], vs. CEI [P = 0.023]), suggesting that the combination of SUV + CEI has greater diagnostic performance than the individual indices. Combining the SUV and CEI provides high accuracy for grading liver fibrosis, especially in differentiating between grades F0 and 2 and F3-4. SUV and gadolinium EOB-diethylenetriaminepentaacetic acid-enhanced MRI can be noninvasive diagnostic methods to guide the selection of clinical treatment options for patients with liver diseases.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Contrast Media , Gadolinium , Gadolinium DTPA , Liver Cirrhosis/diagnosis , Liver/diagnostic imaging , Liver/pathology , Magnetic Resonance Imaging/methods , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/pathology , Tomography, Emission-Computed, Single-Photon , Liver Neoplasms/pathologyABSTRACT
Photobiomodulation has analgesic effects via inhibition of nerve activity, but few reports have examined the effects on the spinal dorsal horn, the entry point for nociceptive information in the central nervous system. In this study, we evaluated the effects of laser irradiation of peripheral nerve axons, which are conduction pathways for nociceptive stimuli, on the neuronal firing in lamina II of the spinal dorsal horn of a rat evoked by mechanical stimulation with von Frey filaments (vFF). In order to record neuronal firing, electrodes were inserted into lamina II of the exposed rat spinal dorsal horn. The exposed sciatic nerve axons were irradiated with an 808 nm laser. The 26.0 g vFF-evoked firing frequency was inhibited from 5 min after laser irradiation and persisted for 3 h. Sham irradiation did not alter the firing frequency. Laser irradiation selectively inhibited 15.0 and 26.0 g vFF-evoked firing, which corresponded to nociceptive stimuli. Histopathological evaluation revealed no damage to the sciatic nerve due to laser irradiation. These results indicate that neuronal firing is inhibited in lamina II of the spinal dorsal horn, suggesting that laser irradiation inhibits Aδ and/or C fibers that conduct nociceptive stimuli.
Subject(s)
Neurons , Spinal Cord Dorsal Horn , Rats , Animals , Rats, Sprague-Dawley , Spinal Cord Dorsal Horn/physiology , Sciatic Nerve , Axons , Posterior Horn Cells/metabolism , Spinal CordABSTRACT
The skin is an important barrier that protects against invasion by foreign substances, including irritants and harmful microorganisms, and holds water in the body. Washing the skin with cleansers and shampoos containing anionic surfactants, for example sodium dodecyl sulfate (SDS), is important for maintaining skin homeostasis. However, surfactants can cause dermatitis, cutaneous hypersensitivity (e.g., alloknesis), and pruritus in humans. Our previous studies revealed an alloknesis response in the skin with SDS-induced dermatitis in C57BL/6 mice. In addition, we found that alloknesis responses and afterdischarge responses following stimulation with light touch are related because they are observed contemporaneously. In this study, we used Hos:HR-1 hairless mice to establish a mouse model to evaluate long-term drug application for alloknesis responses. Alloknesis was observed in HR-1 mice with SDS-induced dermatitis. The mean number of c-Fos (a marker of neural activity) immunopositive neurons was increased in the lamina 1-2 (L1-2) spinal dorsal horn, but not in L3-4, of SDS-treated HR-1 mice compared to vehicle-treated mice. We also discovered that afterdischarge responses were observed in neurons in L1-2. There was also a correlation between the intensity of the afterdischarge responses and depth of the recording site. Thus, the following were suggested: 1) neurons that mediate these afterdischarge responses are located on the superficial layer of the spinal cord; 2) afterdischarge responses can be an index of alloknesis responses, and 3) the mouse model of SDS-induced dermatitis is an appropriate alloknesis model.
