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Diseases of the Esophagus : Official... Jul 2022Saliva is a complex physiologic fluid that contains an abundance of biological analytes, or biomarkers. Recent research has shown that these biomarkers may be able to... (Review)
Review
Saliva is a complex physiologic fluid that contains an abundance of biological analytes, or biomarkers. Recent research has shown that these biomarkers may be able to convey the physiologic health of a person. Work has been done linking derangements in these salivary biomarkers to a wide variety of pathologic disorders ranging from oncologic diseases to atopic conditions. The specific area of interest for this review paper is esophageal disorders. Particularly because the diagnosis and management of esophageal disorders often includes invasive testing such as esophagogastroduodenoscopy, prolonged pH monitoring, and biopsy. The aim of this review will be to explore salivary biomarkers (pepsin, bile, epidermal growth factor, and micro-RNA) that are being studied as they relate specifically to esophageal disorders. Finally, it will explore the benefits of salivary testing and identify areas of possible future research.
Topics: Biomarkers; Esophageal Diseases; Gastroesophageal Reflux; Humans; Pepsin A; Saliva
PubMed: 35397479
DOI: 10.1093/dote/doac018 -
Tissue & Cell Oct 2022The apelin/APJ system, which has a widespread distribution in the body, is involved in the regulation of physiological and pathophysiological mechanisms such as... (Review)
Review
The apelin/APJ system, which has a widespread distribution in the body, is involved in the regulation of physiological and pathophysiological mechanisms such as regulation of blood pressure, stress response, immunological activities, obesity, diabetes, inflammation, and neurodegenerative diseases. Apelin also undertakes various tasks in the digestive system such as cell proliferation, secretion of hormones (eg. cholecystokinin and histamine), modulation of gastric and pancreatic secretions, and motility response. Recent researchs have reported that apelin exerts gastroprotective effects by regulating the components of gastric mucosal barrier. Mucosal disorders that can develop in the stomach due to different reasons such as microbial infections, drug use, smoking habits, alcohol consumption, exposure to stress, pepsin, and acid affect a significant proportion of the human population in the world. This review discusses the role of apelin in the protective mechanisms of gastric mucosa against harmful effects.
Topics: Apelin; Cholecystokinin; Gastric Mucosa; Histamine; Humans; Pepsin A
PubMed: 35940035
DOI: 10.1016/j.tice.2022.101885 -
Annals of the New York Academy of... Dec 2018Extra-esophageal reflux is suspected to cause a wide range of clinical symptoms in the upper airways. Diagnosis and treatment has focused on acid, but realization of the... (Review)
Review
Extra-esophageal reflux is suspected to cause a wide range of clinical symptoms in the upper airways. Diagnosis and treatment has focused on acid, but realization of the role of nonacid reflux has resulted in research investigating the use of pepsin as a biomarker for gastric reflux and aspiration. Pepsin analysis can complement the use of questionnaires and office-based diagnosis and lessen the dependency on invasive and expensive diagnostic tests. Furthermore, pepsin as a first-line diagnostic biomarker has been shown to improve the accuracy of reflux diagnosis. In addition to its use as a diagnostic biomarker, pepsin has been shown to cause inflammation independent of the pH of the refluxate and thus despite acid suppression therapy. Research is ongoing to develop new therapies for airway reflux that specifically target pepsin.
Topics: Biomarkers; Gastroesophageal Reflux; Humans; Pepsin A; Pneumonia, Aspiration
PubMed: 29774546
DOI: 10.1111/nyas.13729 -
Otolaryngologia Polska = the Polish... Dec 2017Laryngopharyngeal reflux (LPR) is a common defect among laryngological and phoniatric patients. Although LPR is categorized as a superficial gastroesophageal reflux... (Review)
Review
Laryngopharyngeal reflux (LPR) is a common defect among laryngological and phoniatric patients. Although LPR is categorized as a superficial gastroesophageal reflux disease (GERD), differential diagnosis should treat these two diseases separately. LPR symptoms can be assessed in the interview using as a tool the reflux symptom index (RSI). In addition, changes in the larynx that occur during LPR might be seen during laryngoscopy and classified according to the reflux finding score (RFS). One of the main mucosal irritants in LPR is pepsin which digests proteins and impairs the functions of the upper respiratory tract cells by affecting carbonate anhydrase (CAIII) and the Sep 70 protein. Pepsin initiates inflammatory changes within the larynx, nasopharynx and nasal cavity. The use of pepsin detection in upper and lower throat secretions is a new direction in LPR diagnostics.
