Proton Pump Research Articles

Origin of the Difference in Proton Transport Direction between Inward and Outward Proton-Pumping Rhodopsins

Origin of the Difference in Proton Transport Direction between Inward and Outward Proton-Pumping Rhodopsins

Seeing double: the persistent dimer-of-dimers structure of drug resistant influenza A M2.

The currently circulating S31N variant of the M2 proton channel of influenza A is resistant to antiviral drugs. Recently, there has been a growing concern regarding the impact of the lipid environment on the structural features of the S31N variant. The native symmetry of the M2 tetramer remains controversial. Here we show that S31N M2 persists in a dimer-of-dimers structure in different lipid preparations independent of the amount of solvating lipids up to at least 180 lipids per tetramer. NMR spectra clearly detect the characteristic resonances of the dimer-of-dimers of M2 (residues 18-60 or 18-62) reconstituted in lipids. NMR-based distance measurements indicate that two isoleucine residues with upfield shifted alpha carbon resonances, typical of extended conformations, are compatible with a particular side-chain rotameric state and helical backbone geometry. These chemical shifts are therefore compatible with the expected native transmembrane helical fold. Symmetry breaking at the pH sensing H37 residues, detected via peak doubling, is a stable feature of S31N M2 based on the reference strain Udorn/1972(H3N2). By contrast, the spectrum is dramatically altered for Columbia/2014/(H3N2) M2, which differs in sequence in the amphipathic helices. This highlights an allosteric coupling between the amphipathic helices and the pH sensing residues.

Diagnosis and treatment of patients with gastroesophageal reflux disease - a systematic review of cost-effectiveness and economic burden.

This study aims to review the existing knowledge on the cost-effectiveness and item costs related to the diagnosis and treatment of gastroesophageal reflux disease (GERD) patients at different stages. The study adhered to the PRISMA guidelines. The systematic search involved several steps: finding and identifying relevant articles, filtering them according to the set criteria, and examining the final number of selected articles to obtain the primary information. The number of articles published between 2013 and September 2024 in the Web of Science and PubMed databases was considered. The CHEERS checklist was used for the risk of bias assessment. Ultimately, 36 studies were included. Regarding the cost-effectiveness of GERD treatment, Proton pump inhibitors (PPIs) appeared to be the dominant solution for non-refractory patients. However, this might change with the adoption of the novel drug vonoprazan, which is more effective and cheaper. With advancements in emerging technologies, new diagnostic and screening approaches such as Endosheath, Cytosponge, and combined multichannel intraluminal impedance and pH monitoring catheters should be considered, with potential implications for optimal GERD management strategies. The new diagnostic methods are reliable, safe, and more comfortable than standard procedures. PPIs are commonly used as the first line of treatment for GERD. Surgery, such as magnetic sphincter augmentation or laparoscopic fundoplication, is only recommended for patients with treatment-resistant GERD or severe symptoms. Advances in emerging technologies for diagnostics and screening may lead to a shift in the entire GERD treatment model, offering less invasive options and potentially improving patients' quality of life.

Evaluating Vonoprazan for the treatment of erosive GERD and heartburn associated with GERD in adults.

Gastroesophageal reflux disease (GERD) is a common debilitating chronic disease presenting in two main forms based on esophageal mucosal appearance, the erosive reflux disease (ERD) and the non-erosive reflux disease (NERD). Acid secretion is a key factor in the disease pathogenesis and management. Potent acid-suppressant drugs have been manufactured since the mid of 1970s, initially with histamine-H2-receptors antagonists, and later, inhibitors of the proton pump (H+-K+-ATPase). More recently, potassium-competitive acid blockers (P-CABs), particularly Vonoprazan, have been introduced. Vonoprazan has shown high efficacy and safety profiles and exhibits several advantages that allow to overcome shortcomings of proton pump inhibitors (PPIs). In this review, we provide an updated summary of Vonoprazan pharmacodynamics and its role in clinical practice for the management of erosive esophagitis and GERD related heartburn. Moreover, we discuss characteristics of Vonoprazan that allow to bypass some limitations of the older PPIs. Long-term safety and efficacy of Vonoprazan have already been demonstrated for the induction and maintenance of ERD, preventing nocturnal acid breakthrough, reducing reflux symptoms in non-responder to standard therapy. Ongoing and future studies are expected to further elucidate its long-term benefits and potential applications in other acid-related disorders.

