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Purpose: This study seeks to investigate the effect of evodiamine on psoriasis and psoriatic pruritus. Methods: Imiquimod-induced psoriasiform dermatitis in mice was used as a model, and evodiamine was topically applied for seven days. The mice were observed daily for skin damage on the back, clinical score and their scratching behavior was recorded. Blood samples were collected on the final day of the experiment, and the serum levels of pruritus-associated inflammatory cytokines tumor necrosis factor (TNF) -α, interleukin (IL) -23, and IL-17A were measured using enzyme-linked immunosorbent assay. Histopathological changes were observed in Hematoxylin and Eosin-stained skin specimens. The expression levels of transient receptor potential vanilloid (TRPV) 1, TRPV3, TRPV4, and the pruritus-related mediators Substance P (SP), nerve growth factor (NGF), and calcitonin gene-related peptide (CGRP) in the skin lesions were analyzed using Western blot and qRT-PCR. The effect of evodiamine on the exploratory behavior, motor, and coordination abilities of mice was assessed using open field, suspension, and Rota-Rod experiments. Molecular docking was utilized to verify the binding of evodiamine to the residues of TRPV1, TRPV3, and TRPV4. Results: Evodiamine reduced pruritus and inhibited inflammation by decreasing the levels of inflammatory mediators TNF-α, IL-23, and IL-17A in the serum of Imiquimod-induced mice and attenuated the mRNA and protein expression levels of SP, NGF, CGRP, TRPV1, TRPV3, and TRPV4 in the skin. Conclusion: Evodiamine is an effective treatment for psoriasis and pruritus, due to its ability to inhibit immune inflammation and pruritic mediators.
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exo-6b2-Methyl-substituted pentabenzocorannulene (exo-PBC-Me) was synthesized by the palladium-catalyzed cyclization of 1,2,3-triaryl-1H-cyclopenta[l]phenanthrene. Its bowl-shaped geometry with an sp3 carbon atom in the backbone and a methyl group located at the convex (exo) face was verified by X-ray crystallography. According to DFT calculations, the observed conformer is energetically more favorable than the endo one by 39.9â kcal/mol. Compared to the nitrogen-doped analogs with intact π-conjugated backbones (see the main text), exo-PBC-Me displayed a deeper bowl depth (avg. 1.93â Å), redshifted and broader absorption (250-620â nm) and emission (from 585 to more than 850â nm) bands and a smaller optical HOMO-LUMO gap (2.01â eV). exo-PBC-Me formed polar crystals where all bowl-in-bowl stacking with close π â â â π contacts is arranged unidirectionally, providing the potential for applications as organic semiconductors and pyroelectric materials. This unusual structural feature, molecular packing, and properties are most likely associated with the assistance of the methyl group and the sp3 carbon atom in the backbone.
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BACKGROUND: This study leverages a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between 1,400 metabolites and pulmonary fibrosis, using genetic variation as instrumental variables. By adhering to stringent criteria for instrumental variable selection, the research aims to uncover metabolic pathways that may influence the risk and progression of pulmonary fibrosis, providing insights into potential therapeutic targets. METHODS: Utilizing data from the OpenGWAS project, which includes a significant European cohort, and metabolite GWAS data from the Canadian Longitudinal Aging Study (CLSA), the study employs advanced statistical methods. These include inverse variance weighting (IVW), weighted median estimations, and comprehensive sensitivity analyses conducted using the R software environment to ensure the robustness of the causal inferences. RESULTS: The study identified 62 metabolites with significant causal relationships with pulmonary fibrosis, highlighting both risk-enhancing and protective metabolic factors. This extensive list of metabolites presents a broad spectrum of potential therapeutic targets and biomarkers for early detection, underscoring the metabolic complexity underlying pulmonary fibrosis. CONCLUSIONS: The findings from this MR study significantly advance our understanding of the metabolic underpinnings of pulmonary fibrosis, suggesting that alterations in specific metabolites could influence the risk and progression of the disease. These insights pave the way for the development of novel diagnostic and therapeutic strategies, emphasizing the potential of metabolic modulation in managing pulmonary fibrosis.