Topics: Adult; Aged; Aged, 80 and over; Female; Gastrointestinal Agents; Humans; Laryngopharyngeal Reflux; Larynx; Male; Middle Aged; Pepsin A
PubMed: 29327685
DOI: 10.5604/01.3001.0010.7194 -
Journal of Voice : Official Journal of... Sep 2023Pepsinogen A (PGA)/pepsin A is often used as a diagnostic marker of extra-gastroesophageal reflux. We aimed to explore whether its positivity in upper aerodigestive...
BACKGROUND
Pepsinogen A (PGA)/pepsin A is often used as a diagnostic marker of extra-gastroesophageal reflux. We aimed to explore whether its positivity in upper aerodigestive tract (UADT) was specific enough to diagnose reflux.
METHODS
PGA/pepsin A protein levels were examined in 10 types of tissues and 10 types of body fluid by immunological staining, western blot or Elisa, using three different commercially available brands simultaneously. Liquid chromatography-tandem mass spectrometry parallel reaction monitoring (LC-MS/MS PRM) served as a gold reference for the detection of PGA/pepsin A proteins. PGA gene expression was analyzed by reverse transcriptase sequencing methods for tissue samples. Specifically, 24 hour pH monitoring technique was conducted for patients who donated saliva samples.
RESULTS
Eight out of ten types of human tissue samples (stomach, esophagus, lung, kidney, colon, parotid gland, nasal turbinate and nasal polyps) were confirmed positive for PGA/pepsin A gene and protein by genetic and PRM technique, respectively. Two out of ten types of body fluid samples (gastric fluid, urine) were confirmed positive for PGA/pepsin A protein by PRM technique. The consistence rates of PGA/pepsin A positivity among three commercial antibody brands and Elisa kit were poor, and Elisa results of salivary did not match with 24-hour pH monitoring.
CONCLUSIONS
Multiple tissues and body fluid could be detected baseline expression levels of PGA/pepsin A gene and protein. However, those commercially available PGA/pepsin A antibodies achieved poor sensitivity and specificity, therefore, relying on the detection of PGA/pepsin A in UADT by single antibodies to diagnose extra-gastroesophageal reflux without a specific positive cut-off value is unreliable.
Topics: Humans; Pepsin A; Pepsinogen A; Chromatography, Liquid; Saliva; Tandem Mass Spectrometry; Gastroesophageal Reflux; Laryngopharyngeal Reflux
PubMed: 34090740
DOI: 10.1016/j.jvoice.2021.04.009 -
Otolaryngology--head and Neck Surgery :... Sep 2017Objective Laryngopharyngeal reflux (LPR) is a common illness of otolaryngology visits. Over the past few years, pepsin has become a promising marker of LPR. The... (Review)
Review
Objective Laryngopharyngeal reflux (LPR) is a common illness of otolaryngology visits. Over the past few years, pepsin has become a promising marker of LPR. The objective of the present research is to analyze the existing literature using pepsin as a diagnostic tool of LPR through a systematic review. Data Sources PubMed (Medline), Trip Database, Cochrane Library, EMBASE, SUMsearch, and Web of Science. Review Methods The outcome assessed was the presence of pepsin in LPR patients. We included articles in which pepsin was studied in LPR patients (clinically suspected or with confirmed diagnosis). Studies with no control group, comparison group, and/or a sample size lower than 20 patients were excluded. Results Twelve studies were included. All included studies, with the exception of 2, found statistically significant differences for pepsin in cases compared with healthy controls. Conclusion Pepsin might be a reliable marker in LPR patients, although questions remain about optimal timing, location, nature, and threshold values for pepsin testing. Future investigations are necessary to clarify the best method to use pepsin in the diagnostic process of LPR.