Bioenergetic suppression by redox-active metabolites promotes antibiotic tolerance in Pseudomonas aeruginosa

The proton-motive force (PMF), consisting of a pH gradient and a membrane potential (ΔΨ) underpins many processes essential to bacterial growth and/or survival. Yet bacteria often enter a bioenergetically diminished state characterized by a low PMF. Consequently, they have increased tolerance for diverse stressors, including clinical antibiotics. Despite the ubiquity of low metabolic rates in the environment, the extent to which bacteria have agency over entry into such a low-bioenergetic state has received relatively little attention. Here, we tested the hypothesis that production of redox-active metabolites (RAMs) could drive such a physiological transition. Pseudomonas aeruginosa is an opportunistic pathogen that produces phenazines, model RAMs that are highly toxic in the presence of molecular oxygen (O2). Under oxic conditions, the phenazines pyocyanin and phenazine-1-carboximide, as well as toxoflavin-a RAM produced by Burkholderia species-suppress the ΔΨ in distinct ways across distributions of single cells, reduce the efficiency of proton pumping, and lower cellular adenosine-triphosphate (ATP) levels. In planktonic culture, the degree and rate by which each RAM lowers the ΔΨ correlates with the protection it confers against antibiotics that strongly impact cellular energy flux. This bioenergetic suppression requires the RAM's presence and corresponds to its cellular reduction rate and abiotic oxidation rate by O2; it can be reversed by increasing the ΔΨ with nigericin. RAMs similarly impact the bioenergetic state of cells in (hyp)oxic biofilm aggregates. Collectively, these findings demonstrate that bacteria can suppress their bioenergetic state by the production of endogenous toxins in a manner that bolsters stress resilience.

Localized Water Restriction in Ternary Eutectic Electrolytes for Ultra-Low Temperature Hydrogen Batteries.

Proton batteries are promising candidates for next-generation large-scale energy storage in extreme conditions due to the small ionic radius and efficient transport of protons. Hydrogen gas, with its low working potentials, fast kinetics, and stability, further enhances the performance of proton batteries but necessitates the development of novel electrolytes with low freezing points and reduced corrosion. This work introduces a localized water restriction strategy by incorporating a tertiary component with a high donor number, which forms strong bonds with water molecules. This approach restricts free water molecules and reduces the average hydrogen bond ratio and strength. As-prepared ternary eutectic electrolytes lowered the freezing point to -103 °C, significantly lower than the traditional binary electrolyte (9.5 m H3PO4, -93 °C). This electrolyte is highly compatible with the Cu0.79Co0.21[Fe(CN)6]0.64·4H2O (CoCuHCF) cathode, reducing material dissolution and current collector corrosion. The H2||CoCuHCF battery using this electrolyte demonstrated a high-power density of 23664.3 W kg-1, excellent performance at -80 °C, and stable cyclability over 1000 cycles (> 30 days) at -50 °C. These findings provide a framework for proton electrolytes, highlighting the potential of hydrogen batteries in challenging environments.

Localized Water Restriction in Ternary Eutectic Electrolytes for Ultra‐Low Temperature Hydrogen Batteries

Proton batteries are promising candidates for next‐generation large‐scale energy storage in extreme conditions due to the small ionic radius and efficient transport of protons. Hydrogen gas, with its low working potentials, fast kinetics, and stability, further enhances the performance of proton batteries but necessitates the development of novel electrolytes with low freezing points and reduced corrosion. This work introduces a localized water restriction strategy by incorporating a tertiary component with a high donor number, which forms strong bonds with water molecules. This approach restricts free water molecules and reduces the average hydrogen bond ratio and strength. As‐prepared ternary eutectic electrolytes lowered the freezing point to −103 °C, significantly lower than the traditional binary electrolyte (9.5 m H3PO4, −93 °C). This electrolyte is highly compatible with the Cu0.79Co0.21[Fe(CN)6]0.64·4H2O (CoCuHCF) cathode, reducing material dissolution and current collector corrosion. The H2||CoCuHCF battery using this electrolyte demonstrated a high‐power density of 23664.3 W kg−1, excellent performance at −80 °C, and stable cyclability over 1000 cycles (> 30 days) at −50 °C. These findings provide a framework for proton electrolytes, highlighting the potential of hydrogen batteries in challenging environments.

Prior antibiotics, proton pump inhibitors, and probiotics in patients with extensive stage small cell lung cancer treated with immune checkpoint blockade: A post-hoc analysis of the phase I/III IMpower 133 trial.

