Xuanfu Daizhe Tang alleviates reflux esophagitis in rats by inhibiting the STAT1/TREM-1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Reflux esophagitis (RE) is a common chronic inflammatory disease of the esophageal mucosa with a high prevalence and recurrence rate, for which a satisfactory therapeutic strategy is still lacking. Chinese medicine has its characteristics and advantages in treating RE, and the clinical application of Xuanfu Daizhe Tang (XDT) in treating RE has achieved sound therapeutic effects. However, there needs to be more research on its mechanism of action. AIM OF THE STUDY: The present work aimed to investigate the mechanism of XDT action in RE through the Signal Transducer and Activator of Transcription 1 (STAT1)/Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) pathway. MATERIALS AND METHODS: The main active components of XDT were analyzed by ultra-performance liquid chromatography-mass spectrometer (UPLC-MS). The effect of XDT on RE was evaluated in a rat model of RE induced by "Cardioplasty + pyloric ligation + Roux-en-Y esophagojejunostomy". Each administration group was treated by gavage. The degree of damage to the esophageal mucosa was evaluated by visual observation, and the Potential of Hydrogen (PH) method and Hematoxylin-eosin staining (HE) staining were performed. Serum levels of Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), and Inducible Nitric Oxide Synthase (iNOS) were measured by ELISA. Quantitative Real-time PCR (qPCR), Western Blot (WB), and Immunofluorescence (IF) methods were used to detect Claudin-4, Claudin-5, TREM-1, and p-STAT1 in esophageal tissues for studying the mechanism of action and signaling pathway of XDT. Immunohistochemistry (IHC) analysis was used to detect the expression of TREM-1 and CD68 in esophageal tissues. Flow Cytometry (FC) was used to detect the polarization of macrophages in the blood. After conducting preliminary experiments to verify our hypothesis, we performed molecular docking between the active component of XDT and STAT1 derived from rats and parallel experiments with STAT1 inhibitor. The selective increaser of STAT1 transcription (2-NP) group was used to validate the mechanism by which XDT acts. RESULTS: XDT alleviated esophageal injury and attenuated histopathological changes in RE rats. XDT also inhibited the inflammatory response and decreased serum IL-1ß, IL-6, TNF-α, and iNOS levels in RE rats. qPCR and WB results revealed that XDT inhibited the expression of Claudin-4, Claudin-5, TREM-1, and STAT1 in the esophageal mucosa of RE rats. IHC and FC results showed that XDT reduced TREM-1 levels in esophageal tissues and polarized macrophages toward M2. The molecular docking results showed that rat-derived STAT1 can strongly bind to Isochronogenic acid A in XDT. The parallel experimental results of STAT1 inhibitor showed that XDT has anti-inflammatory effects similar to STAT1 inhibitors. The 2-NP group confirmed that XDT exerts its therapeutic effect on reflux esophagitis through the STAT1/TREM-1 pathway, with STAT1 as the upstream protein. CONCLUSIONS: This study suggests that XDT may treat reflux esophagitis by modulating the STAT1/TREM-1 pathway.

Elevated Pro-inflammatory Cytokine Levels in Acute Reflux Esophagitis Are Reduced by 1,25 Dihydroxy Vitamin D3.

BACKGROUND/AIM: Gastric acid reflux into the esophagus can cause irritation and inflammation of the esophagus and progress to reflux esophagitis (RE). Vitamin D3 (VitD3) has anti-inflammatory effects and plays an important regulatory role in adaptive and innate immunity. We hypothesized that VitD3 may play a protective role in RE. MATERIALS AND METHODS: Seventy male Sprague-Dawley rats were used, and acute RE (n=35) or chronic RE (n=35) were surgically induced. The effects of different doses of VitD3 on morphological changes and alteration of pro-inflammatory cytokine levels were examined in the rat models. Western blot analysis was performed to determine protein expression levels of IL-1ß, IL-6, and IL-8 in esophageal tissues. Serum levels of VitD3 and calcium were determined using enzyme-linked immunosorbent assays. RESULTS: The protein expression of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8 was found significantly increased in RE. VitD3 treatment significantly reduced the levels of these pro-inflammatory cytokines in both the low-dose and high-dose VitD3 groups compared to control groups in acute RE, but not chronic RE. Macrographic and histopathological examination revealed various degrees of esophageal impairment in rats following surgical induction of acute or chronic RE in rats. These impairments were not improved by VitD3. Morphological grading of esophageal mucosa showed no significant differences between acute and chronic RE. Elevated serum levels of calcium were observed after VitD3 treatment. CONCLUSION: IL-1ß, IL-6, and IL-8 levels were significantly elevated in RE. The abnormal increase in these important pro-inflammatory cytokines was suppressed by VitD3 in the rat models of acute RE. These novel findings suggest a potential protective role of VitD3 in early-stage RE.

