ABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Cytokines/drug effects , Esophageal Mucosa/drug effects , Gastroesophageal Reflux/drug therapy , Isoflavones/pharmacology , Animals , Antioxidants/metabolism , Cell Survival/drug effects , Claudin-4/metabolism , Claudin-5/metabolism , Cytokines/metabolism , Disease Models, Animal , Esophageal Mucosa/injuries , Esophagus/drug effects , Esophagus/metabolism , Gastroesophageal Reflux/chemically induced , Glutathione/metabolism , Lipid Peroxidation/drug effects , Lipopolysaccharides/pharmacology , Male , Mice , Oxidative Stress/drug effects , RAW 264.7 Cells , Rats , Rats, WistarABSTRACT
Gastroesophageal reflux disease (GERD) is induced by the reflux of stomach contents or gastric acid, pepsin into the esophagus for prolonged periods of time due to defection of the lower esophageal sphincter. Reflux esophagitis is a disease found in less than 50% of GERD patients. This study is aimed at evaluating the protective effect of Curcumae longae Rhizoma 30% EtOH extract (CLR) in acute reflux esophagitis (ARE) rats. CLR measured antioxidant activity through in vitro experiments. Based on the results, we performed experiments in vivo. Before 90 min ARE induction, CLR was administered orally by concentration. ARE was derived by linking the metastatic junction between pylorus and forestomach and corpus in Sprague-Dawley rats. And rats were sacrificed 5 h after surgery. We analyzed the expression of antioxidant and inflammatory-related markers by western blot and observed the production of alanine aminotransferase (ALT), aspartate aminotransferase (AST), reactive oxygen species (ROS), peroxynitrite (ONOO-), and thiobarbituric acid reactive substance (TBARS). The administration of CLR reduced esophagus tissue damage in rats with acute reflux esophagitis and decreased the elevated ALT, AST, ROS, ONOO-, and TBARS. In addition, CLR effectively increased antioxidant-related factors and reduced inflammatory protein. Overall, these results suggest that CLR would be used as a therapeutic material in protection and treatment for ARE. Overall, CLR treatment informed that markedly ameliorated inactivation of NF-κB led to the inhibition of the expressions of proinflammatory proteins. These results suggest that CLR would be used as a therapeutic material in protection and treatment for ARE.
Subject(s)
Esophagitis, Peptic , Esophagus , Plant Extracts/pharmacology , Protective Agents/pharmacology , Animals , Curcuma , Esophagitis, Peptic/metabolism , Esophagitis, Peptic/pathology , Esophagus/drug effects , Esophagus/pathology , Male , Rats , Rats, Sprague-DawleyABSTRACT
The high level of nuclear radiation threats in the modern world determines the need to find new means of pharmacological protection of the health of military personnel and civilians from the effects of ionizing radiation. Of particular scientific interest in this aspect are natural polyphenols as a promising basis for the development of newdrugs, radiomodifiers. OBJECTIVE: Justification of the prospects of creating radioprotective agents based on compositions of plantpolyphenolic substances (PPS) and polysaccharides. MATERIAL AND METHODS: The experiments were performed on 130 laboratory white rats-male of Wistar line sexually mature weighting 180-240 g. Animals once received a total X-ray dose equivalent to 4.25 Gy. The effects ofquercetin and patulaten to the processes of reparative regeneration under conditions of X-ray irradiation andagainst the background of butadione suppression were investigated. Indicators in the study groups were compared using the Student's t-test for independent samples; the differences were considered statistically significantat p < 0.05. RESULTS: The various biological properties of quercetin, in particular, the ability to bind hydroxyl radicals, is thepotential for developing radioprotective agents based on it. At the first stage of the study, the effect of PPS andtheir compositions with polysaccharides on reparative regeneration was studied against the background of its suppression in intact and irradiated animals. With the oral administration of PPS and their compositions with pectin towhite rats, 30 minutes before the administration of butadion, an increase in the processes of reparative regeneration in the cells of the covering epitheliumof the esophagus was observed. At the same time, quercetin granulescaused the most expressive effect, which increased the statistically significant value of the mitotic index by 78.5 %in relation to the group of animals injected with butadion. At the second stage of the study, the effect of polyphenolic substances and their compositions with pectin on the processes of reparative regeneration in intact and irradiated white rats was studied on a model of linear skin wounds. The prophylactic administration of quercetin granules and the treatment of wounds with 20 % sterile quercetin gel significantly accelerated the healing process.Experimental data indicate that quercetin granules have the ability to stimulate the processes of reparative regeneration, quercetin showed the greatest efficiency with simultaneous use inside and topically. CONCLUSIONS: The research results indicate the promise of developing radioprotective drugs that can stimulatereparative regeneration processes based on compositions of plant polyphenolic substances and polysaccharides invarious qualitative and quantitative ratios.