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Análisis de la Aleatorización Mendeliana , Metabolómica , Fibrosis Pulmonar , Humanos , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Canadá/epidemiología , Estudio de Asociación del Genoma Completo , Biomarcadores/metabolismo , Biomarcadores/sangre , Progresión de la Enfermedad , Estudios Longitudinales , Masculino , Polimorfismo de Nucleótido Simple , FemeninoRESUMEN
Cancer is a major health challenge and causes millions of deaths worldwide each year, and the incidence of lung cancer has increased. Augmented fluoroscopic bronchoscopy (AFB) procedures, which combine bronchoscopy and fluoroscopy, are crucial for diagnosing and treating lung cancer. However, fluoroscopy exposes patients and physicians to radiation, and therefore, the procedure requires careful monitoring. The National Council on Radiation Protection and Measurement and the International Commission on Radiological Protection have emphasised the importance of monitoring patient doses and ensuring occupational radiation safety. The present study evaluated radiation doses during AFB procedures, focusing on patient skin doses, the effective dose, and the personal dose equivalent to the eye lens for physicians. Skin doses were measured using thermoluminescent dosimeters. Peak skin doses were observed on the sides of the patients' arms, particularly on the side closest to the x-ray tube. Differences in the procedures and experience of physicians between the two hospitals involved in this study were investigated. AFB procedures were conducted more efficiently at Hospital A than at Hospital B, resulting in lower effective doses. Cone-beam computed tomography (CT) contributes significantly to patient effective doses because it has higher radiographic parameters. Despite their higher radiographic parameters, AFB procedures resulted in smaller skin doses than did image-guided interventional and CT fluoroscopy procedures. The effective doses differed between the two hospitals of this study due to workflow differences, with cone-beam CT playing a dominant role. No significant differences in left and right eyeHp(3) values were observed between the hospitals. For both hospitals, theHp(3) values were below the recommended limits, indicating that radiation monitoring may not be required for AFB procedures. This study provides insights into radiation exposure during AFB procedures, concerning radiation dosimetry, and safety for patients and physicians.
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Neoplasias Pulmonares , Exposición Profesional , Médicos , Exposición a la Radiación , Humanos , Broncoscopía , Fluoroscopía , Dosis de Radiación , Neoplasias Pulmonares/diagnóstico por imagen , Exposición Profesional/prevención & control , Exposición Profesional/análisisRESUMEN
BACKGROUND: Ultraviolet (UV) is the main reason to cause photoaging skin which not only hinders beauty, brings the patients with psychological burden, but also pathologically leads to the occurrence of tumors in skin. OBJECTIVE: This study goes into the inhibitory effect and mechanism of seawater pearl hydrolysate (SPH) to address human skin keratinocytes photoaging induced by UVB. METHODS: The photoaging model of Hacat cell was constructed by UVB irradiation, the levels of oxidative stress, apoptosis, aging, autophagy and autophagy-related protein and signal pathway expression were assessed to characterize the inhibitory effect and mechanism of SPH on photoaging Hacat cell. RESULTS: Seawater pearl hydrolysate significantly accelerated (p < 0.05) the activities of superoxide dismutase, catalase, and glutathione peroxidase, and markedly reduced (p < 0.05) the contents of reactive oxygen species (ROS), malondialdehyde, protein carbonyl compound and nitrosylated tyrosine protein, aging level, apoptosis rate in Hacat cell induced by 200 mJ cm-2 UVB after 24 and 48 h of culture; high dose SPH significantly raised (p < 0.05) relative expression level of p-Akt, p-mTOR proteins, and markedly decreased (p < 0.05) relative expression level of LC3II protein, p-AMPK, and autophagy level in Hacat cell induced by 200 mJ cm-2 UVB, or in combination with the intervention of PI3K inhibitor or AMPK overexpression after 48 h of culture. CONCLUSION: Seawater pearl hydrolysate can effectively inhibit 200 mJ cm-2 UVB-induced photoaging of Hacat cells. The mechanism indicates removing the excessive ROS through increasing the antioxidation of photoaging Hacat cells. Once redundant ROS is eliminated, SPH works to reduce AMPK, increase PI3K-Akt pathway expression, activate mTOR pathway to lowdown autophagy level, and as a result, inhibit apoptosis and aging in photoaging Hacat cells.