The potential impact of concomitant medications such as systemic antibiotics, proton pump inhibitors (PPIs), and probiotics in patients with extensive-stage small cell lung cancer (ES-SCLC) receiving first-line chemo-immunotherapy combinations remains unclear. We ran a post hoc analysis of the IMpower133 phase I/III trial, which randomized patients with ES-SCLC to receive carboplatin/etoposide with either atezolizumab or placebo for 4 cycles, followed by maintenance therapy. We included any systemic antibiotic/probiotic exposure within 42 days prior to treatment initiation and any PPIs treatment within 30 days prior to treatment initiation. We explored the potential prognostic impact of antibiotics, PPIs and probiotics across the atezolizumab/chemotherapy and placebo/chemotherapy arms including the multivariable interaction term between the treatment modality and antibiotics/PPIs/probiotics. The analysis included 198 patients in the atezolizumab/chemotherapy arm and 195 in the placebo/chemotherapy arm. Baseline clinic-pathologic features were well balanced between the two cohorts, with 17 (8.6%) and 14 (7.2%) patients on antibiotics, 43 (21.7%) and 55 (28.2%) on PPIs, and 3 (1.5%) and 5 (2.6%) on probiotics among the atezolizumab/chemotherapy and placebo/chemotherapy cohorts, respectively. Exposure to antibiotics, PPIs, or probiotics was not associated with overall survival or progression free survival in either cohort. Furthermore, interaction terms between these medications and treatment modalities were not statistically significant. Baseline use of antibiotics, PPIs or probiotics did not influence clinical outcomes in patients with ES-SCLC treated with first-line atezolizumab/placebo plus chemotherapy, suggesting that they may not have a notable impact on clinical outcomes and could be considered for use in this patient population when necessary.

Magnesium depletion score and depression: a positive correlation among US adults

BackgroundThe Magnesium depletion score (MDS) serves as a novel metric for quantifying magnesium deficiency in the human body, comprehensively assessing four indicators: diuretic use, proton pump inhibitor use, estimated glomerular filtration rate, and alcohol abuse. However, there have been no studies examining the potential association between MDS and depression.MethodsThe study population for this cross-sectional study comprised adults from the National Health and Nutrition Examination Survey database from 2009 to 2018. Participants with a score of 10 or above on the Patient Health Questionnaire-9 were defined as having depression. We employed multivariable logistic regression models to investigate the association between MDS and depression. Furthermore, subgroup analyses were conducted to assess potential differences in this association among populations with diverse characteristics.ResultsA total of 13,197 participants were included in this study. After adjusting for all covariates, a significant positive correlation was observed between MDS and depression. Specifically, for every unit increase in MDS, the likelihood of developing depression increased by 13% (OR = 1.13, 95% CI: 1.04–1.22, p = 0.0025). This positive correlation was consistent across MDS groups, with a 19% increase in depression likelihood in the medium group (OR = 1.19, 95% CI: 1.01–1.41, p = 0.0404) and a 58% increase in the high group (OR = 1.58, 95% CI: 1.21–2.07, p = 0.0007), using the low subgroup as a reference. Subgroup analyses revealed significant differences in the relationship between MDS and depression across races, marital statuses, and hypertension status.ConclusionOur study has uncovered a significant positive association between MDS and depression. Reducing MDS in individuals may play a positive role in both the prevention and treatment of depression.

Insights of the Proton Transport Efficiency of a Membrane Electrode Assembly by Operando Monitoring of the Local Proton Concentration during Water Oxidation

Insights of the Proton Transport Efficiency of a Membrane Electrode Assembly by Operando Monitoring of the Local Proton Concentration during Water Oxidation

Structure and function of the proton channel OTOP1

OTOP1 belongs to the otopetrin family of membrane proteins that form proton channels in cells of diverse types. In mammals, OTOP1 is involved in sour transduction in taste cells and contributes to otoconia formation in the inner ear. From the structural point of view, otopetrins, including OTOP1, represent a quasi-tetramer consisting of four α-barrels. The exact transport pathways mediating proton flux through the OTOP1 channel and gating units modulating its activity are still a matter of debate. This review discusses current data on structural and functional features of OTOP1. Suggested proton transport pathways, regulatory mechanisms, and key amino acid residues determining functionality of the otopetrins are considered. The existing kinetic models of OTOP1 are discussed as well. Based on revealed functional properties, OTOP1 is suggested to operate as a logical XOR element that allows for proton flux only if transmembrane pH gradient exists.

