RESUMEN
Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Capsaicina/uso terapéutico , Esófago/metabolismo , Pirosis/dietoterapia , Nocicepción/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Nervio Vago/metabolismo , Animales , Esófago/inervación , Esófago/patología , Pirosis/metabolismo , Pirosis/patología , Humanos , Nervio Vago/patologíaRESUMEN
Context: Daidzein is a secondary metabolite derived from plants, has a flavonoid structure and is known for its protective activity in gastrointestinal disorders. Objective: The current work determines the preventive effect of daidzein against injury in the esophagus mucosa induced by esophageal reflux (RE) in an animal model. Methods: Adult male Wistar rats were classified into six groups: normal control, ER + different doses of daidzein and ER + omeprazole. RE was induced in all animals except controls and supplemented with daidzein and standard drugs orally for 6 hours. Serum and tissue were used for further biochemical parameters. Results: Daidzein as a flavonoid has antioxidant properties and shows in vitro antioxidant activity. The outcomes also reveal an elevation in lipid peroxidation and a decline in the levels of sulphhydryl groups and glutathione, along with the depletion in the activities of enzymatic antioxidants in the oxidative stress state. In a dose-dependent manner daidzein and omeprazole amended all macroscopic and biochemical variations and protected against the raised level of hydrogen peroxide (H2O2), calcium and free iron levels in esophageal tissue induced during RE. It also improved the expression and level of proinflammatory cytokines. Conclusion: The finding reports that daidzein has a potential to show a shielding effect against esophagus damage induced by RE in rats, at least in part via alteration of inflammatory cytokines.
Asunto(s)
Antiinflamatorios/farmacología , Citocinas/efectos de los fármacos , Mucosa Esofágica/efectos de los fármacos , Reflujo Gastroesofágico/tratamiento farmacológico , Isoflavonas/farmacología , Animales , Antioxidantes/metabolismo , Supervivencia Celular/efectos de los fármacos , Claudina-4/metabolismo , Claudina-5/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Mucosa Esofágica/lesiones , Esófago/efectos de los fármacos , Esófago/metabolismo , Reflujo Gastroesofágico/inducido químicamente , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Lipopolisacáridos/farmacología , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Células RAW 264.7 , Ratas , Ratas WistarRESUMEN
Intraoral lidocaine formulations are applied in children and adults for pain relief. The potential risks associated with orally administered lidocaine due to accidental ingestions were highlighted in a warning letter by the US Food and Drug Administration (FDA). This increases the urgency for a need of a child-appropriate dosage forms. For risk minimization, a novel buccal composite dosage form was developed consisting of a lidocaine containing minitablet centered on top of a bilayered mucoadhesive buccal film, so called composite. The preparation included direct tableting of minitablets as well as film-casting technique. Within a comparability study, the permeation of this composite was classified against marketed lidocaine gel, a single-layer film, and a minitablet. These ex-vivo permeation studies under physiologically related conditions in combination with LC-MS/MS quantification enabled the evaluation of permeation in clinically relevant short-term application. The composite showed comparable permeation to marketed gel (104.26 ± 30.15 µg/cm2 vs 128.17 ± 12.49 µg/cm2 cumulative amount of drug) and a higher permeation compared to film (25.84 ± 6.01 µg/cm2). Therefore, a controlled drug application can be assumed by the composite, whereby the risk of inadvertent swallowing as well as uncontrolled absorbed amount of drug substance may be substantially minimized.
Asunto(s)
Adhesivos/metabolismo , Anestésicos Locales/metabolismo , Formas de Dosificación , Desarrollo de Medicamentos/métodos , Lidocaína/metabolismo , Mucosa Bucal/metabolismo , Adhesivos/administración & dosificación , Anestésicos Locales/administración & dosificación , Animales , Evaluación Preclínica de Medicamentos/métodos , Esófago/efectos de los fármacos , Esófago/metabolismo , Lidocaína/administración & dosificación , Mucosa Bucal/efectos de los fármacos , Técnicas de Cultivo de Órganos , Permeabilidad/efectos de los fármacos , PorcinosRESUMEN
Impairment of the oesophageal epithelium in patients with reflux oesophagitis (RE) is a cytokine-mediated injury rather than a chemical burn. The present study was conducted to explore CaSR/NLRP3 inflammasome pathway activation and cytokines IL-1ß and IL-18 release in oesophageal epithelia injured by refluxates and the effects of Tojapride on that signal regulation. Using a modified RE rat model with Tojapride administration and Tojapride-pretreated SV40-immortalized human oesophageal epithelial cells (HET-1A) exposed to acidic bile salts pretreated with Tojapride, we evaluated the therapeutic effects of Tojapride on oesophageal epithelial barrier function, the expression of CaSR/NLRP3 inflammasome pathway-related proteins and the release of downstream cytokines in response to acidic bile salt irritation. In vivo, Tojapride treatment ameliorated the general condition and pathological lesions of the oesophageal epithelium in modified RE rats. In addition, Tojapride effectively blocked the CaSR-mediated NLRP3 inflammasome activation in modified RE rats. In vitro, Tojapride treatment can reverse the harmful effect of acidic bile salts, which reduced transepithelial electrical resistance (TEER), up-regulated the CaSR-mediated NLRP3 inflammasome pathway and increased caspase-1 activity, LDH release and cytokines secretion. Taken together, these data show that Tojapride can prevent CaSR-mediated NLRP3 inflammasome activation and alleviate oesophageal epithelial injury induced by acidic bile salt exposure.