Subject(s)
Chromones/pharmacology , Pectins/pharmacology , Polyphenols/pharmacology , Quercetin/pharmacology , Radiation Injuries, Experimental/drug therapy , Radiation-Protective Agents/pharmacology , Wound Healing/drug effects , Animals , Epithelial Cells/drug effects , Epithelial Cells/pathology , Epithelial Cells/radiation effects , Esophagus/drug effects , Esophagus/pathology , Esophagus/radiation effects , Male , Mitotic Index , Phenylbutazone/pharmacology , Radiation Injuries, Experimental/etiology , Radiation Injuries, Experimental/pathology , Rats , Rats, Wistar , Skin/drug effects , Skin/pathology , Skin/radiation effects , Wound Healing/physiology , X-Rays/adverse effectsABSTRACT
INTRODUCTION: Eosinophilic esophagitis (EoE) is a T-helper 2 (Th2), eosinophilic disease associated with pathologic tissue remodeling that leads to end-organ dysfunction. During early-stage disease, inflammation and subepithelial fibrosis are coupled and reversible, but in late-stage or therapy-resistant disease, there can be uncoupling of these features with progressive esophageal rigidity and strictures contributing to clinical dysphagia and food impactions. No current pharmacotherapeutic interventions directly target esophageal fibrosis. Based on the ability of the thiazolidinediones (TZD) to regulate intestinal and hepatic fibrosis, we tested the antifibrotic effects of the TZDs, rosiglitazone and pioglitazone, in preclinical studies using primary human esophageal fibroblasts. METHODS: Primary fibroblasts isolated from normal or EoE esophagi were treated with transforming growth factor (TGF)-ß1 in the absence or presence of TZDs and, in some experiments, without or with budesonide and analyzed by quantitative real-time PCR and immunoblotting. Immunohistochemical analysis of human esophageal biopsies was performed. RESULTS: EoE esophageal biopsies and esophageal fibroblasts expressed higher levels of the TZD receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ), than normal controls. PPAR-γ was inducible by the Th2 cytokine, interleukin 4 (IL-4). TZD significantly reduced TGF-ß1-induced myofibroblast and fibrotic gene and protein expression preferentially in EoE, but not normal esophageal fibroblasts. In esophageal fibroblasts, TGF-ß1 increased phosphorylated Smad2/3 and p38, but TZDs preferentially inhibited p38 phosphorylation, suggesting signaling pathway-specific effects. The TZDs were more potent than budesonide at decreasing collagen-1α1 expression. DISCUSSION: The TZDs preferentially exert antifibrotic effects in TGF-ß1-activated EoE fibroblasts and provide a preclinical foundation for further investigation of the potential of the TZDs in EoE pathologic remodeling.
Subject(s)
Eosinophilic Esophagitis/drug therapy , Esophagus/pathology , Myofibroblasts/drug effects , Pioglitazone/pharmacology , Rosiglitazone/pharmacology , Biopsy , Budesonide/pharmacology , Cells, Cultured , Drug Evaluation, Preclinical , Eosinophilic Esophagitis/immunology , Eosinophilic Esophagitis/pathology , Esophagus/cytology , Esophagus/drug effects , Esophagus/immunology , Fibrosis , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Interleukin-4/metabolism , Myofibroblasts/immunology , Myofibroblasts/metabolism , PPAR gamma/metabolism , Pioglitazone/therapeutic use , Primary Cell Culture , Rosiglitazone/therapeutic use , Signal Transduction/drug effects , Signal Transduction/immunology , Transforming Growth Factor beta1/metabolismABSTRACT
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.