Network pharmacology-based prediction and verification of the active ingredients and potential targets of Huagan Decoction for reflux esophagitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Huagan Decoction (HGD), a famous traditional Chinese medicine (TCM) formula, has been widely used in the treatment of reflux esophagitis (RE). However, its effective compounds, potential targets and molecular mechanism remain unclear. AIM OF THE STUDY: To investigate effective compounds, potential targets and molecular mechanism of HGD against RE by using network pharmacology combined with in vitro validation, with the aims of observing the action of HGD and exploring new therapeutic strategies for RE treatment. MATERIALS AND METHODS: Effective compounds and potential targets of HGD, as well as related genes of RE, were collected from public databases. Pharmacological clustering and Gene Ontology (GO) enrichment analysis were applied to find targets that involving in the anti-inflammatory module. The pathways were drawn using Cytoscape 3.8.0. Important ingredients, potential targets, and signaling pathways were determined through the construction of protein-protein interaction (PPI), GO and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, cell experiments were carried out. RESULTS: A total of 54 active ingredients and 240 RE-related gene targets of HGD were identified. The active compound-target network was visualized and pharmacological clustering further sorted 53 proteins that involve in the regulation of inflammatory responses. GO analysis confirmed the classification was statistically significant. Analysis of compound-target network revealed that quercetin and geniposide may be key ingredients for the anti-inflammatory effect of HGD against RE. The potential targets regulated by HGD are IL-6, IL-1ß, PTGS2, AKT1, TNF-α, MAPK1, IL-8, IL-10, CCL2 and MAPK3. In vitro experiment showed that quercetin and geniposide could inhibit the inflammatory response of HET-1A cells through p38MAPK/NF-κB signaling pathway, which was consistent with the prediction by the network pharmacology approach. CONCLUSIONS: Geniposide and quercetin could be effective therapeutic ingredients for the HGD against RE. They play anti-inflammatory effects via down-regulating the pro-inflammatory cytokines and the conduction of p38MAPK/NF-κB signal. This research provides a comprehensive study on the active components, potential targets, and molecular mechanisms of HGD against RE. Moreover, the study supplies a feasible approach to reveal the mechanisms of TCM formula.

Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2021.

In Japan, with the increasing prevalence of gastroesophageal reflux disease (GERD) and growing public interest, the Japanese Society of Gastroenterology issued Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009 and a revised 2nd edition in 2015. A number of studies on GERD were subsequently conducted in Japan and abroad, and vonoprazan, a potassium-competitive acid blocker (P-CAB), became available for the first time in Japan in February 2015. The revised 3rd edition (Japanese edition), which incorporates new findings and information, was published in April 2021. These guidelines are summarized herein, particularly sections related to the treatment of GERD. The important clinical issues addressed in the present revision are (i) the introduction of treatment algorithms that classify GERD into reflux esophagitis and non-erosive reflux disease, (ii) the clarification of treatment algorithms based on to the severity of reflux esophagitis, and (iii) the positioning of vonoprazan in the treatment for GERD. The present guidelines propose vonoprazan as the initial/maintenance treatment for severe reflux esophagitis. They also recommend vonoprazan or PPI as an initial treatment for mild reflux esophagitis and recommended PPI and proposed vonoprazan as maintenance treatment. These updated guidelines offer the best clinical strategies for GERD patients in Japan and hope that they will be of global use for the diagnosis and treatment for GERD.

Tojapride Reverses Esophageal Epithelial Inflammatory Responses on Reflux Esophagitis Model Rats.