Asunto(s)
Ácidos y Sales Biliares/efectos adversos , Epitelio/efectos de los fármacos , Esófago/efectos de los fármacos , Inflamasomas/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fitoquímicos/farmacología , Receptores Sensibles al Calcio/metabolismo , Animales , Células Cultivadas , Epitelio/metabolismo , Epitelio/patología , Esófago/metabolismo , Esófago/patología , Fármacos Gastrointestinales/efectos adversos , Humanos , Inflamasomas/metabolismo , Irritantes/efectos adversos , Masculino , Medicina Tradicional China , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/genéticaRESUMEN
Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This "sleep" hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett's esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett's esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L-tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed.
Asunto(s)
Adenocarcinoma/prevención & control , Esófago de Barrett/prevención & control , Neoplasias Esofágicas/prevención & control , Esofagitis Péptica/prevención & control , Melatonina/uso terapéutico , Animales , Esófago/efectos de los fármacos , Esófago/metabolismo , Esófago/patología , Humanos , Melatonina/metabolismo , Melatonina/farmacología , Modelos Biológicos , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéuticoRESUMEN
p-Hydroxylcinnamaldehyde isolated from the Cochinchina momordica seed (CMSP) has been identified to inhibit growth and metastasis in oesophageal squamous cell carcinoma (ESCC) by inducing differentiation. The aim of the present study was to evaluate the effect and underlying mechanism of CMSP on 4-nitroquinoline 1-oxide (4NQO)-induced oesophageal tumourigenesis. In the present study, a mouse model of oesophageal preneoplastic lesions was established by providing 4NQO-containing drinking water to C57BL/6 mice. The effect of CMSP on tumourigenesis induced by the chemical mutagen and the effect of CMSP on immune function were investigated. The results showed that the incidence and pathological stage of atypical hyperplasia in oesophageal tissues were significantly reduced in CMSP-treated mice compared with untreated mice. Immunohistochemistry and pull-down assay results revealed that the expression levels of p-ERK1/2, p-SAPK/JNK, and GTP-RhoA were significantly decreased in the oesophageal tissue of CMSP-treated mice. In addition, the proportions of CD4+ T cells, CD8+ T cells, and NK cells were increased, while the proportion of CD4+ CD25+ regulatory T cells (Tregs) was decreased, in the peripheral blood of CMSP-treated mice. These results indicated that CMSP could hamper 4NQO-induced oesophageal tumourigenesis by regulating the RhoA-ERK/JNK signaling pathway and promoting immune system function, thus providing a new potential strategy for treating preneoplastic lesions of the oesophagus.
Asunto(s)
Carcinogénesis/efectos de los fármacos , Cinamatos/farmacología , Neoplasias Esofágicas/prevención & control , Carcinoma de Células Escamosas de Esófago/prevención & control , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína de Unión al GTP rhoA/metabolismo , 4-Nitroquinolina-1-Óxido , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/metabolismo , Progresión de la Enfermedad , Neoplasias Esofágicas/inducido químicamente , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/inducido químicamente , Carcinoma de Células Escamosas de Esófago/metabolismo , Esófago/efectos de los fármacos , Esófago/metabolismo , Esófago/patología , Ratones Endogámicos C57BL , Momordica/química , Extractos Vegetales/farmacología , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/prevención & control , Semillas/químicaRESUMEN
p-Hydroxylcinnamaldehyde (CMSP) has been identified as an inhibitor of the growth of various cancer cells. However, its function in oesophageal squamous cell carcinoma (ESCC) and the underlying mechanism remain unclear. The aim of the present study was to characterize the differentiation effects of CMSP, as well as its mechanism in the differentiation of ESCC Kyse30 and TE-13 cells. The function of CMSP in the viability, colony formation, migration and invasion of Kyse30 and TE-13 cells was determined by MTS, colony-formation, wound healing and transwell assays. Western blotting and pull-down assays were used to investigate the effect of CMSP on the expression level of malignant markers of ESCC, as well as the activity of MAPKs, RhoA and GTP-RhoA in Kyse30 and TE-13 cells. We found that CMSP could inhibit proliferation and migration and induce Kyse30 and TE-13 cell differentiation, characterized by dendrite-like outgrowth, decreased expression of tumour-associated antigens, as well as the decreased expression of malignant markers. Furthermore, increased cAMP, p-P38 and decreased activities of ERK, JNK and GTP-RhoA, were detected after treatment with CMSP. These results indicated that CMSP induced the differentiation of Kyse30 and TE-13 cells through mediating the cAMP-RhoA-MAPK axis, which might provide new potential strategies for ESCC treatment.
