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European Annals of Otorhinolaryngology,... Sep 2021This review was conducted according to the Patient/problem Intervention Comparison Outcome (PICO) Statements. Some studies reported that 10-30% of patients consulting in... (Review)
Review
This review was conducted according to the Patient/problem Intervention Comparison Outcome (PICO) Statements. Some studies reported that 10-30% of patients consulting in ENT come with presenting symptoms of laryngopharyngeal reflux (LPR), but the exact prevalence of LPR is still unknown. Management has not changed in 20 years despite a significant increase in the number of publications on epidemiology, clinical presentation, diagnosis and treatment. The development of hypopharyngeal-esophageal multichannel intraluminal impedance pH monitoring (HEMII-pH) and saliva pepsin detection now allow a new multidimensional diagnostic approach associating clinical scores to HEMII-pH and saliva pepsin detection. This new approach may enable personalized treatment according to LPR profile on HEMII-pH (acid, non-acid, mixed; upright, recumbent reflux episodes). Updated treatment of LPR could consist in a 3-month association of dietary measures, proton pump inhibitors, alginate and magaldrate, followed by treatment adaptation.
Topics: Esophageal pH Monitoring; Humans; Hypopharynx; Laryngopharyngeal Reflux; Pepsin A; Saliva
PubMed: 33257265
DOI: 10.1016/j.anorl.2020.11.002 -
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 -
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 -
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 -
Current Opinion in Otolaryngology &... Dec 2020Gastroesophageal and extraesophageal reflux are prevalent and costly diseases. Recognition of the pathogenicity of nonacid reflux has stimulated interest in alternatives... (Review)
Review
PURPOSE OF REVIEW
Gastroesophageal and extraesophageal reflux are prevalent and costly diseases. Recognition of the pathogenicity of nonacid reflux has stimulated interest in alternatives to acid-targeting diagnostics and therapeutics. Pepsin is the most deleterious enzyme in refluxate, eliciting inflammatory and carcinogenic effects irrespective of acid. Its presence in all refluxate and detection in saliva have situated pepsin as the most widely researched biomarker for reflux today. This review summarizes emerging findings regarding pepsin-mediated damage during reflux and developments in pepsin-targeting diagnostics.
RECENT FINDINGS
New evidence supports a role for pepsin in epithelial--mesenchymal transition, an important process in carcinogenesis and fibrosis. The first global transcriptomic analysis of pepsin-exposed laryngeal cells was described, yielding evidence of a putative airway pepsin receptor. Evaluation of pepsin diagnostics highlighted the need for rigorous validation in which pepsin concentrations are corroborated by a secondary quantitative assay, and reflux is confirmed or excluded by multichannel intraluminal impedance pH testing. Standards for sample collection and storage, and normative and pathological values are lacking.
SUMMARY
Progress continues to be made in our understanding of pepsin-mediated damage with implications for novel therapeutic strategies. Salivary pepsin diagnostics continue to garner interest; however, further work appears necessary to improve their accuracy and reproducibility.
Topics: Biomarkers; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Laryngopharyngeal Reflux; Pepsin A; Saliva
PubMed: 33060393
DOI: 10.1097/MOO.0000000000000664 -
Critical Reviews in Biochemistry and... Jun 2020Elastin is an important protein of the extracellular matrix of higher vertebrates, which confers elasticity and resilience to various tissues and organs including lungs,... (Review)
Review
Elastin is an important protein of the extracellular matrix of higher vertebrates, which confers elasticity and resilience to various tissues and organs including lungs, skin, large blood vessels and ligaments. Owing to its unique structure, extensive cross-linking and durability, it does not undergo significant turnover in healthy tissues and has a half-life of more than 70 years. Elastin is not only a structural protein, influencing the architecture and biomechanical properties of the extracellular matrix, but also plays a vital role in various physiological processes. Bioactive elastin peptides termed elastokines - in particular those of the GXXPG motif - occur as a result of proteolytic degradation of elastin and its non-cross-linked precursor tropoelastin and display several biological activities. For instance, they promote angiogenesis or stimulate cell adhesion, chemotaxis, proliferation, protease activation and apoptosis. Elastin-degrading enzymes such as matrix metalloproteinases, serine proteases and cysteine proteases slowly damage elastin over the lifetime of an organism. The destruction of elastin and the biological processes triggered by elastokines favor the development and progression of various pathological conditions including emphysema, chronic obstructive pulmonary disease, atherosclerosis, metabolic syndrome and cancer. This review gives an overview on types of human elastases and their action on human elastin, including the formation, structure and biological activities of elastokines and their role in common biological processes and severe pathological conditions.