OBJECTIVE: To investigate the mechanism of Tojapride, a Chinese herbal formula extract, on strengthening the barrier function of esophageal epithelium in rats with reflux esophagitis (RE). METHODS: Ten out of 85 SD rats were randomly selected as the sham group (n10), and 75 rats were developed a reflux esophagitis model (RE) by the esophageal and duodenal side-to-side anastomosis. Fifty successful modeling rats were divided into different medicated groups through a random number table including the model, low-, medium-, and high-dose of Tojapride as well as omeprazole groups (n10). Three doses of Tojapride [5.73, 11.46, 22.92 g/(kg•d)] and omeprazole [4.17 mg/(kg•d)] were administrated intragastrically twice daily for 3 weeks. And the rats in the sham and model groups were administered 10 mL/kg distilled water. Gastric fluid was collected and the supernatant was kept to measure for volume, pH value and acidity. Esophageal tissues were isolated to monitor the morphological changes through hematoxylin-eosin (HE) staining, and esophageal epithelial ultrastructure was observed by transmission electron microscopy. The expressions of nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-KBp65), κB kinase beta (IKKß), occludin, and zonula occludens-1 (ZO-1) in the esophageal tissues were measured by immunohistochemistry and Western blot, respectively. RESULTS: The gastric pH value in the model group was significantly lower than the sham group (P<0.05). Compared with the model group, gastric pH value in the omeprazole and medium-dose of Tojapride groups were significantly higher (P<0.05). A large area of ulceration was found on the esophageal mucosa from the model rats, while varying degrees of congestion and partially visible erosion was observed in the remaining groups. Remarkable increase in cell gap width and decrease in desmosome count was seen in RE rats and the effect was reversed by Tojapride treatment. Compared with the sham group, the IKKß levels were significantly higher in the model group (P<0.05). However, the IKKß levels were down-regulated after treatment by all doses of Tojapride (P<0.01 or P<0.05). The occluding and ZO-1 levels decreased in the model group compared with the sham group (Ps0.01 or Ps0.05), while both indices were significantly up-regulated in the Tojapride-treated groups (P<0.01 or P<0.05). CONCLUSIONS: Tojapride could improve the pathological conditions of esophageal epithelium in RE rats. The underlying mechanisms may involve in down-regulating the IKKß expression and elevating ZO-1 and occludin expression, thereby alleviating the inflammation of the esophagus and strengthening the barrier function of the esophageal epithelium.

[The role of the traditional surgical procedures for gastroesophageal reflux disease cannot be ignored].

Gastroesophageal reflux disease (GERD) is a common digestive disease with characteristics of a multitude of pathogenesis, a variety of clinical manifestations and a strong negative impact on physical and mental health of the patients. GERD is classified into non-erosive reflux disease and reflux esophagitis in terms of absence or presence of mucosal damage at endoscopic findings. Proton pump inhibitors (PPI) are widely used in the treatment of GERD, especially for patients with non-erosive reflux disease or mild reflux esophagitis. However, PPI do not affect pathophysiologic mechanisms of GERD or reduce the number of reflux events. When PPI fails to adequately control the symptoms of GERD as a result of gastroesophagel junction structural defects, the antireflux surgical procedures are indicated to create a mechanical barrier to reflux. The laparoscopic fundoplication remains the most commonly performed and is the current "gold-standard" anti-reflux procedure. The outcomes of the antireflux surgical procedures are superior to medical therapy for GERD in light of subjective symptoms, objective examinations, quality of life and patient satisfaction. As of now, enough attention has not been paid to the traditional surgical procedures of GERD in China. It is controversial about which is optimal among the three major types of procedures, selection should be tailored to classification, mechanism, age, mental status and esophageal motility. GERD is a chronic disease and either medical or surgical therapy may put the patient at different risk, therefore the patient's preferences should be considered adequately before choosing the treatment protocols.

Ameliorative effects of Magnolia sieboldii buds hexane extract on experimental reflux esophagitis.

Gastroesophageal reflux disease (GERD) is a disease that stomach contents continually refluxing into esophagus causes symptoms and/or complications. The study was working to find natural plant extracts with good effects and small side effects to treat reflux esophagitis (RE). The anti-inflammatory effects of hexane extract of Magnolia sieboldii (MsHE) were conducted on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The ameliorative effects of MsHE on esophageal damage in rats induced by gastric acid reflux was explored in vivo. The results showed that MsHE decreased the production of nitric oxide (NO) and expression levels of iNOS, COX-2 and TNF-α on LPS-stimulated RAW 264.7 cells and MsHE treatment ameliorated the rats' esophageal tissue damage induced by gastric acid and inhibited the increase of inflammatory mediators and pro-inflammatory cytokines by regulating NF-κB signaling pathway. In addition, MsHE protected the function of barrier of epithelial cells against inflammatory conditions through increasing the expression of tight junctions. Furthermore, liquid chromatography-mass spectrometry analysis was used for determine the active ingredients contained in MsHE. The results show that MsHE can alleviate experimental rat RE by regulating NF-κB signaling pathway. In summary, MsHE may be used as a source material of drug candidate for the treatment of RE.