Asunto(s)
Acroleína/análogos & derivados , Carcinoma de Células Escamosas/metabolismo , Cinamatos/farmacología , Neoplasias Esofágicas/metabolismo , Acroleína/farmacología , Animales , Biomarcadores de Tumor/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , AMP Cíclico/metabolismo , Carcinoma de Células Escamosas de Esófago , Esófago/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Medicina Tradicional China , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
BACKGROUND: Rhei Rhizoma has been widely used as a traditional herbal medicine to treat various inflammatory diseases. The present study was conducted to evaluate its anti-inflammatory activity against experimental reflux-induced esophagitis (RE) in SD rats. METHODS: Rhei Rhizoma was administered at 125 or 250 mg/kg body weight per day for 7 days prior to the induction of reflux esophagitis, and its effect was compared with RE control and normal rats. RESULTS: Rhei Rhizoma administration markedly ameliorated mucosal damage on histological evaluation. The elevated reactive oxygen species in the esophageal tissue of RE control rats decreased with the administration of Rhei Rhizoma. RE control rats exhibited the down-regulation of antioxidant-related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression levels, in the presence of esophagitis; however, the levels with Rhei Rhizoma treatment were significantly higher than those in RE control rats. Moreover, RE control rats exhibited the up-regulation of protein expressions related to oxidative stress in the presence of esophagitis, but Rhei Rhizoma administration significantly reduced the expression of inflammatory proteins through mitogen-activated protein kinase (MAPK)-related signaling pathways. The protein expressions of inflammatory mediators and cytokines by nuclear factor-kappa B (NF-κB) activation were modulated through blocking the phosphorylation of inhibitor of nuclear factor kappa B (IκB)α. CONCLUSION: Our findings support the therapeutic evidence for Rhei Rhizoma ameliorating the development of esophagitis via regulating inflammation through the activation of the antioxidant pathway.
Asunto(s)
Esofagitis Péptica/prevención & control , Fitoterapia , Sustancias Protectoras/uso terapéutico , Rheum/química , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/uso terapéutico , Biomarcadores/metabolismo , Esofagitis Péptica/patología , Esófago/metabolismo , Mucosa Gástrica/metabolismo , Reflujo Gastroesofágico/prevención & control , Concentración de Iones de Hidrógeno , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Extractos Vegetales/uso terapéutico , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Esophageal cancer is one of the most common types of cancer in the world, and it demonstrates a distinct geographical distribution pattern in China. In the last decade, inducing apoptosis with traditional Chinese medicine (TCM) has become an active area in both fundamental and clinical research on cancer therapy. In this review, we summarize the molecular mechanisms by which TCM induces apoptosis in esophageal cancer cells. These mechanisms are generally related but not limited to targeting the extrinsic death receptor pathway, the intrinsic mitochondrial pathway, and the endoplasmic reticulum (ER) stress pathway. By using different monomers and composite prescriptions of TCM, it is possible to modulate the ratio of Bcl-2/Bax, regulate the expression of caspase proteases and mitochondrial transmembrane potential, increase the expression of Fas and p53, down-regulate NF-κB pathway and the expression of Chop and survivin, and block cell cycle progression.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Esófago/efectos de los fármacos , Medicina Tradicional China/métodos , Animales , Antineoplásicos Fitogénicos/farmacología , Caspasas/metabolismo , Medicamentos Herbarios Chinos/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Esófago/metabolismo , Esófago/patología , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Terapia Molecular Dirigida/métodos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Berberine is an isoquinoline alkaloid found in several plant species like famous chinese herb, Rhizoma coptidis which has been used locally as a strong gastrointestinal remedy for thousands of years. The inhibitory effects of berberine on tumor progression properties have been reported before. In this study, we investigated the effect of berberine on an esophageal cancer cell line, KYSE-30 with emphasis on its effects on the expression of certain chemokine receptors. The cytotoxic effect of berberine on KYSE-30 cells was analyzed by MTT assay. In vitro cell migration assay was also applied to the treated cells and the expression levels of the selected chemokine receptors (CXCR4 and CCR7) was measured at mRNA level. A retarded growth, associated with increasing concentrations of berberine, was obvious. On the other hand, the migration rate of the cells was decreased when they were treated with different concentrations of berberine and the expression levels of the two chemokine receptors, involved in the migration and metastasis of esophageal cancer cells, were decreased following the same treatments. With these results, we tend to conclude that berberine might be a proper candidate for further investigations, by targeting the chemokine receptors, and possible applications as anti-metastatic agent in cancer studies.