Subject(s)
Adhesives/metabolism , Anesthetics, Local/metabolism , Dosage Forms , Drug Development/methods , Lidocaine/metabolism , Mouth Mucosa/metabolism , Adhesives/administration & dosage , Anesthetics, Local/administration & dosage , Animals , Drug Evaluation, Preclinical/methods , Esophagus/drug effects , Esophagus/metabolism , Lidocaine/administration & dosage , Mouth Mucosa/drug effects , Organ Culture Techniques , Permeability/drug effects , SwineABSTRACT
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.
Subject(s)
Bile Acids and Salts/adverse effects , Epithelium/drug effects , Esophagus/drug effects , Inflammasomes/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Phytochemicals/pharmacology , Receptors, Calcium-Sensing/metabolism , Animals , Cells, Cultured , Epithelium/metabolism , Epithelium/pathology , Esophagus/metabolism , Esophagus/pathology , Gastrointestinal Agents/adverse effects , Humans , Inflammasomes/metabolism , Irritants/adverse effects , Male , Medicine, Chinese Traditional , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Rats , Rats, Sprague-Dawley , Receptors, Calcium-Sensing/geneticsABSTRACT
Heweijiangni decoction (HWJND) is an effective traditional Chinese medicine prescription in clinical treatment of nonerosive reflux disease (NERD). Esophageal hypersensitivity and acid contribute to the disease. However, the exact underlying mechanism of action remains unclear. In this study, we observed the effect of HWJND on esophageal morphology in a rat model of ovalbumin (OVA)-induced visceral hypersensitivity followed by acid exposure. Esophageal morphology was assessed by measuring the extent of dilated intercellular spaces (DIS), desmosome disruption, and mitochondrial fragmentation. HWJND in low, moderate, and high doses relieved DIS and desmosome disruption in esophageal epithelium compared with model group (P<0.05 for all doses). In addition, HWJND in high dose protected mitochondria from fragmentation (P<0.05). Other findings suggest that DIS and mitochondrial fragmentation are independent events, and that omeprazole protects mitochondria. Overall, HWJND significantly resists esophageal morphology changes in OVA-induced and acid exposure rat model.
Subject(s)
Drugs, Chinese Herbal/therapeutic use , Esophagus/drug effects , Gastroesophageal Reflux/chemically induced , Gastroesophageal Reflux/drug therapy , Hydrochloric Acid/pharmacology , Ovalbumin/pharmacology , Animals , Desmosomes/drug effects , Disease Models, Animal , Esophagus/pathology , Extracellular Space/drug effects , Hydrochloric Acid/administration & dosage , Injections, Intraperitoneal , Male , Mitochondria/drug effects , Omeprazole/pharmacology , Ovalbumin/administration & dosage , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND/AIMS: Dysphagia is a common complication after acute stroke. While there are several innovative treatments being tested to improve the swallowing function of stroke patients with dysphagia, our aim is to explore the use of readily available natural capsaicin in stroke patients with dysphagia. STUDY DESIGN: A randomized, double-blind study. METHODS: Sixty-nine hospitalized stroke patients were enrolled in this study. The capsaicin intervention group received thermal tactile stimulation with supplementation of natural capsaicin and additional nectar viscosity boluses. The control group received stimulation and boluses with placebo. Swallowing function was evaluated before and after the 3-week treatment, using Volume-Viscosity Swallow Test, Eating Assessment Tool, Standardized Swallowing Assessment, and Water Swallow Test. RESULTS: The score decreases in the Eating Assessment Tool and Standardized Swallowing Assessment of the capsaicin intervention group were significantly greater than that of the placebo control group (P < .01). Among the 60 patients, the capsaicin intervention group exhibited effectiveness in a higher number of patients (nâ¯=â¯27, 90%) than the placebo group (nâ¯=â¯9, 30%, P < .001). CONCLUSIONS: Regular use of natural capsaicin could promote the recovery of swallow function in stroke patients with dysphagia. The ample availability of natural capsaicin could provide a low cost, easily accessible, and safe alternative method to address dysphagia in stoke patients.