Subject(s)
Dermatitis, Irritant , Irritants , Humans , Mice , Animals , Mice, Hairless , Mice, Inbred C57BL , Posterior Horn Cells , Spinal Cord Dorsal Horn , Disease Models, Animal , Surface-Active Agents/pharmacologyABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that requires further pathological elucidation to establish effective treatment strategies. We previously showed that amyloid ß (Aß) toxic conformer with a turn at positions 22-23 is essential for forming highly toxic oligomers. In the present study, we evaluated phenotypic changes with aging in AD model AppNL-P-F/NL-P-F (NL-P-F) mice with Swedish mutation (NL), Iberian mutation (F), and mutation (P) overproducing E22P-Aß, a mimic of toxic conformer utilizing the knock-in technique. Furthermore, the role of the toxic conformer in AD pathology was investigated. NL-P-F mice produced soluble toxic conformers from an early age. They showed impaired synaptic plasticity, glial cell activation, and cognitive decline, followed by the accumulation of Aß plaques and tau hyperphosphorylation. In addition, the protein expression of hypoxia-inducible factor (HIF)-1α was increased, and gene expression of HIF-3α was decreased in NL-P-F mice. HIF dysregulation due to the production of soluble toxic conformers may be involved in AD pathology in NL-P-F mice. This study could reveal the role of a highly toxic Aß on AD pathogenesis, thereby contributing to the development of a novel therapeutic strategy targeting the toxic conformer.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Amyloid beta-Protein Precursor , Hypoxia-Inducible Factor 1 , Animals , Mice , Alzheimer Disease/metabolism , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Disease Models, Animal , Gene Knock-In Techniques , Mice, Transgenic , Phenotype , Plaque, Amyloid/metabolism , Hypoxia-Inducible Factor 1/genetics , Hypoxia-Inducible Factor 1/metabolismABSTRACT
Since amyloid ß (Aß) oligomers are more cytotoxic than fibrils, various dimer models have been synthesized. We focused on the C-terminal region that could form a hydrophobic core in the aggregation process and identified a toxic conformer-restricted dimer model (E22P,G38DAP-Aß40 dimer) with an l,l-2,6-diaminopimelic acid linker (n = 3) at position 38, which exhibited moderate cytotoxicity. We synthesized four additional linkers (n = 2, 4, 5, 7) to determine the most appropriate distance between the two Aß40 monomers for a toxic dimer model. Each di-Fmoc-protected two-valent amino acid was synthesized from a corresponding dialdehyde or cycloalkene followed by ozonolysis, using a Horner-Wadsworth-Emmons reaction and asymmetric hydrogenation. Then, the corresponding Aß40 dimer models with these linkers at position 38 were synthesized using the solid-phase Fmoc strategy. Their cytotoxicity toward SH-SY5Y cells suggested that the shorter the linker length, the stronger the cytotoxicity. Particularly, the E22P,G38DAA-Aß40 dimer (n = 2) formed protofibrillar aggregates and exhibited the highest cytotoxicity, equivalent to E22P-Aß42, the most cytotoxic analogue of Aß42. Ion mobility-mass spectrometry (IM-MS) measurement indicated that all dimer models except the E22P,G38DAA-Aß40 dimer existed as stable oligomers (12-24-mer). NativePAGE analysis supported the IM-MS data, but larger oligomers (30-150-mer) were also detected after a 24 h incubation. Moreover, E22P,G38DAA-Aß40, E22P,G38DAP-Aß40, and E22P,G38DAZ-Aß40 (n = 5) dimers suppressed long-term potentiation (LTP). Overall, the ability to form fibrils with cross ß-sheet structures was key to achieving cytotoxicity, and forming stable oligomers less than 150-mer did not correlate with cytotoxicity and LTP suppression.