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Berberina/farmacología , Biomarcadores de Tumor/antagonistas & inhibidores , Medicamentos Herbarios Chinos/farmacología , Regulación Neoplásica de la Expresión Génica , ARN Mensajero/antagonistas & inhibidores , Antineoplásicos Fitogénicos/aislamiento & purificación , Berberina/aislamiento & purificación , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/aislamiento & purificación , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Esófago/efectos de los fármacos , Esófago/metabolismo , Esófago/patología , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores CCR7/antagonistas & inhibidores , Receptores CCR7/genética , Receptores CCR7/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transducción de SeñalRESUMEN
There is a requirement for the development of oral dosage forms that are adhesive and allow extended oesophageal residence time for localised therapies, or are non-adhesive for ease of swallowing. This study provides an initial assessment of the in vitro oesophageal retention characteristics of several widely utilised pharmaceutical coating materials. To this end, a previously described apparatus has been used to measure the force required to pull a coated disc-shaped model tablet across a section of excised oesophageal tissue. Of the materials tested, the well-studied mucoadhesive polymer sodium alginate was found to be associated with significant oesophageal adhesion properties that was capable of 'self-repairing'. Hydroxypropylmethylcellulose exhibited less pronounced bioadhesive behaviour and blending this with plasticiser or with low molecular weight polymers and surfactants did not significantly affect this. Low molecular weight water soluble polymers, were found to behave similarly to the uncoated glass control disc. Polysorbates exhibited bioadhesion behaviour that was majorly influenced by the nature of the surfactant. The insoluble polymer ethylcellulose, and the relatively lipophilic surfactant sorbitan monooleate were seen to move more readily than the uncoated disc, suggesting that these may have a role as 'easy-to-swallow' coatings.
Asunto(s)
Adhesivos/química , Esófago , Derivados de la Hipromelosa/química , Polietilenglicoles/química , Adhesivos/administración & dosificación , Adhesivos/metabolismo , Administración Oral , Formas de Dosificación , Evaluación Preclínica de Medicamentos/métodos , Esófago/efectos de los fármacos , Esófago/metabolismo , Excipientes/administración & dosificación , Excipientes/química , Excipientes/metabolismo , Derivados de la Hipromelosa/administración & dosificación , Derivados de la Hipromelosa/metabolismo , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/metabolismo , Polietilenglicoles/administración & dosificación , Polietilenglicoles/metabolismo , Comprimidos RecubiertosRESUMEN
Mucoadhesive nanoparticles loaded with curcumin were developed as a new approach to deliver curcumin for the local treatment of oral cancer. PCL nanoparticles coated with chitosan displaying different molar masses were prepared by using the nanoprecipitation technique. The mucoadhesive properties of nanoparticle suspensions were demonstrated by their strong ability to interact with the glycoprotein mucin through electrostatic interactions. Similar permeation profiles of curcumin loaded in uncoated and chitosan-coated nanoparticles across porcine esophageal mucosa were verified. Curcumin concentrations retained in the mucosa suggest the possibility of a local effect of the drug. In vitro studies demonstrated that free curcumin.and curcumin loaded into nanoparticles coated with chitosan caused significant reduction of SCC-9 human oral cancer cell viability in a concentration and time-dependent manner. However, no significant cell death was observed after 24 h of treatment with unloaded nanoparticles coated with chitosan. In addition, curcumin-loaded nanoparticles showed reduced cytotoxicity, when compared with the free drug. Therefore, chitosan-coated PCL nanoparticles may be considered a promising strategy to deliver curcumin directly into the oral cavity for the treatment of oral cancer.