Subject(s)
Capsaicin/therapeutic use , Deglutition Disorders/drug therapy , Deglutition/drug effects , Esophagus/drug effects , Sensory System Agents/therapeutic use , Stroke/complications , Aged , Capsaicin/adverse effects , China , Deglutition Disorders/diagnosis , Deglutition Disorders/etiology , Deglutition Disorders/physiopathology , Double-Blind Method , Esophagus/physiopathology , Female , Humans , Male , Middle Aged , Recovery of Function , Sensory System Agents/adverse effects , Stroke/diagnosis , Stroke/physiopathology , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Ginger has been used as an herbal medicine worldwide to relieve nausea/vomiting and gastrointestinal discomfort, but the cellular and molecular mechanisms of its neuronal action remain unclear. The present study aimed to determine the effects of ginger constituent 6-shogaol on gastroesophageal vagal nodose C-fibers. METHODS: Extracellular single-unit recording and two-photon nodose neuron imaging were performed, respectively, in ex vivo gastroesophageal-vagal preparations from wild type and Pirt-GCaMP6 transgenic mice. The action potential discharge or calcium influx evoked by mechanical distension and chemical perfusions applied to the gastroesophageal vagal afferent nerve endings were recorded, respectively, at their intact neuronal cell soma in vagal nodose ganglia. The effects of 6-shogaol on nodose C-fiber neurons were then compared and determined. KEY RESULTS: Gastroesophageal application of 6-shogaol-elicited intensive calcium influxes in nodose neurons and evoked robust action potential discharges in most studied nodose C-fibers. Such activation effects were followed by a desensitized response to the second application of 6-shogaol. However, action potential discharges evoked by esophageal mechanical distension, after 6-shogaol perfusion, did not significantly change. Pretreatment with TRPA1 selective blocker HC-030031 inhibited 6-shogaol-induced action potential discharges in gastric and esophageal nodose C-fiber neurons, suggesting that TRPA1 played a role in mediating 6-shogaol-induced activation response. CONCLUSION AND INFERENCES: This study provides evidence that ginger constituent 6-shogaol directly activates vagal afferent C-fiber peripheral gastrointestinal endings. This activation leads to desensitization to subsequent application of 6-shogaol but not subsequent esophageal mechanical distension. Further investigation is required to establish a possible contribution in its anti-emetic effects.
Subject(s)
Catechols/pharmacology , Nerve Fibers, Unmyelinated/drug effects , Neurons, Afferent/drug effects , Nodose Ganglion/drug effects , Action Potentials/drug effects , Animals , Esophagus/drug effects , Esophagus/innervation , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Stomach/drug effects , Stomach/innervationABSTRACT
BACKGROUND: Due to its smooth muscle relaxing properties, peppermint oil (PO) may relieve dysphagia and chest pain due to esophageal motility disorders. AIM: To explore the impact of PO on dysphagia and/or chest pain in patients referred for motility testing. METHODS: Patients initiated on PO for dysphagia and/or chest pain from 2013 to 2016 were identified. We excluded patients with obstructing esophageal lesions, patients lost to follow-up, and those with preexisting cardiac conditions. Concentrated PO was given as commercially available dissolvable peppermint tablets; two tablets before meals were prescribed to patients with dysphagia and on an as-needed basis for patients with chest pain. Patient-reported symptom response was assessed using a modified five-point Likert scale. RESULTS: Thirty-eight patients were included. Twenty-four patients (63%) reported improvement; 12 were much better and 12 were slightly better. Fourteen experienced no change and none reported feeling worse. Based on pre-treatment HRM, patients with distal esophageal spasm (DES) (n = 10) and esophagogastric junction outflow obstruction (EGJOO) (n = 8) appeared to demonstrate the best subjective improvement (83% and 100%, respectively) (P < 0.05). CONCLUSION: PO appears to provide symptomatic relief in some patients with dysphagia and CP. Presence of a well-defined manometric disorder, particularly DES or EGJOO, appeared to predict response.