Topics: Biomarkers; Humans; Laryngopharyngeal Reflux; Pepsin A; Reproducibility of Results; Saliva
PubMed: 28585488
DOI: 10.1177/0194599817709430 -
The Laryngoscope Jan 2023More than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary/lifestyle modifications and alginates provide benefit to some, there is no...
OBJECTIVE
More than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary/lifestyle modifications and alginates provide benefit to some, there is no gold standard medical therapy. Increasing evidence suggests that pepsin is partly, if not wholly, responsible for damage and inflammation caused by laryngopharyngeal reflux. A treatment specifically targeting pepsin would be amenable to local, inhaled delivery, and could prove effective for endoscopic signs and symptoms associated with nonacid reflux. The aim herein was to identify small molecule inhibitors of pepsin and test their efficacy to prevent pepsin-mediated laryngeal damage in vivo.
METHODS
Drug and pepsin binding and inhibition were screened by high-throughput assays and crystallography. A mouse model of laryngopharyngeal reflux (mechanical laryngeal injury once weekly for 2 weeks and pH 7 solvent/pepsin instillation 3 days/week for 4 weeks) was provided inhibitor by gavage or aerosol (fosamprenavir or darunavir; 5 days/week for 4 weeks; n = 3). Larynges were collected for histopathologic analysis.
RESULTS
HIV protease inhibitors amprenavir, ritonavir, saquinavir, and darunavir bound and inhibited pepsin with IC in the low micromolar range. Gavage and aerosol fosamprenavir prevented pepsin-mediated laryngeal damage (i.e., reactive epithelia, increased intraepithelial inflammatory cells, and cell apoptosis). Darunavir gavage elicited mild reactivity and no discernable protection; aerosol protected against apoptosis.
CONCLUSIONS
Fosamprenavir and darunavir, FDA-approved therapies for HIV/AIDS, bind and inhibit pepsin, abrogating pepsin-mediated laryngeal damage in a laryngopharyngeal reflux mouse model. These drugs target a foreign virus, making them ideal to repurpose. Reformulation for local inhaled delivery could further improve outcomes and limit side effects.
LEVEL OF EVIDENCE
NA. Laryngoscope, 133:S1-S11, 2023.
Topics: Animals; Mice; Laryngopharyngeal Reflux; Larynx; Pepsin A; Sulfonamides; Carbamates; Furans
PubMed: 35678265
DOI: 10.1002/lary.30242 -
Analytical Chemistry Jan 2022Human pepsin is a digestive protease that plays an important role in the human digestive system. The secondary structure of human pepsin determines its bioactivity....
Human pepsin is a digestive protease that plays an important role in the human digestive system. The secondary structure of human pepsin determines its bioactivity. Therefore, an in-depth understanding of human pepsin secondary structure changes is particularly important for the further improvement of the efficiency of human pepsin biological function. However, the complexity and diversity of the human pepsin secondary structure make its analysis difficult. Herein, a convenient method has been developed to quickly detect the secondary structure of human pepsin using a portable Raman spectrometer. According to the change of surface-enhanced Raman spectroscopy (SERS) signal intensity and activity of human pepsin at different pH values, we analyze the change of the human pepsin secondary structure. The results show that the content of the β-sheet gradually increased with the increase in the pH in the active range, which is in good agreement with circular dichroism (CD) measurements. The change of the secondary structure improves the sensitivity of human pepsin SERS detection. Meanwhile, human pepsin is a commonly used disease marker for the noninvasive diagnosis of gastroesophageal reflux disease (GERD); the detection limit of human pepsin we obtained is 2 μg/mL by the abovementioned method. The real clinical detection scenario is also simulated by spiking pepsin solution in saliva, and the standard recovery rate is 80.7-92.3%. These results show the great prospect of our method in studying the protein secondary structure and furthermore promote the application of SERS in clinical diagnosis.