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Envejecimiento de la Piel , Humanos , Especies Reactivas de Oxígeno/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Queratinocitos/metabolismo , Estrés Oxidativo , Apoptosis , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/farmacología , Autofagia , Rayos Ultravioleta/efectos adversosRESUMEN
Chronic itch is the most prominent feature of atopic dermatitis (AD), and antihistamine treatment is often less effective in reducing clinical pruritus severity in AD. Multiple studies have shown that histamine-independent itch pathway is thought to predominate in AD-induced chronic itch. Mas-related G-protein-coupled receptor (Mrgpr) A3+ sensory neurons have been identified as one of the major itch-sensing neuron populations, and transient receptor potential (TRP) channel A1 is the key downstream of MrgprA3-mediated histamine-independent itch. MrgprA3-TRPA1 signal pathway is necessary for the development of chronic itch and may be the potentially promising target of chronic itch in AD. Dictamnine is one of the main quinoline alkaloid components of Cortex Dictamni (a traditional Chinese medicine widely used in clinical treatment of skin diseases). However, the anti-inflammatory and anti-pruritic effect of dictamnine on AD have not been reported. In this study, we used the 2,4-dinitrofluorobenzene (DNFB)-induced AD mouse model to observe the scratching behavior, inflammatory manifestations, and to detect the expression of MrgprA3 and TRPA1 in skin and DRG. The data demonstrated that dictamnine effectively inhibited AD-induced chronic itch, inflammation symptoms, epidermal thickening, inflammatory cell infiltration, and downregulated the expression of MrgprA3 and TRPA1. Furthermore, dictamnine restrained the excitability of MrgprA3+ and TRPA1+ neurons. Molecular docking also indicated that dictamnine has better binding affinity with MrgprA3. These results suggest that dictamnine may inhibit chronic itch caused by AD through the MrgprA3-TRPA1 mediated histamine-independent itch pathway, and may have a potential utility in AD treatment.
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Dermatitis Atópica , Quinolinas , Canales de Potencial de Receptor Transitorio , Ratones , Animales , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/metabolismo , Dinitrofluorobenceno , Histamina/metabolismo , Simulación del Acoplamiento Molecular , Prurito/inducido químicamente , Prurito/tratamiento farmacológico , Prurito/metabolismo , Quinolinas/farmacología , Canales de Potencial de Receptor Transitorio/metabolismo , Células Receptoras Sensoriales , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Osthole has been isolated from the fruits of Cnidium monnieri (L.) Cusson, which has been used in Chinese traditional medicine to treat pruritic disorders for a long time. However, the antipruritic mechanism of osthole is not fully understood. In the present study, using calcium imaging, molecular docking, and animal scratching behavior, we analyzed the pharmacological effects of osthole on transient receptor potential vanilloid 1 (TRPV1). The results showed that osthole significantly induced calcium influx in a dose-dependent manner in dorsal root ganglion (DRG) neurons. Osthole-induced calcium influx was inhibited by AMG9810, an antagonist of TRPV1. Osthole and the TRPV1 agonist capsaicin-induced calcium influx were desensitized by pretreatment with osthole. Furthermore, molecular docking results showed that osthole could bind to TRPV1 with a hydrogen bond by anchoring to the amino acid residue ARG557 in the binding pocket of TRPV1. In addition, TRPV1 is a downstream ion channel for the histamine H1 and H4 receptors to transmit itch signals. Osthole attenuated scratching behavior induced by histamine, HTMT (histamine H1 receptor agonist), and VUF8430 (histamine H4 receptor agonist) in mice. These results suggest that osthole inhibition of histamine-dependent itch may be due to the activation and subsequent desensitization of TRPV1 in DRG neurons.