Subject(s)
Chest Pain/drug therapy , Deglutition Disorders/drug therapy , Deglutition/drug effects , Esophagus/drug effects , Gastrointestinal Agents/administration & dosage , Plant Oils/administration & dosage , Aged , Chest Pain/diagnosis , Chest Pain/physiopathology , Deglutition Disorders/diagnosis , Deglutition Disorders/physiopathology , Esophagus/physiopathology , Female , Gastrointestinal Agents/adverse effects , Humans , Male , Mentha piperita , Middle Aged , Pilot Projects , Plant Oils/adverse effects , Recovery of Function , Retrospective Studies , Time Factors , Treatment OutcomeABSTRACT
Reflux esophagitis (RE) is a gastrointestinal disease caused by the reflux of gastric acid and stomach contents, and it leads to esophageal damage. Therefore, it is necessary to study the improvement of esophageal damage on a RE-induced model. The present study was accomplished to demonstrate the protective effects of a dichloromethane fraction of Geranium koreanum (DGK) plant on esophageal damage in an acute RE rat model. First, we examined the potential of anti-inflammatory effects of various fractions measured by cell cytotoxicity, morphological changes and nitric oxide (NO) production on lipopolysaccharide (LPS)-induced Raw 264.7 macrophage cells. Then, to evaluate the protective effects on RE, rats were partitioned into the following groups: normal control, RE-induced control and RE rats pre-treated with DGK 100 and 200 mg/kg body weight. The esophageal mucosal ulcer ratio was measured by the Image J program and histological changes were examined using a hematoxylin and eosin staining of the esophageal mucosa. The expression of pro-inflammatory proteins, cytokines and tight junction proteins involved in the esophageal mucosal damage were investigated using Western blotting and an enzyme-linked immunosorbent assay (ELISA) kit with esophagus tissue. DGK chemical profile and phenolic contents were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). The results showed that DGK exhibited anti-inflammatory effects against LPS-stimulated cells by significantly inhibiting NO production. Additionally, the results in vivo showed that improvement effects of DGK on esophageal mucosal damage. The expression of inflammatory proteins involved in nuclear factor κB (NF-κB) signaling pathways and tight junction protein (claudin-4 and -5) were significantly decreased in esophageal mucosa. We found the potential of DGK as source of replacement therapy products for inflammatory and RE disease.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Esophagitis, Peptic/drug therapy , Esophagus/pathology , Geranium/chemistry , Methylene Chloride/chemistry , Plant Extracts/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacology , Cell Shape/drug effects , Cell Survival/drug effects , Chromatography, Liquid , Claudins/metabolism , Esophagitis, Peptic/pathology , Esophagus/drug effects , Inflammation/complications , Inflammation/pathology , Lipopolysaccharides , Mice , Mucous Membrane/drug effects , Mucous Membrane/pathology , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/metabolism , Plant Extracts/pharmacology , Polyphenols/analysis , RAW 264.7 Cells , Rats , Tandem Mass Spectrometry , Tight Junctions/metabolismABSTRACT
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.
Subject(s)
Adenocarcinoma/prevention & control , Barrett Esophagus/prevention & control , Esophageal Neoplasms/prevention & control , Esophagitis, Peptic/prevention & control , Melatonin/therapeutic use , Animals , Esophagus/drug effects , Esophagus/metabolism , Esophagus/pathology , Humans , Melatonin/metabolism , Melatonin/pharmacology , Models, Biological , Protective Agents/pharmacology , Protective Agents/therapeutic useABSTRACT
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.