Subject(s)
Alzheimer Disease , Cycloparaffins , Neuroblastoma , Ozone , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Diaminopimelic Acid , Humans , Peptide Fragments/metabolismABSTRACT
Some chemical Nrf2 inducers possess antioxidant and anti-inflammatory properties. TPNA10168, which was identified from a chemical library as a potential activator of the Keap1-Nrf2-ARE pathway, exhibits a neuroprotective effect against oxidative stress-induced injury. However, it has not been investigated as an anti-inflammatory agent. Here we examined the effect of TPNA10168 on interferon-γ-induced proinflammatory gene expression in mouse microglial BV-2 cells. TPNA10168 significantly reduced the transcription of inflammatory genes, including TNF-α, IL-1ß, IL-6, and iNOS; however, the inhibition of proinflammatory cytokine gene expression was not attenuated by inhibitors of Nrf2-regulated enzymes. Furthermore, TPNA10168 showed anti-inflammatory effects, even in Nrf2-deficient cells, and inhibited interferon-γ-induced phosphorylation of extracellular-signal-regulated kinase (ERK). Studies with an ERK pathway inhibitor demonstrated a role for ERK in the transcription of inflammatory genes. These results suggest that TPNA10168 attenuates microglial proinflammatory activation independently of Nrf2, at least in part, by suppressing interferon-γ-induced ERK signaling.
Subject(s)
Extracellular Signal-Regulated MAP Kinases , NF-E2-Related Factor 2 , Animals , Extracellular Signal-Regulated MAP Kinases/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Mice , Microglia/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative StressABSTRACT
Amyloid ß (Aß) oligomers play a critical role in the pathology of Alzheimer's disease. Recently, we reported that a conformation-restricted Aß42 with an intramolecular disulfide bond through cysteine residues at positions 17/28 formed stable oligomers with potent cytotoxicity. To further optimize this compound as a toxic conformer model, we synthesized three analogues with a combination of cysteine and homocysteine at positions 17/28. The analogues with Cys-Cys, Cys-homoCys, or homoCys-Cys, but not the homoCys-homoCys analogue, exhibited potent cytotoxicity against SH-SY5Y and THP-1 cells even at 10â nM. In contrast, the cytotoxicity of conformation-restricted analogues at positions 16/29 or 18/27 was significantly weaker than that of wild-type Aß42. Furthermore, thioflavin-T assay, non-denaturing gel electrophoresis, and morphological studies suggested that the majority of these conformation-restricted analogues exists in an oligomeric state in cell culture medium, indicating that the toxic conformation of Aß42, rather than the oligomeric state, is essential to induce cytotoxicity.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Alzheimer Disease/pathology , Amyloid/chemistry , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/toxicity , Cysteine , Disulfides/chemistry , Humans , Peptide Fragments/chemistry , Peptide Fragments/toxicityABSTRACT
Mechanical stimulation of cultured keratinocytes and a living epidermis increases intracellular calcium ion concentrations ([Ca2+]i) in stimulated cells. This action propagates a Ca2+ wave to neighboring keratinocytes via ATP/P2Y2 receptors. Recent behavioral, pharmacological studies revealed that exogenous ATP induces itching via P2X3 receptors in mice. We previously showed that alloknesis occurs when an external stimulus is applied to the skin with increased epidermal histamine in the absence of spontaneous pruritus. Based on these results, we investigated the effects of histamine at a concentration that does not cause itching on ATP-induced itching. The mean number of scratching events induced by the mixture of ATP and histamine increased by 28% over the sum of that induced by histamine alone or ATP alone. A317491, a P2X3 receptor antagonist, suppressed the mixture-induced scratching more often than the ATP-induced scratching. Next, we examined the ATP-induced [Ca2+]i change before and after histamine stimulation using normal human epidermal keratinocytes. Some cells did not respond to ATP before histamine stimulation but responded to ATP afterward, the phenomenon suppressed by chlorpheniramine maleate. These findings suggest that histamine enhances ATP-induced itching and that a potential mechanism could involve increased responsiveness to ATP in keratinocytes.