The Role of Cholesterol in M2 Clustering and Viral Budding Explained.

The influenza A M2 homotetrameric channel consists of four transmembrane (TM) and four amphipathic helices (AHs). This viral proton channel is suggested to form clusters in the catenoid budding neck areas in raft-like domains of the plasma membrane, resulting in cell membrane scission and viral release. The channel clustering environment is rich in cholesterol. Previous experiments have shown that cholesterol significantly contributes to lipid bilayer undulations in viral buds. However, a clear explanation of membrane curvature from the distribution of cholesterol around the M2TM-AH clusters is lacking. Using coarse-grained molecular dynamics simulations of M2TM-AH in bilayers, we observed that M2 channels form specific, C2-symmetric, clusters with conical shapes driven by the attraction of their AHs. We showed that cholesterol stabilized the formation of M2 channel clusters by filling and bridging the conical gap between M2 channels at specific sites in the N-termini of adjacent channels or via the C-terminal region of TM and AHs, with the latter sites displaying a longer interaction time and higher stability. The potential of mean force calculations showed that when cholesterols occupy the identified interfacial binding sites between two M2 channels, the dimer is stabilized by 11 kJ/mol. This translates to the cholesterol-bound dimer being populated by almost 2 orders of magnitude compared to a dimer lacking cholesterol. We demonstrated that the cholesterol-bridged M2 channels can exert a lateral force on the surrounding membrane to induce the necessary negative Gaussian curvature profile, which permits spontaneous scission of the catenoid membrane neck and leads to viral buds and scission.

Activation of the Influenza B M2 Proton Channel (BM2).

Influenza B viruses have cocirculated during most seasonal flu epidemics and can cause significant human morbidity and mortality due to their rapid mutation, emerging drug resistance, and severe impact on vulnerable populations. The influenza B M2 proton channel (BM2) plays an essential role in viral replication, but the mechanisms behind its symmetric proton conductance and the involvement of a second histidine (His27) cluster remain unclear. Here we performed membrane-enabled continuous constant-pH molecular dynamics simulations on wildtype BM2 and a key H27A mutant channel to explore its pH-dependent conformational switch. Simulations captured the activation as the first histidine (His19) protonates and revealed the transition at lower pH values compared to AM2 is a result of electrostatic repulsions between His19 and preprotonated His27. Crucially, we provided an atomic-level understanding of the symmetric proton conduction by identifying preactivating channel hydration in the C-terminal portion. This research advances our understanding of the function of BM2 function and lays the groundwork for further chemically reactive modeling of the explicit proton transport process as well as possible antiflu drug design efforts.

A Proton Pump Inhibitor Independently Elevates Gastrin Levels as a Marker for Metachronous Gastric Cancer After Endoscopic Submucosal Dissection

Background and Objective: Serum markers such as gastrin and pepsinogen are useful for stratifying gastric cancer risk. However, their utility in predicting metachronous gastric cancer after endoscopic submucosal dissection (ESD) in patients with gastric cancer after Helicobacter pylori eradication (GCAE) is unclear. This study aimed to clarify predictive factors for metachronous gastric cancer after ESD with a focus on serum markers. Methods: A retrospective analysis was conducted on 197 patients with 224 GCAE lesions who underwent ESD at Hiroshima University Hospital between April 2010 and December 2019. In total, 63 patients with 74 differentiated-type lesions were classified into metachronous gastric cancer (MG) and non-metachronous gastric cancer (NMG) groups, excluding proton pump inhibitor (PPI) users, female patients, and undifferentiated-type cases. The predictive value of serum markers was assessed using ROC curve analysis, and their association with carcinogenesis was evaluated using multiple logistic regression. Furthermore, the incidence of MG was compared between long-term PPI users and non-users. Results: ROC analysis revealed that serum gastrin had the highest discriminative ability for MG (AUC 0.77, cut-off 99 pg/mL, sensitivity 61.6%, and specificity 80.0%). Severe mucosal atrophy and high gastrin levels were significantly more common in the MG group and were independent predictors (p < 0.01). Although serum gastrin levels were significantly elevated in PPI users, no increased risk of MG was observed. Conclusions: In addition to severe mucosal atrophy, PPI-independent elevated serum gastrin levels may be associated with an increased risk of MG after ESD. Serum gastrin may serve as a valuable marker for post-ESD cancer surveillance in GCAE patients.