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OBJECTIVE: To evaluate the effectiveness and safety of acupuncture treatment for dysphagia as a complication of stroke. Methods and Design. This is a multicenter, pragmatic, nonrandomized, self-controlled clinical trial. A total of 39 patients were recruited from several Chinese medicine outpatient clinics and hospital-affiliated speech therapy outpatient clinics in Hong Kong. 26 patients completed all the 24 sessions of acupuncture treatment within two months, and only 12 of them were used as self-control. For the self-control group, the retrospective clinical data was taken from the electronic patient records with patient consent. The descriptive swallowing function data were converted into the quantitative Royal Brisbane Hospital Outcome Measure for Swallowing (RBHOMS) scores by two registered speech therapists through a validation process. And the data were validated by reaching consensus between the two speech therapists. All subjects underwent a baseline assessment before commencement of treatment, and outcome assessments were conducted upon the completion of treatment. The primary outcome measure is the RBHOMS score, which is a swallowing disability rating scale for monitoring difficulties in daily swallowing function. Secondary outcome measures include the Chinese version of the Swallow Quality-of-Life Questionnaire and adverse events. All the primary and secondary outcomes were assessed at baseline as well as at the end of acupuncture treatment (month 2). RESULTS: A total of 39 participants aged 46 to 89 years were enrolled in the study, and the male-to-female ratio was 15 : 11. The mean baseline RBHOMS score of all 39 participants was 5.92 ± 2.23. The mean retrospective RBHOMS score of the 12 subjects who were used as self-control was 5.67 ± 1.72 before enrollment, while the mean RBHOMS score of the 26 participants who completed all the 24 sessions of treatment was 6.92 ± 2.07. There were statistically significant differences between the RBHOMS score at the completion of treatment and baseline (p=0.006), and retrospective data (p=0.042). Moreover, a significant difference was also found in terms of swallow quality-of-life score before and after acupuncture treatment (p < 0.01). CONCLUSIONS: This pilot study provides preliminary evidence for the effectiveness of acupuncture for poststroke dysphagia. The findings from this trial can be used as a foundation for future full-scale randomized controlled clinical trials to assess the efficacy and safety of acupuncture for poststroke dysphagia. Ethics and Dissemination. The ethical approval of the clinical research study was granted by the Research Ethics Committee of both New Territories East and West Cluster of Hong Kong. Written informed consent was obtained from all participants, and the study was undertaken according to the ICH-GCP Guidelines. Trial Registration. This trial is registered with ChiCTR-TRC-12002621 and the registration date is 2012-10-26.
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Atopic dermatitis (AD) is a common inflammatory skin disease characterized by intense pruritus and skin lesions. The exact cause of AD is not yet known and the available therapeutic strategies for AD are limited. Fructus cnidii is commonly used in traditional Chinese medicine as an herb for treating chronic itch. However, the mechanism underlying the antipruritic effects of Fructus cnidii is not well understood. In the present study, we investigated the antipruritic effect of locally administered ethyl acetate extract from Fructus cnidii (EAEFC) to 2,4-dinitrofluorobenzene- (DNFB-) induced AD in a mouse model. The scratching behavior, skin thickness, dermatitis score, weight, blood immunoglobulin E (IgE) level, and itch-related cytokine levels were subsequently monitored and evaluated. Results showed that EAEFC treatment attenuated the DNFB-induced AD-like symptoms by alleviating the skin lesions and decreasing the dermatitis score. Hematoxylin and eosin (H&E) and toluidine blue (TB) staining analyses demonstrated that EAEFC mitigated the DNFB-induced increase in skin thickness and prevented the infiltration of mast cells. Behavioral tests showed that EAEFC decreased the DNFB-induced acute and chronic scratching behaviors. Furthermore, EAEFC reduced the levels of itch-related cytokines, such as thymic stromal lymphopoietin (TSLP), interleukin- (IL-) 17, IL-33, and IL-31, and the DNFB-induced boost in serum IgE. Collectively, these results suggest that EAEFC is a potential therapeutic candidate for the treatment of chronic itch in AD.