Subject(s)
Adenosine Triphosphate/metabolism , Adenosine Triphosphate/pharmacology , Histamine/pharmacology , Keratinocytes/metabolism , Pruritus/chemically induced , Pruritus/drug therapy , Animals , Calcium/metabolism , Cells, Cultured , Dose-Response Relationship, Drug , Male , Mice, Inbred ICR , Phenols/pharmacology , Phenols/therapeutic use , Physical Stimulation , Polycyclic Compounds/pharmacology , Polycyclic Compounds/therapeutic use , Purinergic P2X Receptor Agonists , Receptors, Purinergic P2X3/metabolism , Receptors, Purinergic P2Y2/metabolismABSTRACT
PURPOSE: The enhancement effect ratio using ethoxybenzyl (EOB) contrast is useful in the assessment of liver fibrosis. Since the enhancement effect ratio is calculated by setting a region of interest (ROI) in the liver, the ROI setting method may affect the enhancement effect ratio. One of the methods of setting the ROI in liver fibrosis evaluation is by placing the ROI in each Quinault segment, but this method requires considerable time. Therefore, it is necessary to consider a reproducible ROI setting method in contrast to the method of placing ROIs in each Quinault segment. METHOD: In contrast to the method of placing one ROI in each Quinault segment, we examined the method of setting four ROIs (two in the right lobe and two in the left lobe) and two ROIs (one in the right lobe and one in the left lobe). The size of the ROI was set to 1 cm2, 4 cm2, and the maximum area that fits within each placement area. CONCLUSION: In the ROI setting method for CEI calculation, reproducibility can be maintained by setting the number of ROIs in four locations and by setting ROIs of 4 cm2 or more.
Subject(s)
Liver Cirrhosis , Humans , Liver Cirrhosis/diagnostic imaging , Reproducibility of ResultsABSTRACT
The present study investigated the therapeutic effects of the curcumin derivative 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]ethenyl]-1H-pyrazole (GT863) in amyotrophic lateral sclerosis (ALS). The inhibitory effect of GT863 on superoxide dismutase 1 (SOD1) aggregation was evaluated in cell-free assays. GT863 interfered with the conformational changes of the SOD1 protein and later, oligomeric aggregation. Furthermore, its antioxidant, anti-inflammatory, and neuroprotective effects were evaluated in cell-free and cultured cell assays. GT863 inhibited H2O2- and glutamate-induced cytotoxicity and activated an antioxidant responsive element pathway. Additionally, in vivo effects of GT863 in the ALS mice model were evaluated by its oral administration to H46R mutant SOD1 transgenic mice. Rotarod test showed that GT863 administration significantly slowed the progression of motor dysfunction in the mice. In addition, GT863 substantially reduced highly-aggregated SOD1, further preserving large neurons in the spinal cord of GT863-treated mice. Collectively, these results indicated that GT863 could be a viable therapeutic agent with multiple vital actions for the treatment of ALS.
Subject(s)
Amyotrophic Lateral Sclerosis , Curcumin , Mice , Animals , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Curcumin/pharmacology , Curcumin/therapeutic use , Antioxidants/therapeutic use , Hydrogen Peroxide/metabolism , Hydrogen Peroxide/therapeutic use , Mice, Transgenic , Superoxide Dismutase/genetics , Disease Models, Animal , Spinal Cord/metabolismABSTRACT
Brain inflammation is a pathological characteristic of neurodegenerative diseases. In this condition, excessively activated microglia elevate proinflammatory mediator levels. We previously reported that panaxytriol inhibited lipopolysaccharide (LPS)-induced microglia activation in vitro. However, the effects of panaxytriol on microglia activation in vivo require confirmation. In the present study, we found that panaxytriol suppressed both microglia and astrocyte activation by injected LPS intracerebrally to mice with LPS-induced brain inflammation. Panaxytriol was more effective on microglia than astrocytes. Moreover, panaxytriol tended to reduce LPS-induced spontaneous motor activity dysfunction. These results suggested that panaxytriol could improve brain health by suppressing microglia activation in neurodegenerative diseases.