Subject(s)
Carcinogenesis/drug effects , Cinnamates/pharmacology , Esophageal Neoplasms/prevention & control , Esophageal Squamous Cell Carcinoma/prevention & control , MAP Kinase Signaling System/drug effects , rhoA GTP-Binding Protein/metabolism , 4-Nitroquinoline-1-oxide , Animals , Carcinogenesis/chemically induced , Carcinogenesis/metabolism , Disease Progression , Esophageal Neoplasms/chemically induced , Esophageal Neoplasms/metabolism , Esophageal Squamous Cell Carcinoma/chemically induced , Esophageal Squamous Cell Carcinoma/metabolism , Esophagus/drug effects , Esophagus/metabolism , Esophagus/pathology , Mice, Inbred C57BL , Momordica/chemistry , Plant Extracts/pharmacology , Precancerous Conditions/chemically induced , Precancerous Conditions/metabolism , Precancerous Conditions/prevention & control , Seeds/chemistryABSTRACT
Quisqualis indica L., Syn. Combretum indicum (L.) DeFilipps., known as Rangoon creeper or Chinese Honeysuckle, is an abundant source of phenols and flavonoids thathave crucial role in free radical scavenging. Therefore, here we investigated whether extract of Q. indica flower has any role against esophagitis through scavenging of free radical oxygen species. In this study, we elucidated the effect of ethanolic flower extract of Q. indica on experimental esophagitis in albino Wister rats. The fasted animals divided into six groups and received carboxymethyl cellulose (CMC) (0.25%, 3 mL/kg, Sham control) or toxic control or pantoprazole (30 mg/kg) or flower extract of different doses (100, 200 and 300 mg/kg) were subjected to pylorus and fore stomach ligation. All the animals were sacrificed after 8 h and evaluated for various parameters such as total acidity, free acidity, gastric pH, volume of gastric juices and esophagitis index. Esophageal tissues were subjected to estimation of various oxidative stress parameters like malonaldehyde (MDA), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and protein carbonyl (PC). In a separate experiment, in vitro antioxidant assays such as DPPH and H2O2 assays, total phenolic and flavonoid contents were also conducted. The results revealed that treatments with pantoprazole and flower extracts significantly inhibited the gastric secretion, total acidity and esophagitis index. Various oxidative stress parameters also restored to normal level in the treated groups. This action could be due to the presence of higher phenolic and flavonoid contents. All these findings collectively suggest that the flower extract of Q. indica possibly possess anti-esophagitis potential.
Subject(s)
Antioxidants , Combretum/chemistry , Esophagitis , Flowers/chemistry , Plant Extracts , Animals , Antioxidants/chemistry , Antioxidants/pharmacology , Antioxidants/therapeutic use , Biphenyl Compounds , Esophagitis/drug therapy , Esophagitis/pathology , Esophagus/drug effects , Esophagus/pathology , Flavonoids , Oxidative Stress/drug effects , Phenols , Picrates , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Rats , Rats, WistarABSTRACT
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.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis/drug effects , Drugs, Chinese Herbal/therapeutic use , Esophageal Neoplasms/drug therapy , Esophagus/drug effects , Medicine, Chinese Traditional/methods , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Caspases/metabolism , Drugs, Chinese Herbal/pharmacology , Endoplasmic Reticulum Stress/drug effects , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Esophagus/metabolism , Esophagus/pathology , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/pathology , Molecular Targeted Therapy/methods , NF-kappa B/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , bcl-2-Associated X Protein/metabolismABSTRACT
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.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Berberine/pharmacology , Biomarkers, Tumor/antagonists & inhibitors , Drugs, Chinese Herbal/pharmacology , Gene Expression Regulation, Neoplastic , RNA, Messenger/antagonists & inhibitors , Antineoplastic Agents, Phytogenic/isolation & purification , Berberine/isolation & purification , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/isolation & purification , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Cells/pathology , Esophagus/drug effects , Esophagus/metabolism , Esophagus/pathology , Humans , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, CCR7/antagonists & inhibitors , Receptors, CCR7/genetics , Receptors, CCR7/metabolism , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolism , Signal TransductionABSTRACT
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.
Subject(s)
Adhesives/chemistry , Esophagus , Hypromellose Derivatives/chemistry , Polyethylene Glycols/chemistry , Adhesives/administration & dosage , Adhesives/metabolism , Administration, Oral , Dosage Forms , Drug Evaluation, Preclinical/methods , Esophagus/drug effects , Esophagus/metabolism , Excipients/administration & dosage , Excipients/chemistry , Excipients/metabolism , Hypromellose Derivatives/administration & dosage , Hypromellose Derivatives/metabolism , Mouth Mucosa/drug effects , Mouth Mucosa/metabolism , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/metabolism , Tablets, Enteric-CoatedABSTRACT
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.