Topics: Aging; Animals; Cardiovascular Diseases; Cysteine Proteases; Elastin; Humans; Matrix Metalloproteinases; Neoplasms; Pancreatic Elastase; Pepsin A; Proteolysis; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface; Serine Proteases; Tropoelastin
PubMed: 32530323
DOI: 10.1080/10409238.2020.1768208 -
Current Gastroenterology Reports Nov 2021The purpose of this article is to review the cornerstone and most recent literature regarding laryngopharynoesophageal reflux (LPR) including epidemiological... (Review)
Review
The purpose of this article is to review the cornerstone and most recent literature regarding laryngopharynoesophageal reflux (LPR) including epidemiological characteristics, pathophysiology, symptoms, diagnosis, and management. The role of pepsin in the pathophysiology of LPR is highlighted in addition to new diagnostic modalities and pharmacologic therapies that target pepsin.
Topics: Humans; Laryngopharyngeal Reflux; Pepsin A
PubMed: 34799757
DOI: 10.1007/s11894-021-00823-4 -
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 -
Biomaterials Nov 2023Idiopathic Pulmonary Fibrosis (IPF) is a progressively debilitating lung condition characterized by oxidative stress, cell phenotype shifts, and excessive extracellular...
Idiopathic Pulmonary Fibrosis (IPF) is a progressively debilitating lung condition characterized by oxidative stress, cell phenotype shifts, and excessive extracellular matrix (ECM) deposition. Recent studies have shown promising results using decellularized ECM-derived hydrogels produced through pepsin digestion in various lung injury models and even a human clinical trial for myocardial infarction. This study aimed to characterize the composition of ECM-derived hydrogels, assess their potential to prevent fibrosis in bleomycin-induced IPF models, and unravel their underlying molecular mechanisms of action. Porcine lungs were decellularized and pepsin-digested for 48 h. The hydrogel production process, including visualization of protein molecular weight distribution and hydrogel gelation, was characterized. Peptidomics analysis of ECM-derived hydrogel contained peptides from 224 proteins. Probable bioactive and cell-penetrating peptides, including collagen IV, laminin beta 2, and actin alpha 1, were identified. ECM-derived hydrogel treatment was administered as an early intervention to prevent fibrosis advancement in rat models of bleomycin-induced pulmonary fibrosis. ECM-derived hydrogel concentrations of 1 mg/mL and 2 mg/mL showed subtle but noticeable effects on reducing lung inflammation, oxidative damage, and protein markers related to fibrosis (e.g., alpha-smooth muscle actin, collagen I). Moreover, distinct changes were observed in macroscopic appearance, alveolar structure, collagen deposition, and protein expression between lungs that received ECM-derived hydrogel and control fibrotic lungs. Proteomic analyses revealed significant protein and gene expression changes related to cellular processes, pathways, and components involved in tissue remodeling, inflammation, and cytoskeleton regulation. RNA sequencing highlighted differentially expressed genes associated with various cellular processes, such as tissue remodeling, hormone secretion, cell chemotaxis, and cytoskeleton engagement. This study suggests that ECM-derived hydrogel treatment influence pathways associated with tissue repair, inflammation regulation, cytoskeleton reorganization, and cellular response to injury, potentially offering therapeutic benefits in preventing or mitigating lung fibrosis.
Topics: Swine; Rats; Humans; Animals; Hydrogels; Actins; Pepsin A; Proteomics; Extracellular Matrix; Idiopathic Pulmonary Fibrosis; Lung; Fibrosis; Collagen; Inflammation; Bleomycin
PubMed: 37820517
DOI: 10.1016/j.biomaterials.2023.122338