Beyond acid suppression: Novel therapeutic targets for gastro-esophageal reflux disease based on a murine model
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE63403 | GEO | 2015/12/16
SECONDARY ACCESSION(S): PRJNA267663
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-12-16 | E-GEOD-63403 | biostudies-arrayexpress
Project description:Background & Aims: Because the pathophysiology of GERD is not fully understood, presently used drug target only one or more of the known underlying mechanisms but are not fully effective in all patients. 1Identifying novel central targets may pave the way to develop more effective agents. Methods: A surgical model of sub-chronic reflux esophagitis was developed. Wistar rats were pretreated for 7days with omeprazole (standard proton pump inhibitor) or STW5 (herbal preparation of established efficacy in gastro-intestinal disorders). Treatment was continued for 10days after surgery, rats were sacrificed and esophagi excised. Histological, proteomic and transcriptomic methods were applied to identify reflux induced changes and treatment responses. Results: Protection against reflux induced inflammation was achieved by both test drugs. Both reduced macroscopic and microscopic lesions of the esophagi as well as most measured pro-inflammatory cytokines without significantly affecting NF-kB activity. Proteomic and transcriptomic analysis identified CINC1-3, MIP-1/3α, MIG, RANTES and IL-1β as highly relevant mediators in GERD. Other highly regulated genes were those of IL-6, CCL3, CCL7 and LOX-1. Many affected cyto-/chemokines were involved in the TREM-1 signaling pathway. The fatty acid receptor GPR84 was highly up-regulated in esophagitis but down-regulated by both drugs. This was confirmed by Western blot and immune-histochemical staining, showing for the first time expression of this receptor in esophageal tissue and its possible involvement in GERD. Conclusion: STW5 and omeprazole target a broad spectrum of molecules involved in immunological and inflammatory processes, of which IL-8 (CINC1-3), TREM-1 pathway and GPR84 are proposed to be most promising novel targets for the treatment of GERD. Refluxesophagitis was surgically induced. Wistar rats were pretreated for 7 days with omeprazole or STW5. Treatment was continued for 10days after surgery, rats were sacrificed and esophagi exiced. The study had 5 groups. Group 1: sham operated, Group 2: esophagitis group, untreated, Group3: esophagitis treated with STW5 0.5ml/kg. Group 4: esophagitis treated with STW5 2ml/kg. Group 5: esophagitis treated with Omeprazole (30mg/kg). 4 microarrays from esophageal tissue and blood from 4 animals of each group were performed.
2015-12-16 | E-GEOD-63401 | biostudies-arrayexpress
Project description:Background & Aims: Because the pathophysiology of GERD is not fully understood, presently used drug target only one or more of the known underlying mechanisms but are not fully effective in all patients. 1Identifying novel central targets may pave the way to develop more effective agents. Methods: A surgical model of sub-chronic reflux esophagitis was developed. Wistar rats were pretreated for 7days with omeprazole (standard proton pump inhibitor) or STW5 (herbal preparation of established efficacy in gastro-intestinal disorders). Treatment was continued for 10days after surgery, rats were sacrificed and esophagi excised. Histological, proteomic and transcriptomic methods were applied to identify reflux induced changes and treatment responses. Results: Protection against reflux induced inflammation was achieved by both test drugs. Both reduced macroscopic and microscopic lesions of the esophagi as well as most measured pro-inflammatory cytokines without significantly affecting NF-kB activity. Proteomic and transcriptomic analysis identified CINC1-3, MIP-1/3α, MIG, RANTES and IL-1β as highly relevant mediators in GERD. Other highly regulated genes were those of IL-6, CCL3, CCL7 and LOX-1. Many affected cyto-/chemokines were involved in the TREM-1 signaling pathway. The fatty acid receptor GPR84 was highly up-regulated in esophagitis but down-regulated by both drugs. This was confirmed by Western blot and immune-histochemical staining, showing for the first time expression of this receptor in esophageal tissue and its possible involvement in GERD. Conclusion: STW5 and omeprazole target a broad spectrum of molecules involved in immunological and inflammatory processes, of which IL-8 (CINC1-3), TREM-1 pathway and GPR84 are proposed to be most promising novel targets for the treatment of GERD.