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Spinal α-motoneurons directly innervate skeletal muscles and function as the final common path for movement and behavior. The processes that determine the excitability of motoneurons are critical for the execution of motor behavior. In fact, it has been noted that spinal motoneurons receive various neuromodulatory inputs, especially monoaminergic one. However, the roles of histamine and hypothalamic histaminergic innervation on spinal motoneurons and the underlying ionic mechanisms are still largely unknown. In the present study, by using the method of intracellular recording on rat spinal slices, we found that activation of either H1 or H2 receptor potentiated repetitive firing behavior and increased the excitability of spinal α-motoneurons. Both of blockage of K+ channels and activation of Na+-Ca2+ exchangers were involved in the H1 receptor-mediated excitation on spinal motoneurons, whereas the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels were responsible for the H2 receptor-mediated excitation. The results suggest that, through switching functional status of ion channels and exchangers coupled to histamine receptors, histamine effectively biases the excitability of the spinal α-motoneurons. In this way, the hypothalamospinal histaminergic innervation may directly modulate final motor outputs and actively regulate spinal motor reflexes and motor execution.
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Histamina , Neuronas Motoras , Animales , Histamina/farmacología , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Ratas , Receptores Histamínicos H2/metabolismo , Intercambiador de Sodio-Calcio/metabolismoRESUMEN
AIMS: The purpose of this study was to investigate plumbagin (PL) on liver fibrosis in vitro and in vivo and to explore the underlying mechanisms. METHODS: Carbon tetrachloride (CCl4) was used to establish a rat liver fibrosis model, primary hepatic stellate cells (HSCs) were isolated from the rat liver, and fibrosis-related indicators were detected. RESULTS: The results revealed that PL significantly prevented CCl4-induced liver fibrosis, as evidenced by the attenuation of histopathological changes, the decrease of MDA and the increase of SOD and GSH-P X . In addition, PL downregulated the mRNA levels of NOX4 and procollagen I; the protein expression levels of NOX4 and p-IκB; and the transcriptional activity of NF-κB in liver fibrosis rats. Moreover, PL significantly decreased ROS expression, protein expression of α-SMA and collagen III, and activation of NF-κB and inhibited the nuclear translocation of NF-κB p65 in IL-1ß-stimulated HSCs in vitro. CONCLUSION: The results of our study indicate that PL can mitigate liver fibrosis in vitro and in vivo, which may be related to the ROS-mediated NF-кB signaling pathway.
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Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , FN-kappa B/metabolismo , Naftoquinonas/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Animales , Antioxidantes/metabolismo , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Interleucina-1beta/metabolismo , Cirrosis Hepática/patología , Masculino , NADPH Oxidasa 4/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Naftoquinonas/farmacología , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Factor de Transcripción ReIA/metabolismoRESUMEN
In our bioassay protocol, the Ag@4MBA@DNA-biotin probes were synthesized by linking biotin-modified DNA and 4-mercaptobenzoic acid-covered Ag nanoparticles, and the Si@Ag@anti-digoxin/digoxin-DNA substrate was fabricated by immune linking of digoxin-DNA and anti-digoxin immobilized on a Ag-coated wafer. Then, the probes, miRNA-21 and the substrate were constructed into a "sandwich structure" to detect the variation in the SERS signals with respect to miRNA-21 concentrations. Next, streptavidin and extra probes were alternately introduced to implement the cascade amplification of the SERS signal to increase the detection sensitivity. The results show that the limit of detection (LOD) with cascade amplification is remarkably improved from 97.81 pM to 38.02 fM, which is three orders of magnitude higher than the original data without cascade amplification. Furthermore, the SERS-based cascade amplification mechanism was analyzed and is attributed to the "hot spots effect" of the noble metal nanostructure. The biotin-streptavidin (B-S) system was introduced into the SERS detection platform, and the novel SERS-based cascade amplification bioassay protocol has significant creativity for the detection of nucleic acids.