Asunto(s)
Antineoplásicos/farmacocinética , Quitosano/farmacocinética , Curcumina/farmacocinética , Neoplasias de la Boca/metabolismo , Nanopartículas/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quitosano/química , Quitosano/farmacología , Curcumina/química , Curcumina/farmacología , Esófago/química , Esófago/metabolismo , Humanos , Mucinas/metabolismo , Nanopartículas/toxicidad , PorcinosRESUMEN
Rhizoma Paridis Saponins (RPS), a natural compound purified from Rhizoma Paridis, has been found to inhibit cancer growth in vitro and in animal models of cancer. However, its effects on esophageal cancer remain unexplored. The purpose of this study was to investigate the effects of RPS on tumor growth in a rat model of esophageal cancer and the molecular mechanism underlying the effects. A rat model of esophageal cancer was established by subcutaneous injection of N-nitrosomethylbenzylamine (NMBA, 1 mg/kg) for 10 weeks. RPS (350 mg/kg or 100 mg/kg) was administered by oral gavage once daily for 24 weeks starting at the first NMBA injection. RPS significantly reduced the size and number of tumors in the esophagus of rats exposed to NMBA and inhibited the viability, migration, and invasion of esophageal cancer cells EC9706 and KYSE150 in a dose dependent manner (all P < 0.01). Flow cytometry revealed that RPS induced apoptosis and cell cycle G2/M arrest in the esophageal cancer cells. The expression of cyclooxygenases-2 (COX-2) and Cyclin D1 in rat esophageal tissues and the esophageal cancer cells were also significantly reduced by RPS (all P < 0.01). Consistently, RPS also significantly decreased the release of prostaglandin E2, a downstream molecule of COX-2, in a dose-dependent manner (P < 0.01). Our study suggests that RPS inhibit esophageal cancer development by promoting apoptosis and cell cycle arrest and inhibiting the COX-2 pathway. RPS might be a promising therapeutic agent for esophageal cancer.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Dimetilnitrosamina/análogos & derivados , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Extractos Vegetales/farmacología , Rizoma/química , Saponinas/farmacología , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina D1/metabolismo , Dimetilnitrosamina/efectos adversos , Dinoprostona/metabolismo , Neoplasias Esofágicas/inducido químicamente , Neoplasias Esofágicas/patología , Esófago/efectos de los fármacos , Esófago/metabolismo , Esófago/patología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Masculino , Extractos Vegetales/química , Ratas , Ratas Endogámicas F344 , Saponinas/químicaRESUMEN
There is a growing interest in the pharmaceutical field concerning isoflavones topical delivery systems, especially with regard to their skin care properties and antiherpetic activity. In this context, the present work describes an ultra-fast liquid chromatography method (UFLC) for determining daidzein, glycitein, and genistein in different matrices during the development of topical systems containing isoflavone aglycones (IA) obtained from soybeans. The method showed to be specific, precise, accurate, and linear (0.1 to 5 µg mL(-1)) for IA determination in soybean acid extract, IA-rich fraction obtained after the purification process, IA loaded-nanoemulsions, and topical hydrogel, as well as for permeation/retention assays in porcine skin and porcine esophageal mucosa. The matrix effect was determined for all complex matrices, demonstrating low effect during the analysis. The stability indicating UFLC method was verified by submitting IA to acidic, alkaline, oxidative, and thermal stress conditions, and no interference of degradation products was detected during analysis. Mass spectrometry was performed to show the main compounds produced after acid hydrolysis of soybeans, as well as suggest the main degradation products formed after stress conditions. Besides the IA, hydroxymethylfurfural and ethoxymethylfurfural were produced and identified after acid hydrolysis of the soybean extract and well separated by the UFLC method. The method's robustness was confirmed using the Plackett-Burman experimental design. Therefore, the new method affords fast IA analysis during routine processes, extract purification, products development, and bioanalytical assays.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Genisteína/aislamiento & purificación , Glycine max/química , Isoflavonas/aislamiento & purificación , Administración Tópica , Animales , Transporte Biológico , Esófago/efectos de los fármacos , Esófago/metabolismo , Furaldehído/análogos & derivados , Furaldehído/química , Furaldehído/aislamiento & purificación , Furaldehído/farmacología , Genisteína/química , Genisteína/farmacología , Hidrogeles , Hidrólisis , Isoflavonas/química , Isoflavonas/farmacología , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/metabolismo , Permeabilidad , Extractos Vegetales/química , Piel/efectos de los fármacos , Piel/metabolismo , PorcinosRESUMEN
Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter found in blood platelets, the gastrointestinal (GI) tract, and the central nervous system (CNS) of animals and humans. The signaling pathways of 5-hydroxytryptamine (5-HT)-induced contractions in cat esophageal smooth muscle cell (ESMC)s have been identified, but the downstream components of the 5-HT signaling pathway remain unclear. DA-9701 is the standardized extract of the Pharbitis nil Choisy seed (Pharbitidis Semen, Convolvulaceae) and the root of Corydalis yahusuo W.T. Wang (Corydalis Tuber, Papaveraceae). DA-9701 is known to have strong gastroprokinetic effects and a good safety profile. In this study, we investigated the 5-HT signaling pathway at the G-protein level, and we explored the mechanisms by which DA-9701 induces smooth muscle contraction. Freshly isolated smooth muscle cells were harvested from the feline esophagus, and cells were permeabilized to measure their length. 5-HT produced esophageal smooth muscle contractions in a dose-dependent manner. Furthermore, 5-HT produced a relatively long-acting contraction. 5-HT binds to the 5-HT2, 5-HT3 and 5-HT4 receptors to induce smooth muscle contraction in feline ESMCs. These receptors, which are located in esophageal smooth muscle, are coupled to Gαq, Gαo and Gαs. These G proteins activate PLC, which leads to Ca2+/calmodulin-dependent MLCK activation, resulting in MLC20 phosphorylation and cell contraction. Conversely, DA-9701 inhibits 5-HT-induced contraction by inhibiting MLC20 phosphorylation.