Improvement of Inflammation through Antioxidant Pathway of Gardeniae Fructus 50% EtOH Extract (GE) from Acute Reflux Esophagitis Rats.

Gardeniae Fructus 50% EtOH extract (GE) is a traditional herb that has been used to treat a variety of diseases. In this study, we investigate the antioxidant, anti-inflammatory, and antiapoptotic properties of GE on acute reflux-induced esophagitis (RE) model in rats. 2,2'-Azino-bis (3-ethylbenzothiazolin-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays were performed to determine the antioxidant activity of GE. GE was given orally at 50 and 100 mg/kg body weight 1h 30 min prior to RE induction. And its effect was assessed in comparison with RE control and normal groups. The administration of the extract of the GE showed remarkable protection of mucosal damage in esophageal tissue, and the histologic observation showed that the gastric lesion was improved. Increased reactive oxygen species (ROS) levels in the serum were diminished by GE treatment. The antioxidative biomarkers including nuclear factor-erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) were significantly increased. GE administration significantly reduced the inflammatory protein expression through MAPK-related signaling pathways and the nuclear factor-kappa B (NF-κB) pathway. These results suggest that GE protects the esophagus mucosal membrane by attenuating oxidative stress and inflammatory response under reflux esophagitis condition through the antioxidant pathway. Therefore, it is suggested that GE may be a potential remedy for the treatment of reflux esophagitis.

Dichloromethane Extracts of Geranium Koreanum Kom. Alleviates Esophagus Damage in Acute Reflux Esophagitis-Induced Rats by Anti-Inflammatory Activities.

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.

Low-Molecular-Weight Oligonol, a Polyphenol Derived from Lychee Fruit, Attenuates Experimental Reflux Esophagitis and HCl/Ethanol-Induced Gastric Ulcer.

Oligonol, a polyphenol derived from lychee fruit, is produced by an oligomerization process that converts high-molecular-weight polyphenol polymers into low-molecular-weight oligomers. Evidence suggests that oligonol exerts its beneficial effects based on antioxidant and anti-inflammatory properties. This study was the first to investigate the antioxidative and anti-inflammatory effects of oligonol on gastroesophageal inflammatory models: surgically induced acute reflux esophagitis (RE) and gastric ulcer (GU) induced by HCl/ethanol. In the in vitro study, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazolin-6-sulfonic acid) (ABTS) radical scavenging assays were performed to determine the antioxidant activity of oligonol. The experimental groups were each composed of normal, vehicle, and oligonol groups. RE rats and GU mice were treated orally with oligonol (100 mg/kg bw) or distilled water as a vehicle (n = 8 for each group). Oligonol exhibited potent free radical-scavenging capacities for DPPH and ABTS radicals, activities that were similar to those of ascorbic acid. The in vivo study revealed that oligonol consumption significantly prevented RE and GU formation and decreased the gross mucosal injury from oxidative stress. Oligonol decreased the reactive oxygen species levels and elevated levels of both inflammatory mediators and cytokines (p-IκB, NF-κBp65, COX-2, iNOS, TNF-α, and IL-1ß) in the RE and GU models. Oligonol had a protective effect against oxidative stress by regulating antioxidant enzyme (superoxide dismutase, catalase, and GPx-1/2) activities in GU mice. Oligonol has potential as a preventive and therapeutic agent for gastroesophageal inflammatory diseases, including RE and GU.

Anti-apoptotic effect of banhasasim-tang on chronic acid reflux esophagitis.