Subject(s)
Cyclooxygenase 2/metabolism , Dimethylnitrosamine/analogs & derivatives , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/metabolism , Plant Extracts/pharmacology , Rhizome/chemistry , Saponins/pharmacology , Animals , Cell Cycle Checkpoints/drug effects , Cell Movement/drug effects , Cell Survival/drug effects , Cyclin D1/metabolism , Dimethylnitrosamine/adverse effects , Dinoprostone/metabolism , Esophageal Neoplasms/chemically induced , Esophageal Neoplasms/pathology , Esophagus/drug effects , Esophagus/metabolism , Esophagus/pathology , G2 Phase Cell Cycle Checkpoints/drug effects , Male , Plant Extracts/chemistry , Rats , Rats, Inbred F344 , Saponins/chemistryABSTRACT
BACKGROUND: A poor prognosis associated with esophageal cancer leads to surgical resection not suitable for most patients. Nitinol stents loaded with 50% 5-fluorouracil (5-FU) or paclitaxel (PTX), functioning both as a stent and local chemotherapy, could provide a new therapy modality for these patients. OBJECTIVE: To investigate esophageal tissue responses to nitinol stents loaded with 50% 5-FU or PTX implanted in the esophagus of healthy pigs. DESIGN: Twenty-three healthy Bama mini-pigs were randomly divided into 4 groups for stent implantation: group A (PTX stent, n = 13), group B (5-FU stent, n = 8), group C (blank film-covered stent, n = 1), and group D (bare stent, n = 1). Tissue responses were observed by endoscopy or pathologic analyses, and 5-FU or PTX concentrations were measured in the esophagus at the stent implantation site at different time points. SETTING: Animal laboratory. INTERVENTIONS: Endoscopic placement of esophagus stent. MAIN OUTCOME MEASUREMENTS: Endoscopic examination, histology, and drug concentration analysis. RESULTS: In general, the esophageal tissue responses varied according to different parts of 5-FU or PTX stent (middle part [drug-containing part] and bare ends [drug-free part]). Severe tissue responses at the bare ends of the stent included inflammation, ulceration, and granulation. However, the tissue responses were greatly reduced in the middle part of the stent. The drug concentrations in the esophagus that had contact with the 5-FU stent or PTX stent were very high, especially for the first period after implantation, which did not cause obvious tissue damage. LIMITATION: Some subjects had incomplete follow-up because of unexpected deaths and stent migration. CONCLUSION: The nitinol stents loaded with 50% 5-FU or PTX did not cause severe esophageal tissue responses, although there was a large concentration of the drug in these tissues.
Subject(s)
Alloys , Antineoplastic Agents/pharmacology , Drug-Eluting Stents , Esophagus/drug effects , Fluorouracil/pharmacology , Paclitaxel/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Esophagoscopy , Esophagus/chemistry , Esophagus/pathology , Fluorouracil/administration & dosage , Fluorouracil/pharmacokinetics , Paclitaxel/administration & dosage , Paclitaxel/pharmacokinetics , Random Allocation , SwineABSTRACT
OBJECTIVE: To explore the effect of aluminum phosphate gel and Kangfuxin on esophageal pathology and expressions of interleukin-8 (IL-8) and prostaglandin E2 (PGE2) in rats with reflux esophagitis and explore the possible mechanisms. METHODS: Sixty SD rats were randomized into aluminum phosphate gel group (n=10), Kangfuxin group (n=10), aluminum phosphate gel+Kangfuxin group (n=10), model group (n=20), and control group (n=10). Except for those in the control group, all the rats were subjected to infusion of diluted lysolecithin with hydrochloric acid in the esophagus for 14 days. Ten rats in the model group and those in the control group were sacrificed to examine the pathological changes and contents of IL-8 and PGE2 in the esophagus using optical and electron microscopes and radioimmunoassay. The next day the rest rats were given corresponding treatments (saline in model group) administered into the esophagus on a daily basis for 14 days, after which esophageal pathologies and IL-8 and PGE2 contents were examined. RESULTS: The model rats showed obvious esophageal pathologies including inflammatory cell infiltration, vacuolar degeneration of the epithelial cells, esophageal erosion and even ulceration, with severe detachment of the epithelial cells. The rats in all the intervention groups showed lessened esophageal pathologies and lowered esophageal IL-8 and PGE2 contents compared with those in the model group. Esophageal mucosal injury index and IL-8 and PGE2 contents were all significantly lower in rats receiving combined treatment with aluminum phosphate and Kangfuxin than in those receiving either of the treatments (P<0.05). CONCLUSIONS: Both Kangfuxin and aluminum phosphate gel are effective in the treatment for reflux esophagitis induced by lysolecithin and hydrochloric acid, and their therapeutic effects are achieved possibly by reducing IL-8 and PGE2 levels in the esophagus.