2015-12-16 | GSE63401 | GEO
Project description:Background & Aims: Because the pathophysiology of GERD is not fully understood, presently used drug target only one or more of the known underlying mechanisms but are not fully effective in all patients. 1Identifying novel central targets may pave the way to develop more effective agents. Methods: A surgical model of sub-chronic reflux esophagitis was developed. Wistar rats were pretreated for 7days with omeprazole (standard proton pump inhibitor) or STW5 (herbal preparation of established efficacy in gastro-intestinal disorders). Treatment was continued for 10days after surgery, rats were sacrificed and esophagi excised. Histological, proteomic and transcriptomic methods were applied to identify reflux induced changes and treatment responses. Results: Protection against reflux induced inflammation was achieved by both test drugs. Both reduced macroscopic and microscopic lesions of the esophagi as well as most measured pro-inflammatory cytokines without significantly affecting NF-kB activity. Proteomic and transcriptomic analysis identified CINC1-3, MIP-1/3α, MIG, RANTES and IL-1β as highly relevant mediators in GERD. Other highly regulated genes were those of IL-6, CCL3, CCL7 and LOX-1. Many affected cyto-/chemokines were involved in the TREM-1 signaling pathway. The fatty acid receptor GPR84 was highly up-regulated in esophagitis but down-regulated by both drugs. This was confirmed by Western blot and immune-histochemical staining, showing for the first time expression of this receptor in esophageal tissue and its possible involvement in GERD. Conclusion: STW5 and omeprazole target a broad spectrum of molecules involved in immunological and inflammatory processes, of which IL-8 (CINC1-3), TREM-1 pathway and GPR84 are proposed to be most promising novel targets for the treatment of GERD. Refluxesophagitis was surgically induced. Wistar rats were pretreated for 7 days with omeprazole or STW5. Treatment was continued for 10days after surgery, rats were sacrificed and esophagi exiced. The study had 5 groups. Group 1: sham operated, Group 2: esophagitis group, untreated, Group3: esophagitis treated with STW5 0.5ml/kg. Group 4: esophagitis treated with STW5 2ml/kg. Group 5: esophagitis treated with Omeprazole (30mg/kg). 4 microarrays from esophageal tissue and blood from 4 animals of each group were performed.
2015-12-16 | E-GEOD-63402 | biostudies-arrayexpress
Project description:Background & Aims: Because the pathophysiology of GERD is not fully understood, presently used drug target only one or more of the known underlying mechanisms but are not fully effective in all patients. 1Identifying novel central targets may pave the way to develop more effective agents. Methods: A surgical model of sub-chronic reflux esophagitis was developed. Wistar rats were pretreated for 7days with omeprazole (standard proton pump inhibitor) or STW5 (herbal preparation of established efficacy in gastro-intestinal disorders). Treatment was continued for 10days after surgery, rats were sacrificed and esophagi excised. Histological, proteomic and transcriptomic methods were applied to identify reflux induced changes and treatment responses. Results: Protection against reflux induced inflammation was achieved by both test drugs. Both reduced macroscopic and microscopic lesions of the esophagi as well as most measured pro-inflammatory cytokines without significantly affecting NF-kB activity. Proteomic and transcriptomic analysis identified CINC1-3, MIP-1/3α, MIG, RANTES and IL-1β as highly relevant mediators in GERD. Other highly regulated genes were those of IL-6, CCL3, CCL7 and LOX-1. Many affected cyto-/chemokines were involved in the TREM-1 signaling pathway. The fatty acid receptor GPR84 was highly up-regulated in esophagitis but down-regulated by both drugs. This was confirmed by Western blot and immune-histochemical staining, showing for the first time expression of this receptor in esophageal tissue and its possible involvement in GERD. Conclusion: STW5 and omeprazole target a broad spectrum of molecules involved in immunological and inflammatory processes, of which IL-8 (CINC1-3), TREM-1 pathway and GPR84 are proposed to be most promising novel targets for the treatment of GERD.