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Bioensayo/métodos , MicroARNs/análisis , Espectrometría Raman/métodos , Benzoatos/química , Biotina/química , ADN/química , ADN/genética , Digoxina , Límite de Detección , Nanopartículas del Metal/química , MicroARNs/genética , Hibridación de Ácido Nucleico , Plata/química , Estreptavidina/química , Compuestos de Sulfhidrilo/químicaRESUMEN
Sophorae Flavescentis Radix (SFR) is a medicinal herb with many functions that are involved in anti-inflammation, antinociception, and anticancer. SFR is also used to treat a variety of itching diseases. Matrine (MT) is one of the main constituents in SFR and also has the effect of relieving itching, but the antipruritic mechanism is still unclear. Here, we investigated the effect of MT on anti-pruritus. In acute and chronic itch models, MT significantly inhibited the scratching behavior not only in acute itching induced by histamine (His), chloroquine (CQ) and compound 48/80 with a dose-depended manner, but also in the chronic pruritus models of atopic dermatitis (AD) and acetone-ether-water (AEW) in mice. Furthermore, MT could be detected in the blood after intraperitoneal injection (i.p.) and subcutaneous injection (s.c.). Finally, electrophysiological and calcium imaging results showed that MT inhibited the excitatory synaptic transmission from dorsal root ganglion (DRG) to the dorsal horn of the spinal cord by suppressing the presynaptic N-type calcium channel. Taken together, we believe that MT is a novel drug candidate in treating pruritus diseases, especially for histamine-independent and chronic pruritus, which might be attributed to inhibition of the presynaptic N-type calcium channel.
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Alcaloides/administración & dosificación , Antipruriginosos/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Prurito/tratamiento farmacológico , Quinolizinas/administración & dosificación , Alcaloides/química , Animales , Antipruriginosos/química , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo N/efectos de los fármacos , Canales de Calcio Tipo N/genética , Modelos Animales de Enfermedad , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Masculino , Ratones , Prurito/genética , Prurito/patología , Quinolizinas/química , Sophora/química , Asta Dorsal de la Médula Espinal/efectos de los fármacos , Asta Dorsal de la Médula Espinal/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/genética , MatrinasRESUMEN
Hinokitiol, a natural monoterpenoid from the heartwood of Calocedrus formosana, has been reported to have anticancer effects against various cancer cell lines. However, the detailed molecular mechanisms and the inhibiting roles of hinokitiol on adenocarcinoma A549 cells remain to be fully elucidated. Thus, the current study was designed to evaluate the effect of hinokitiol on the migration of human lung adenocarcinoma A549 cells in vitro. The data demonstrates that hinokitiol does not effectively inhibit the viability of A549 cells at up to a 10 µM concentration. When treated with non-toxic doses (1-5 µM) of hinokitiol, the cell migration is markedly suppressed at 5 µM. Hinokitiol significantly reduced p53 expression, followed by attenuation of Bax in A549 cells. A dose-dependent inhibition of activated caspase-9 and -3 was observed in the presence of hinokitiol. An observed increase in protein expression of matrix metalloproteinases (MMPs) -2/-9 in A549 cells was significantly inhibited by hinokitiol. Remarkably, when A549 cells were subjected to hinokitiol (1-5 µM), there was an increase in the activities of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) from the reduction in cells. In addition, the incubation of A549 cells with hinokitiol significantly activated the cytochrome c expression, which may be triggered by activation of caspase-9 followed by caspase-3. These observations indicate that hinokitiol inhibited the migration of lung cancer A549 cells through several mechanisms, including the activation of caspases-9 and -3, induction of p53/Bax and antioxidant CAT and SOD, and reduction of MMP-2 and -9 activities. It also induces cytochrome c expression. These findings demonstrate a new therapeutic potential for hinokitiol in lung cancer chemoprevention.
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Metaloproteinasas de la Matriz/metabolismo , Monoterpenos/farmacología , Tropolona/análogos & derivados , Células A549 , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Catalasa/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citocromos c/metabolismo , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Superóxido Dismutasa/metabolismo , Tropolona/farmacologíaRESUMEN
Chronic itch, a distressing symptom of many cutaneous and systemic diseases, significantly impairs quality of life. However, its underlying molecular mechanism is still unclear. Mas-related G protein-coupled receptor A3 (MrgprA3) is considered an itch-specific receptor. MrgprA3 neurons are identified as a class of itch-specific neurons, but the role of MrgprA3 in chronic itch remains elusive. An acetone-ether-water (AEW) model as a histamine-independent itch model is often used in the study of chronic pruritus. In this study, behavioral tests, immunostaining, cell culture, calcium imaging, and other experiments were carried out to examine the expression of MrgprA3. The results showed that the scratching bouts induced by chloroquine increased significantly under the AEW condition; the density of MrgprA3 sensory fibers in the AEW-treated skin area and the number of MrgprA3 neurons in dorsal root ganglia from the AEW model mice also increased significantly. Further analysis showed that the MrgprA3 in mRNA level was also increased after AEW treatment. These results indicated that MrgprA3 played a crucial role in chronic pruritus in the AEW model.