Asunto(s)
Fármacos Gastrointestinales/farmacología , Contracción Muscular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Preparaciones de Plantas/farmacología , Serotonina/farmacología , Animales , Gatos , Esófago/citología , Esófago/efectos de los fármacos , Esófago/metabolismo , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Regulación de la Expresión Génica , Humanos , Contracción Muscular/genética , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/metabolismo , Quinasa de Cadena Ligera de Miosina/genética , Quinasa de Cadena Ligera de Miosina/metabolismo , Fosforilación , Unión Proteica , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Transducción de Señal , Fosfolipasas de Tipo C/genética , Fosfolipasas de Tipo C/metabolismoRESUMEN
BACKGROUND: Delivery of a pharmacologically effective drug dosage to a target tissue is critical. Barrett's epithelia are a unique challenge for drug delivery of orally administered zinc due to rapid transit down the esophageal lumen, incomplete absorptive differentiation of these epithelia, and the use of proton-pump inhibitor drugs abrogating intestinal uptake of supplemental zinc. METHODS: Barrett's esophagus patients were administered oral zinc gluconate (26 mg zinc twice daily) for 14 days prior to biopsy procurement. Barrett's biopsies were analyzed for total zinc content by atomic absorption spectroscopy and by western immunoblot for cellular proteins known to be regulated by zinc. RESULTS: Cellular levels of both the Znt-1 transport protein and the alpha isoform of PKC were over 50% lower in the zinc treatment group. CONCLUSION: Oral zinc administration can result in effective delivery of zinc to Barrett's epithelia with resulting effects on intracellular signal transduction.
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Esófago de Barrett/tratamiento farmacológico , Suplementos Dietéticos , Sistemas de Liberación de Medicamentos , Esófago/efectos de los fármacos , Gluconatos/administración & dosificación , Administración Oral , Adulto , Anciano , Esófago de Barrett/metabolismo , Esófago de Barrett/patología , Biopsia , Western Blotting , Proteínas de Transporte de Catión/efectos de los fármacos , Proteínas de Transporte de Catión/metabolismo , Esófago/metabolismo , Esófago/patología , Femenino , Gluconatos/farmacocinética , Humanos , Masculino , Metaplasia , Persona de Mediana Edad , Proteína Quinasa C-alfa/metabolismo , Transducción de Señal/efectos de los fármacos , Espectrofotometría Atómica , Factores de Tiempo , Resultado del TratamientoRESUMEN
102 patients with GERD were examined: 70 female (68%) and 32 men (32%). Age of respondents ranged from 20 to 65 years (average of 45.8 ±8,2). All patients were randomly divided into 2 groups. In the first (control) group (30 people) traditional drug treatment were used according to the standard therapy of GERD (proton pump inhibitors, antacids, prokinetics), patients in the second (main) group (70 people) along with drug therapy has received a course of intravenous laser therapy according to the methods ILIB-405. For intravenous laser treatment Russian apparatus "Matrix-ILIB" ("Matrix", Russia) was used with wavelength 0,405 µm, output power at the end of the main optical path of 1-1.5 mW. Laser blood irradiation was carried out for 15 minutes in the CW mode, the course of treatment was 10 daily treatments with a break on Saturday and Sunday. Conclusions: 1. Intravenous laser irradiation of blood in the complex therapy of patients with gastroesophageal reflux disease improved significantly of HRV due to the alignment of parasympathetic regulation circuit and reducing the activity of sympathetic autonomic regulation, 2. the inclusion of intravenous laser irradiation of blood in the complex therapy of patients with GERD was accompanied by reliable normalization of the indicators of the daily pH-metry of the esophagus in patients with GERD.