Topics: Gastroesophageal Reflux; Humans; Pepsin A; Saliva; Spectrum Analysis, Raman
PubMed: 34928126
DOI: 10.1021/acs.analchem.1c04531 -
Brazilian Journal of Otorhinolaryngology 2023Salivary pepsin has emerged as a biomarker for Laryngopharyngeal Reflux (LPR), which, however, has been questioned for its efficacy due to a lack of supporting medical... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Salivary pepsin has emerged as a biomarker for Laryngopharyngeal Reflux (LPR), which, however, has been questioned for its efficacy due to a lack of supporting medical data. Therefore, this study analyzed the diagnostic value of salivary pepsin for LPR and assessed a better cutoff value.
METHODS
Studies were searched in PubMed, Embase, and Cochrane Library from their receptions to October 1, 2021. Then, RevMan 5.3 and Stata 14.0 were utilized to summarize the diagnostic indexes for further meta-analysis. Data were separately extracted by two reviewers according to the trial data extraction form of the Cochrane Handbook. The risk of bias in Randomized Control Trials (RCTs) was evaluated with the Cochrane Risk of Bias Tool.
RESULTS
A total of 16 studies matched the criteria and were subjected to meta-analysis. The results revealed a pooled sensitivity of 61% (95% CI 50%-71%), a pooled specificity of 67% (95% CI 48%-81%), a positive likelihood ratio of 2 (95% CI 1.2-2.8), a negative likelihood ratio of 0.58 (95% CI 0.47‒0.72), and the area under the receiver operating characteristic curve of 0.67 (95% CI 0.63‒0.71). Subgroup analyses indicated that the cutoff value of pepsin at 50 ng/mL had a higher degree of diagnostic accuracy than that of pepsin at 16 ng/mL in cohort studies.
CONCLUSION
The review demonstrated low diagnostic performance of salivary pepsin for LPR and that the cutoff value of 50 ng/mL pepsin had superior diagnostic accuracy. Nevertheless, the diagnostic value may vary dependent on the utilized diagnostic criteria. Therefore, additional research is needed on the improved way of identifying salivary pepsin in the diagnosis of LPR, and also longer-term and more rigorous RCTs are warranted to further assess the effectiveness of salivary pepsin.
Topics: Humans; Laryngopharyngeal Reflux; Pepsin A; Saliva; ROC Curve; Biomarkers
PubMed: 36347787
DOI: 10.1016/j.bjorl.2022.10.050 -
Digestive Diseases (Basel, Switzerland) 2018Functional dyspepsia is a heterogeneous disorder lacking an established therapeutic strategy. Historical treatment attempts with pepsin products were shrugged off, as a... (Review)
Review
BACKGROUND
Functional dyspepsia is a heterogeneous disorder lacking an established therapeutic strategy. Historical treatment attempts with pepsin products were shrugged off, as a simple calculation shows that quantitative substitution is pointless. However, such attempts might have been right for the wrong reason.
SUMMARY
Today, the role of pepsins is primarily seen in the provision of signalling amino acids (especially phenylalanine and tryptophan) and peptides, which initiate processes promoting digestion. Proteolysis benefits from pepsin variants showing, contrary to common belief, activities of up to a pH value of 5.0. Non-clinical and clinical studies support the view that liberated amino acids produce a variety of direct and indirect effects. Signal chains stimulated by (mostly aromatic) amino acids lead to secretion of gastrin and cholecystokinin (CCK), mediated, respectively, by CCK2 (gastrin) and Ca2+-sensing receptors in the parietal cell, and Ca2+-sensing receptors in the antral and duodenal mucosa. Thus, CCK effects such as secretion of pancreatic enzymes and promotion of gastric accommodation are (also) consequential to peptic liberation of amino acids. Key Message: As functional dyspepsia represents a heterogeneous disorder, it may be intriguing to view pepsin as a potential (although still to be proven) treatment modality, distinguished by a diversity of pro-digestive effects.
Topics: Amino Acids; Animals; Digestion; Dyspepsia; Humans; Pepsin A; Proteolysis; Stomach
PubMed: 28982106
DOI: 10.1159/000481399