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Ganglios Espinales/metabolismo , Neuronas/metabolismo , Prurito/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Acetona , Animales , Calcio/metabolismo , Cationes Bivalentes/metabolismo , Células Cultivadas , Cloroquina , Enfermedad Crónica , Modelos Animales de Enfermedad , Éter , Ganglios Espinales/patología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/patología , Prurito/patología , ARN Mensajero/metabolismo , Receptores Acoplados a Proteínas G/genética , AguaRESUMEN
This was a prospective multicenter observational study, aiming to explore the effects of acupuncture on smoking cessation in Hong Kong. From March of 2010 to August of 2015, a total of 5202 smokers were recruited based on inclusion criteria and treated with acupuncture for 8 weeks. As a result, 2940 subjects finished the study with a drop-out rate of 43.48%. The self-reported 7-day point abstinence rate was 34.00% in Week 8 and 18.40% in Week 52. The exhaled carbon monoxide level and the number of cigarettes smoked per day were reduced significantly after treatment. The time to relapse was calculated to be 38.71 days. In addition, "cigarettes smoked per day," "Fagerstrom Test for Nicotine Dependence," "total sessions of acupuncture," "whether finished 8 acupuncture treatments in the first month," and "total sessions of acupuncture" were believed to be essential factors for abstinence success. It was concluded that acupuncture was a safe method for smoking cessation and was effective in helping smokers to quit; therefore, acupuncture could be considered as one of the methods to help smokers quit. Further studies regarding the effect differences between acupuncture and medications were needed to clarify the overall benefits of acupuncture.
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Osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson, has long been used in China as an antipruritic herbal medicine; however, the antipruitic mechanism of osthole is unknown. We studied the molecular mechanism of osthole in histamine-dependent itch by behavioral test, Ca(2+) imaging, and electrophysiological experiments. First, osthole clearly remitted the scratching behaviors of mice induced with histamine, HTMT, and VUF8430. Second, in cultured dorsal root ganglion (DRG) neurons, osthole showed a dose-dependent inhibitory effect to histamine. On the same neurons, osthole also decreased the response to capsaicin and histamine. In further tests, the capsaicin-induced inward currents were inhibited by osthole. These results revealed that osthole inhibited histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how osthole exerts anti-pruritus effects and suggests that osthole may be a useful treatment medicine for histamine-dependent itch.
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Cumarinas/farmacología , Activación del Canal Iónico/efectos de los fármacos , Prurito/prevención & control , Canales Catiónicos TRPV/metabolismo , Animales , Antipruriginosos/farmacología , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Capsaicina/farmacología , Células Cultivadas , Ganglios Espinales/citología , Histamina , Masculino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Prurito/inducido químicamente , Prurito/metabolismoRESUMEN
Itch is described as an unpleasant or irritating skin sensation that elicits the desire or reflex to scratch. MrgprA3, one of members of the Mrgprs family, is specifically expressed in a subpopulation of dorsal root ganglion (DRG) in the peripheral nervous system (PNS). These MrgprA3-expressing DRG neurons have been identified as itch-specific neurons. They can be activated by the compound, chloroquine, which is used as a drug to treat malaria. In the present study, we labeled these itch-specific neurons using the method of molecular genetic markers, and then studied their electrophysiological properties. We also recorded the cutaneous MrgprA3(-) neurons retrogradely labeled by Dil dye (MrgprA3(-)-Dil). We first found that MrgprA3(+) neurons have a lower excitability than MrgprA3(-) neurons (MrgprA3(-)-non-Dil and MrgprA3(-)-Dil). The number of action potential (AP) was reduced more obviously in MrgprA3(+) neurons than that of in MrgprA3(-) neurons. In most cases, MrgprA3(+) neurons only generated single AP; however, in MrgprA3(-) neurons, the same stimulation could induce multiple AP firing due to the greater voltage-gated potassium (Kv) current existence in MrgprA3(+) than in MrgprA3(-) neurons. Thus, Kv current plays an important role in the regulation of excitability in itch-specific neurons.