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Sistema Nervioso Autónomo/efectos de la radiación , Esófago/metabolismo , Reflujo Gastroesofágico/sangre , Reflujo Gastroesofágico/radioterapia , Terapia por Luz de Baja Intensidad/métodos , Adulto , Anciano , Sistema Nervioso Autónomo/fisiología , Monitorización del pH Esofágico , Esófago/inervación , Esófago/patología , Femenino , Reflujo Gastroesofágico/fisiopatología , Humanos , Cinética , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: To investigate the effect of Tangweian Jianji (TWAJJ) on the biomechanical and morphometrical remodeling of the upper gastrointestinal tract in diabetic rats. METHODS: Diabetes was induced in 27 rats by injecting streptozotocin (40 mg/kg body weight), the animals were then divided into three groups (n = 9 in each group), i.e., diabetic control (DM); high dose (10 g/kg, T1) and low dose (5 g/kg, T2). Another 10 rats acted as normal controls (Control). TWAJJ was administered by gavage once daily. Blood glucose and serum insulin levels were measured. Circumferential length, wall thickness and opening angle were measured from esophageal, duodenal, jejunal and ileal ring segments. The residual strain was calculated from the morphometric data. Step-wise distension was carried out on esophageal and jejunal segments. The obtained data on the length, diameter and pressure changes were then used to calculate the circumferential and longitudinal stresses and strains. Real-time reverse transcription polymerase chain reaction was used to detect the receptor of advanced glycation end-products (RAGE) mRNA level in jejunal tissues. RESULTS: At the end of the experiment, the blood glucose level was significantly higher and the serum insulin level was significantly lower in DM, T1 and T2 groups than in the control group (Glucose: 30.23 ± 0.41 mmol/L, 27.48 ± 0.27 mmol/L and 27.84 ± 0.29 mmol/L vs 5.05 ± 0.04 mmol/L, P = 1.65 × 10(-16), P = 5.89 × 10(-19) and P = 1.63 × 10(-18), respectively; Insulin: 1.47 ± 0.32 µg/L, 2.66 ± 0.44 µg/L, 2.03 ± 0.29 µg/L and 4.17 ± 0.54 µg/L, P = 0.0001, P = 0.029 and P = 0.025, respectively). However, these levels did not differ among the DM, T1 and T2 groups. The wet weight per unit length, wall thickness and opening angle of esophageal and intestinal segments in the DM group were significantly higher than those in the control group (from P = 0.009 to P = 0.004). These parameters in the T1 group were significantly lower than those in the DM group (wet weight, duodenum: 0.147 ± 0.003 g/cm vs 0.158 ± 0.001 g/cm, P = 0.047; jejunum, 0.127 ± 0.003 g/cm vs 0.151 ± 0.002 g/cm, P = 0.017; ileum, 0.127 ± 0.004 g/cm vs 0.139 ± 0.003 g/cm, P = 0.046; wall thickness, esophagus: 0.84 ± 0.03 mm vs 0.94 ± 0.02 mm, P = 0.014; duodenum: 1.27 ± 0.06 mm vs 1.39 ± 0.05 mm, P = 0.031; jejunum: 1.19 ± 0.07 mm vs 1.34 ± 0.04 mm, P = 0.047; ileum: 1.09 ± 0.04 mm vs 1.15 ± 0.03 mm, P = 0.049; opening angle, esophagus: 112.2 ± 13.2Ë vs 134.7 ± 14.7Ë, P = 0.027; duodenum: 105.9 ± 12.3Ë vs 123.1 ± 13.1Ë, P = 0.046; jejunum: 90.1 ± 15.4Ë vs 115.5 ± 13.3Ë, P = 0.044; ileum: 112.9 ± 13.4Ë vs 136.1 ± 17.1Ë, P = 0.035). In the esophageal and jejunal segments, the inner residual stain was significantly smaller and the outer residual strain was larger in the DM group than in the control group (P = 0.022 and P = 0.035). T1 treatment significantly restored this biomechanical alteration (P = 0.011 and P = 0.019), but T2 treatment did not. Furthermore, the circumferential and longitudinal stiffness of the esophageal and jejunal wall increased in the DM group compared with those in the control group. T1, but not T2 treatment, significantly decreased the circumferential wall stiffness in the jejunal segment (P = 0.012) and longitudinal wall stiffness in the esophageal segment (P = 0.023). The mRNA level of RAGE was significantly decreased in the T1 group compared to that in the DM group (P = 0.0069). CONCLUSION: TWAJJ (high dose) treatment partly restored the morphometric and biomechanical remodeling of the upper gastrointestinal tract in diabetic rats.