AIM: To evaluate the anti-apoptotic effect of banhasasim-tang (BHSST) on chronic acid reflux esophagitis (CARE) using a rat model. METHODS: A surgically-induced CARE model was established in Sprague-Dawley rats. The modeled rats were divided into a treatment group or untreated group, and given BHSST (1 g/kg body weight per day) or water, respectively, for 15 consecutive days (n = 7 each group). Changes in expression of proteins related to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and apoptosis were assessed by western blotting. Changes in esophageal pathology were analyzed by gross and histological examinations. RESULTS: The CARE exposure modeled rats showed increased levels of the NADPH oxidase subunit, NOX4 and p47phox in the esophagus. The BHSST treatment completely resolved these CARE-related increases. The CARE rats also showed markers of cytokine stress, including elevated levels of TNF-α and reactive oxygen species as well as of the consequent increase in JNK activation, and subsequent decrease in pro-survival gene expression, such as of Bcl-2. BHSST treatment resolved the CARE-related changes. BHSST also exerted an anti-apoptotic effect, as evidenced by altered expression of the apoptosis-related genes for bax, cytochrome c, and caspase 3. Finally, the BHSST treatment markedly ameliorated the CARE-related esophageal mucosal ulcerations. CONCLUSION: In the rat model of CARE, BHSST can suppress development of esophageal mucosal ulceration via regulation of reactive oxygen species-dependent apoptosis.

[Pathophysiology and treatment of reflux esophagitis].

Reflux esophagitis (RE) is characterized by excessive esophageal acid exposure. The number of acid reflux episodes, the way acid comes up after reflux and the delay of acid bolus clearance cause excessive esophageal acid exposure. Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of acid reflux in both healthy subjects (HS) and in patients with RE, but there is no difference in the rate of TLESRs or in the rate of acid reflux during TLESRs above the LES between HS and patients with RE. In patients with severe RE, refluxed acid above the LES rises more easily to the proximal esophagus but it does not clear easily from the esophagus when compared with HS. To cure RE, it is necessary to normalize excessive esophageal acid exposure. In GERD guideline in Japanese Society of Gastroenterology, standard dose proton pump inhibitor (PPI) is recommended as the first-line therapy. The response to a standard dose of PPI in patients with mild RE is 90-95%, and that in patients with severe RE is 80-85%. In case that standard dose of PPI is not effective, it is possible that the change to other PPI, the change of administration method (before a meal) and double-dose PPI therapy are effective.

[Effect of aluminum phosphate gel and Kangfuxin on esophageal pathology and IL-8 and PGE2 expressions in a rat model of reflux esophagitis].

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.

Effect of rikkunshito on the expression of substance P and CGRP in dorsal root ganglion neurons and voluntary movement in rats with experimental reflux esophagitis.

BACKGROUND: While there are reports that the herbal medicine rikkunshito (RKT) relieves upper gastrointestinal disease symptoms, the effect of RKT on primary afferent neurons is unknown. METHODS: A model of reflux esophagitis (RE) was implemented using male Wistar rats aged 6-7 weeks. Ten days after surgery, the total area of esophageal mucosal erosion sites was determined. Th8-10 dorsal root ganglia (DRG) were dissected out and the expression of substance P (SP), calcitonin gene-related peptide (CGRP), and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) was determined in DRG using immunohistochemistry. RKT (0.6%/WV) or omeprazole (OME) (10 mg/kg) was administered for 10 days beginning on the day after surgery. Voluntary movement was measured with an infrared sensor for 22 h each day. KEY RESULTS: RE rats showed esophageal mucosal erosion and significantly increased number of SP/CGRP- and p-ERK1/2-immunoreactive neurons in DRG. Treatment with OME improved the size of erosive lesions in the esophageal mucosa of RE rats, while RKT did not. Treatment with RKT or OME significantly reduced the expression of SP/CGRP and p-ERK1/2 in DRG, and significantly increased voluntary movement in RE rats. CONCLUSIONS & INFERENCES: RKT inhibited the activation of ERK1/2 and decreased the expression of SP and CGRP in DRG of RE rats, which may be associated with the observed amelioration of voluntary movement.

Protection effect of Xuanfudaizhetang on reflux esophagitis in rats.

OBJECTIVE: To study protection effect of Xuanfudaizhetang on reflux esophagitis in rats. METHODS: A total of 50 Wistar rats were randomly divided into groups A, B, C, D and E with 10 in each. Reflux esophagitis model in rats was established by incomplete helicobacter seam+lower esophagus sphincterotomy. All rats were divided into 5 groups: group A as control group, group B as model group, group C with saline lavage treatment, group D with motilium treatment, group E with Xuanfudaizhetang lavage treatment. Recovery of esophageal, gastric mucosa and pH changes of rats were compared between groups. RESULTS: Weight gain in group D and E was significantly higher in than group C; the esophageal mucosa grades and esophagus tissue pathological morphology grades of group D and E were higher than that of group B and C with significant difference between groups (P<0.05); pH of lower esophageal mucosa in group D and E increased significantly than that in the group B and C (P<0.05), and the distal mucosal pH dropped significantly in the group B and C (P<0.05). CONCLUSIONS: Xuanfudaizhetang can obviously improve the pH of lower esophageal mucosa in rats with reflux esophagitis, decrease pH value of gastric mucosal, thus improve esophageal mucosa pathological conditions to achieve therapeutic effect on reflux esophagitis.