Asunto(s)
Potenciales de Acción/genética , Ganglios Espinales/citología , Neuronas/fisiología , Canales de Potasio con Entrada de Voltaje/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Potenciales de Acción/efectos de los fármacos , Aminoácidos/administración & dosificación , Animales , Fenómenos Biofísicos/efectos de los fármacos , Fenómenos Biofísicos/genética , Biofisica , Células Cultivadas , Estimulación Eléctrica , Femenino , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Potasio/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Receptores Acoplados a Proteínas G/genética , Tetraetilamonio/farmacologíaRESUMEN
Histamine H4 receptor has been confirmed to play a role in evoking peripheral pruritus. However, the ionic and intracellular signaling mechanism of activation of H4 receptor on the dorsal root ganglion (DRG) neurons is still unknown. By using cell culture and calcium imaging, we studied the underlying mechanism of activation of H4 receptor on the DRG neuron. Immepip dihydrobromide (immepip)-a histamine H4 receptor special agonist under cutaneous injection-obviously induced itch behavior of mice. Immepip-induced scratching behavior could be blocked by TRPV1 antagonist AMG9810 and PLC pathway inhibitor U73122. Application of immepip (8.3-50 µM) could also induce a dose-dependent increase in intracellular Ca(2+) ([Ca(2+)]i) of DRG neurons. We found that 77.8% of the immepip-sensitized DRG neurons respond to the TRPV1 selective agonist capsaicin. U73122 could inhibit immepip-induced Ca(2+) responses. In addition, immepip-induced [Ca(2+)]i increase could be blocked by ruthenium red, capsazepine, and AMG9810; however it could not be blocked by TRPA1 antagonist HC-030031. These results indicate that TRPV1 but not TRPA1 is the important ion channel to induce the DRG neurons' responses in the downstream signaling pathway of histamine H4 receptor and suggest that TRPV1 may be involved in the mechanism of histamine-induced itch response by H4 receptor activation.
Asunto(s)
Ganglios Espinales/metabolismo , Neuronas/metabolismo , Prurito/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Canales Catiónicos TRPV/metabolismo , Fosfolipasas de Tipo C/metabolismo , Acetanilidas/farmacología , Acrilamidas/farmacología , Animales , Antipruriginosos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Calcio/metabolismo , Capsaicina/farmacología , Relación Dosis-Respuesta a Droga , Ganglios Espinales/efectos de los fármacos , Agonistas de los Receptores Histamínicos/farmacología , Imidazoles/farmacología , Ratones , Neuronas/efectos de los fármacos , Piperidinas/farmacología , Purinas/farmacología , Receptores Histamínicos , Receptores Histamínicos H4 , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
Insights into function of central histaminergic system, a general modulator originating from the hypothalamus for whole brain activity, in motor control are critical for understanding the mechanism underlying somatic-nonsomatic integration. Here, we show a novel selective role of histamine in the cerebellar nuclei, the final integrative center and output of the cerebellum. Histamine depolarizes projection neurons but not interneurons in the cerebellar nuclei via the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to histamine H2 receptors, which are exclusively expressed on glutamatergic and glycinergic projection neurons. Furthermore, blockage of HCN channels to block endogenous histaminergic afferent inputs in the cerebellar nuclei significantly attenuates motor balance and coordination. Therefore, through directly and quickly modulation on projection neurons but not interneurons in the cerebellar nuclei, central histaminergic system may act as a critical biasing force to not only promptly regulate ongoing movement but also realize a rapid integration of somatic and nonsomatic response.