2015-12-16 | GSE63402 | GEO
Project description:Persistent variability observed during spirometry, even when technical and personal factors are controlled, has prompted interest in uncovering its underlying mechanisms. Notably, our prior investigations have unveiled that spirometry has the potential to trigger gastro-esophageal reflux in a susceptible population. This current study embarks on elucidating the intricate mechanisms orchestrating reflux induced by spirometry. To achieve this, we enlisted twenty-four (24) participants exhibiting reflux symptoms for esophageal assessment. These participants underwent two sets of spirometry sessions, interspersed with a 10-minute intermission, during which we closely scrutinized fluid flow dynamics and esophageal function through high-resolution impedance esophageal manometry. Our comprehensive evaluation juxtaposed baseline manometric parameters against their equivalents during the initial spirometry session, the intervening rest period, and the subsequent spirometry session. Remarkably, impedance values, serving as a metric for fluid quantity, exhibited a substantial elevation during each spirometry session and the ensuing recovery interval in the pan-esophageal and hypopharyngeal regions when compared to baseline levels. Additionally, the resting pressure of the lower esophageal sphincter experienced a noteworthy reduction subsequent to the first bout of spirometry (13.6 ± 8.8 mmHg) in comparison to the baseline pressure (22.5 ± 13.3 mmHg). Furthermore, our observations unveiled a decline in spirometric parameters-FEV1 (0.14 ± 0.24 L, P = 0.042) and PEFR (0.67 L/s, P = 0.34)-during the second spirometry session when contrasted with the first session. Collectively, our study underscores the compelling evidence that spirometry maneuvers can elicit gastro-esophageal reflux by eliciting intra-esophageal pressure differentials and inducing temporary relaxation of the lower esophageal sphincter.
| S-EPMC10499194 | biostudies-literature
Project description:The aim is to investigate the evidence for shared genetic architecture between each of asthma, allergic rhinitis and eczema with gastro-esophageal reflux disease (GERD). Structural equation models (SEM) and polygenic risk score (PRS) analyses are applied to three Swedish twin cohorts (n = 46,582) and reveal a modest genetic correlation between GERD and asthma of 0.18 and bidirectional PRS and phenotypic associations ranging between OR 1.09-1.14 and no correlations for eczema and allergic rhinitis. Linkage disequilibrium score regression is applied to summary statistics of recently published GERD and asthma/allergic disease genome wide association studies and reveals a genetic correlation of 0.48 for asthma and GERD, and Genomic SEM supports a single latent factor. A gene-/gene-set analysis using MAGMA reveals six pleiotropic genes (two at 12q13.2) associated with asthma and GERD. This study provides evidence that there is a common genetic architecture unique to asthma and GERD that may explain comorbidity and requires further investigation.
| S-EPMC11369275 | biostudies-literature
Project description:BackgroundGender-related factors might play an important role in the development of reflux esophagitis (RE) and symptomatic gastro-esophageal reflux disease (GERD). We aimed to evaluate the prevalence and risk factors for RE and symptomatic GERD and determine whether gender specific differences exist.MethodsThis study was conducted on a health cohort consisting of 10,158 participants who underwent comprehensive health screening. Lifestyles and gastrointestinal symptoms were investigated using a self-reported structured questionnaire. Questionnaires about menstrual status were added for the women.ResultsThe prevalence of RE in men was significantly higher than that in women (10.6% vs. 2.0%, P < 0.001); however, symptomatic GERD showed predominance in women (6.2% vs. 2.5%, P < 0.001). Although the prevalence of RE gradually increased with the duration of menopause stratified by decade (P = 0.007), that of symptomatic GERD rapidly increased across the menopausal transit in women. Apart from common risk factors of obesity and current smoking for RE, over 70 years of age in women and hiatal hernia and hypertriglyceridemia in men were significant risk factors. In symptomatic GERD, high somatization was a common risk factor. Excessive alcohol drinking was a significant risk factor in men, but not in women.ConclusionThis study showed a predominance of RE in men, but a predominance of symptomatic GERD in women. In women, dynamic increase in the prevalence of GERD is closely related to the menopause conditions and its duration. There are specific risk factors for RE and symptomatic GERD according to gender differences.