[Effect of pungent dispersion bitter purgation method on the esophageal mucosal intercellular space of reflux esophagitis model rats].

OBJECTIVE: To observe the effect of pungent dispersion bitter purgation method (PDBPM) on the esophageal mucosal intercellular space of reflux esophagitis (RE) model rats. METHODS: Totally 100 Wistar rats were randomly divided into the control group, the model group, the Western medicine group (WM), the Chinese medicine group (CM), 25 rats in each group. Rats in the control group only received switch operation. Rats in the rest three groups received modified partial cardia muscle incision combined pylorus ligation of external parts to prepare the RE rat model. Starting from the 3rd day after operation, WM mixture (Motilium 3. 2 mg/kg + Omeprazole Capsule 4.3 mg/kg + Hydrotalcite Tablet 161.4 mg/kg) was administered by gastrogavage to rats in the WM group. Rats in the CM group was administered by gastrogavage with Modified Banxia Xiexin Decoction (5.7 g/kg), 2.5 mL each time, twice daily for 14 consecutive days. Equal volume of normal saline was administered by gastrogavage to rats in the control group and the model group. On day 7 and 14, the lower esophagus pH value, general specimen of mucosa and histopathologic changes were observed. Intercellular spaces of esophageal epithelium were measured for a control study. RESULTS: Compared with the same group at day 7, the lower esophagus pH value increased at day 14 (P < 0.01); the naked eye integral of esophageal mucosa and intercellular spaces of esophageal epithelium also decreased at day 14 in the CM group and the WM group (P < 0.05). Compared with the control group at the same time point, the lower esophagus pH value decreased in the model group (P < 0.01). The naked eye integral of esophageal mucosa, and intercellular spaces of esophageal epithelium increased in the model group with increased intercellular spaces (P < 0.01). Compared with the model group at the same time point, the lower esophagus pH value increased and the naked eye integral of esophageal mucosa decreased in the CM group and the WM group at day 7 and 14 (P < 0.01). Intercellular spaces of esophageal epithelium of RE model rats at day 14 was lower in the CM group and the WM group than in the model group (P < 0.01). Compared with the WM group, the lower esophagus pH value decreased at day 7 in the CM group (P < 0.05); the naked eye integral of esophageal mucosa and intercellular spaces of esophageal epithelium decreased at day 14 in the CM group (P < 0.05). CONCLUSIONS: PDBPM had favorable treatment effect on RE model rats. The therapeutic effect was more obvious along with the therapeutic course went by. Its mechanism might be achieved through good repair effect on damaged mucosa, increasing the pressure of esophageal sphincter, and inhibiting gastric acid.

An experimental study of using Chai Lai Prescription to treat in vitro rabbit models of reflux esophagitis.

BACKGROUND: Chai Lai Prescription is a Chinese herbal compound which is used to sooth the liver, strengthen the spleen and harmonize the stomach for descending adverse Qi. We initiated the study to investigate its mechanism of treating in vitro rabbit reflux esophagitis models. METHODS: Adult male Japanese white rabbits, weighing 1.8-2.2 kg, were divided into five groups of three each, which were: normal control group (Krebs buffer, pH7.4), esophagitis model group (Krebs buffer, pH5.8), esophagitis model proup+low-dose Chinese herbal medicine protection group (0.6 mg × ml(-1)× kg(-1)), esophagitis model group+moderate-dose Chinese herbal medicine protection group (6 mg × ml(-1)× kg(-1)), esophagitis model group+high-dose Chinese herbal medicine protection group (60 mg × ml(-1)×kg(-1)). The RT-PCR method was used to test the influence of Chai Lai Prescription on IL-1 and IL-6 in in vitro rabbit models of esophagitis. We treated the in vitro models with different doses of Chinese herbal medicine. RESULTS: Esophageal mucosa were filled with various liquids. IL-6 and IL-1ß mRNA expression was increased in rabbit esophageal mucosa stimulated with acid. Chinese herbal medicine significantly reduced the levels of IL-6 and IL-1ß mRNA expression in the in vitro cultured rabbit esophageal mucosa. Using Chinese herbal medicine to treat in vitro models of RE, we found that the IL-6 and IL-1ß mRNA expression levels went down, near to or lower than the normal control levels, compared with the group treated with acidified buffer solution. CONCLUSIONS: Chai Lai Prescription lowered the IL-1ß and IL-6 cytokine mRNA levels and protected the esophageal mucosa in the in vitro models of reflux esophagitis, suggesting that the traditional Chinese herbal compound may be able to treat reflux esophagitis by inhibiting the its inflammatory mediators.