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Esófago/efectos de los fármacos , Fármacos Gastrointestinales/farmacología , Enfermedades Gastrointestinales/tratamiento farmacológico , Motilidad Gastrointestinal/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Animales , Fenómenos Biomecánicos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Duodeno/efectos de los fármacos , Duodeno/patología , Duodeno/fisiopatología , Esófago/metabolismo , Esófago/patología , Esófago/fisiopatología , Fármacos Gastrointestinales/administración & dosificación , Enfermedades Gastrointestinales/sangre , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/patología , Enfermedades Gastrointestinales/fisiopatología , Íleon/efectos de los fármacos , Íleon/patología , Íleon/fisiopatología , Insulina/sangre , Intestino Delgado/metabolismo , Intestino Delgado/patología , Intestino Delgado/fisiopatología , Yeyuno/efectos de los fármacos , Yeyuno/patología , Yeyuno/fisiopatología , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/efectos de los fármacos , Receptores Inmunológicos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estrés MecánicoRESUMEN
BACKGROUND: Gastro-oesophageal reflux (GOR) is common in preterm infants; conservative interventions (i.e. dietary changes) should represent the first-line approach. AIM: To evaluate by combined pH and impedance monitoring (pH-MII) the effect of a new preterm formula thickened with amylopectin (TPF) on GOR features in symptomatic preterm infants. METHODS: Twenty-eight symptomatic preterm newborns underwent a 24-hour pH-MII; each baby received eight meals (four of TPF and four of a preterm formula [PF]). GOR indexes (number, acidity, duration and height of GORs) after TPF and PF meals were compared by Wilcoxon Signed Ranks Test. Viscosity of PF and TPF was measured. RESULTS: TPF significantly decreased the number of acid GORs detected by pH-monitoring (TPF vs. PF: median 20 vs. 24.5, p = 0.009), while it had no influence on Reflux Index (RIpH), nor on acid and non-acid GOR indexes detected by MII, GOR physical features, and GOR height. TPF's viscosity was extremely higher than PF's, and further increased at pH 3 after the addition of pepsin. CONCLUSIONS: The new formula was found to reduce the number of acid GORs detected by pH-monitoring; it did not reduce neither total oesophageal acid exposure nor non-acid GORs. At present its extended clinical use cannot be recommended.
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Reflujo Gastroesofágico/dietoterapia , Fórmulas Infantiles/administración & dosificación , Enfermedades del Prematuro/dietoterapia , Almidón/administración & dosificación , Suplementos Dietéticos , Impedancia Eléctrica , Esófago/química , Esófago/metabolismo , Esófago/fisiopatología , Femenino , Alimentos Fortificados , Reflujo Gastroesofágico/congénito , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/metabolismo , Edad Gestacional , Humanos , Concentración de Iones de Hidrógeno , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/diagnóstico , Masculino , Proyectos Piloto , Resultado del TratamientoRESUMEN
Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC). In a rat model, chronic ZD induces an inflammatory gene signature that fuels ESCC development. microRNAs regulate gene expression and are aberrantly expressed in cancers. Here we investigated whether chronic ZD (23 weeks) also induces a protumorigenic microRNA signature. Using the nanoString technology, we evaluated microRNA profiles in ZD esophagus and six additional tissues (skin, lung, pancreas, liver, prostate and peripheral blood mononuclear cells [PBMC]). ZD caused overexpression of inflammation genes and altered microRNA expression across all tissues analyzed, predictive of disease development. Importantly, the inflammatory ZD esophagus had a distinct microRNA signature resembling human ESCC or tongue SCC miRNAomes with miR-31 and miR-21 as the top-up-regulated species. Circulating miR-31 was also the top-up-regulated species in PBMCs. In ZD esophagus and tongue, oncogenic miR-31 and miR-21 overexpression was accompanied by down-regulation of their respective tumor-suppressor targets PPP2R2A and PDCD4. Importantly, esophageal miR-31 and miR-21 levels were directly associated with the appearance of ESCC in ZD rats, as compared with their cancer-free Zn-sufficient or Zn-replenished counterparts. In situ hybridization analysis in rat and human tongue SCCs localized miR-31 to tumor cells and miR-21 to stromal cells. In regressing tongue SCCs from Zn-supplemented rats, miR-31 and miR-21 expression was concomitantly reduced, establishing their responsiveness to Zn therapy. A search for putative microRNA targets revealed a bias toward genes in inflammatory pathways. Our finding that ZD causes miR-31 and miR-21 dysregulation associated with inflammation provides insight into mechanisms whereby ZD promotes ESCC.