| S-EPMC6543060 | biostudies-literature
Project description:BackgroundGastroesophageal reflux disease (GERD) is a commonly prevalent gastrointestinal disorder in adults. Very few studies on magnitude of GERD in student community have been done and there is none so far from India. Rigorous MBBS curriculum makes medical students prone for reflux symptoms. Hence, this study was conducted to determine the prevalence of GERD in medical students and the potential risk factors associated with it.MethodsThis was a cross sectional observational study conducted on medical students in a premier medical college of India. All participants were interviewed for GERD symptoms using the validated questionnaire on frequency scale for the symptoms of GERD. Additional 11 questions include enquiries on medical history and lifestyle factors.ResultsOf the 600 students, 150 (25%) had GERD symptoms. Of these, 88 (58.6%) had mild, 58 (38.6%) moderate, and 4 (2.7%) severe reflux symptoms. Fifty eight (38.6%) of students with GERD had associated dyspepsia. On univariate analysis higher BMI, final years of MBBS course, use of NSAID or alcohol, inadequate sleep, sleeping within one hour of taking dinner, missing breakfast regularly and quick eating were significantly associated with GERD (p < 0.05).ConclusionsPrevalence of symptoms of GERD in medical students is 25%, majority had mild symptoms. Associated dyspeptic symptoms were present in 38.6%. Factors predisposing to GERD in them are higher BMI, final years of MBBS course, use of NSAID, inadequate sleep, sleeping within one hour of taking dinner, missing breakfast on regular basis and quick eating.
| S-EPMC6081271 | biostudies-literature
Project description:BackgroundProton pump inhibitors are commonly used to treat gastro-esophageal reflux disease (GERD) and nonerosive GERD (NERD) in adolescents and adults. Despite the efficacy of available medications, many patients have persisting symptoms, indicating a need for more effective agents.AimsTo assess the safety and efficacy of dexlansoprazole dual delayed-release capsules in adolescents for treatment of symptomatic NERD.MethodsA phase 2, open-label, multicenter study was conducted in adolescents aged 12-17 years. After a 21-day screening period, adolescents with endoscopically confirmed NERD received a daily dose of 30-mg dexlansoprazole for 4 weeks. The primary endpoint was treatment-emergent adverse events (TEAEs) experienced by ≥5% of patients. The secondary endpoint was the percentage of days with neither daytime nor nighttime heartburn. Heartburn symptoms and severity were recorded daily in patient electronic diaries and independently assessed by the investigator, along with patient-reported quality of life, at the beginning and end of the study.ResultsDiarrhea and headache were the only TEAEs reported by ≥5% of patients. Dexlansoprazole-treated patients (N = 104) reported a median 47.3% of days with neither daytime nor nighttime heartburn. Symptoms such as epigastric pain, acid regurgitation, and heartburn improved in severity for 73-80% of patients. Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire-Adolescents-Short Form symptom and impact subscale scores (scaled 1-5) each decreased by an average of 0.7 units at week 4.ConclusionsUse of 30-mg dexlansoprazole in adolescent NERD was generally well tolerated and had beneficial effects on improving heartburn symptoms and quality of life.Trial registrationThis study has the ClinicalTrials.gov identifier NCT01642602.
| S-EPMC5649596 | biostudies-literature