Effect of rikkunshito, a Japanese herbal medicine, on gastrointestinal symptoms and ghrelin levels in gastric cancer patients after gastrectomy.

BACKGROUND: Gastric cancer patients who undergo gastrectomy suffer from a post-gastrectomy syndrome that includes weight loss, dumping syndrome, reflux esophagitis, alkaline gastritis, and finally malnutrition. It is important to ameliorate the post-gastrectomy symptoms to restore postoperative quality of life (QoL). The aim of this study was to investigate the effect of rikkunshito, a Japanese herbal medicine, on postoperative symptoms and ghrelin levels in gastric cancer patients after gastrectomy. METHODS: Twenty-five patients who had undergone gastrectomy received 2.5 g of rikkunshito before every meal for 4 weeks, and a drug withdrawal period was established for the next 4 weeks. Changes in gastrointestinal hormones, including ghrelin, and appetite visual analog scale scores were measured, and QoL was estimated by using the European Organization for Research and Treatment of Cancer core questionnaire QLQ-C30. The Dysfunction After Upper Gastrointestinal Surgery for Cancer (DAUGS) scoring system was used to evaluate gastrointestinal symptoms after gastrectomy. RESULTS: Sixteen men and nine women (mean age 61.9 years) were enrolled in the study. All patients had either stage I (n = 24) or II (n = 1) disease and had undergone either distal gastrectomy (n = 17) or total gastrectomy (n = 8) by a laparoscopy-assisted approach. The mean ratio of the acyl-/total ghrelin concentration increased significantly after rikkunshito administration (Pre: 7.8 ± 2.1, 4 weeks: 10.5 ± 1.7 %, p = 0.0026). The total DAUGS score, as well as the scores reflecting limited activity due to decreased food consumption, reflux symptoms, dumping symptoms, and nausea and vomiting significantly improved after rikkunshito administration. CONCLUSIONS: The present study demonstrated a significant attenuation of gastrointestinal symptoms after gastrectomy by treatment with rikkunshito. Rikkunshito is potentially useful to minimize gastrointestinal symptoms after gastrectomy.

Effect of Curculigo orchioides on reflux esophagitis by suppressing proinflammatory cytokines.

This study was performed to investigate effects of Curculigo orchioides rhizome (curculiginis rhizome) on acute reflux esophigitis (RE) in rats that are induced by pylorus and forestomach ligation operation. Proinflammatory cytokine, as well as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were all assayed and the expression of TNF-α and COX2 analyzed by RT-PCR. The esophagic tissue damage of reflux esophagitis rat was increased compared to that of normal intact group. However, the esophagic damage percentage from the extract of curculiginis rhizoma (ECR) 600 mg/kg and ECR 300 mg/kg were significantly lower than that of the RE control group. Administration of α-tocopherol (30 mg/kg) and ECR (600 mg/kg, 300 mg/kg, and 150 mg/kg) had a significant effect on the gastric acid pH in rats with induced reflux esophagitis (p < 0.05). The treatment with ECR significantly reduced the production of cytokines TNF-α, IL-1ß and IL-6 levels compared to the model group (p < 0.05). The expression of TNF-α and COX2 in the intact esophageal mucosa was low while those of the RE control group were significantly higher due to an inflammatory reaction in the esophagus. Compare to the model group, treatment with α-tocopherol or ECR significantly inhibited the expression levels of COX2 and TNF-α in a dose-dependent manner. These results suggest that anti-inflammatory and protective effects of ECR could attenuate the severity of reflux esophagitis and prevent esophageal mucosal damage.