In-silico Studies, Synthesis, and Antacid Activities of Magnesium (II) Complexes.

Nowadays, acidity is a severe problem worldwide caused by excessive gastric acid secretion by the stomach and proximal intestine. Antacids are drugs capable of buffering stomach acid. Therefore, in our research work, we have reported the in-silico studies, synthesis, characterization, and evaluation of antacid activities of magnesium (II) complexes via the acid-base neutralization process. In this research, some magnesium complexes were synthesized and their antacid behavior was compared with marketed products. Also, in-silico studies were performed on H+/K+ ATPase (Proton pump). All synthesized compounds were characterized by various spectroscopic techniques like UV-Vis, FT-IR, XRD, and DSC techniques. Spectroscopic analysis results showed that the semicarbazone ligand shows keto-enol isomerism and forms a coordinated stable complex with magnesium ions in the crystalline phase. The FT-IR results confirmed the presence of Mg-O stretching, N-H bending, and C=N stretching vibrations in Mg (II) complexes. The antacid activities of Mg (II) complexes were excellent as compared to the semicarbazone ligand and comparable with that of marketed antacid drugs like ENO, and Pantop-D. Insilco studies also confirmed that semicarbazone ligand and its Mg (II) complexes were both found to be fitted into the active sites of molecular targets, and Mg (II) complexes showed better binding affinities towards macromolecular as compared to semicarbazone ligand.

Formation and Dynamics of Imidazole Supramolecular Chains Investigated by Deep Potential Molecular Dynamics Simulation.

Imidazole-based materials have attracted considerable attention due to their promising potential for facilitating anhydrous proton transport at high temperatures. Herein, a machine learning-based deep potential (DP) model for bulk imidazole with first-principles accuracy is developed. The trained model exhibits remarkable accuracy in predicting energies and forces, with minor errors of 4.71 × 10-4 eV/atom and 3.23 × 10-2 eV/Å, respectively. Utilizing DP molecular dynamics simulations, we have systematically investigated the temperature-dependent formation and dynamics of imidazole supramolecular chains through the partial radial distribution function, quantification of hydrogen bond numbers, incoherent intermediate scattering function, and diffusion coefficient. The findings reveal the influence of temperature on the proton transport path following either the "Grotthuss" and "vehicle" mechanism.

Efficacy of Bismuth Quadruple Therapy in the Treatment of Helicobacter pylori-Infected Peptic Ulcer Children in Vietnam.

The continuous increase in drug-resistant strains, the lack of novel antibiotics, and the fewer options available to combat antibiotic-resistant infections in pediatrics pose significant challenges to the eradication of Helicobacter pylori (H. pylori) in children. This study evaluated the efficacy of first-line therapy with bismuth quadruple therapy in H. pylori-positive pediatric patients with peptic ulcers. 136 patients (aged between 8 and 17 years) diagnosed with active peptic ulcers with H. pylori infection were enrolled in this study. Patients with H. pylori strain sensitive to tetracycline and metronidazole were assigned to bismuth quadruple therapy, including a proton pump inhibitor (PPI), bismuth, tetracycline, and metronidazole. Antibiotic resistance of H. pylori was analyzed by the Epsilometer test. Treatment efficacy was evaluated at 12 weeks based on H. pylori eradication and peptic ulcer healing rates. H. pylori infection status was evaluated by a 13C-urea breath test. Most isolates showed extremely high rates of resistance to commonly prescribed antibiotics used for children, including clarithromycin (97.0%) and amoxicillin (84.6%), while the low rate of resistance to levofloxacin (16.2%). The overall success rate of eradication therapy in the intention-to-treat and the per-protocol group were 86.0% and 89.3%, respectively. Peptic ulcer healing rates for total patients at 6 weeks and 12 weeks were 75.0% and 97.7%, respectively. There were no entail unpleasant adverse events, and peptic ulcer symptoms decreased steadily over time in all cases. The bismuth quadruple therapy with a 2-week PPI pretreatment and followed by prolonged PPI was highly successful in eradicating H. pylori infection and healing ulcers in pediatric patients with active peptic ulcer. This might be preferable as a first-line empiric treatment regimen for H. pylori-positive pediatric patients with peptic ulcers, especially in populations with high rates of resistance to amoxicillin and clarithromycin.

The effect of antibiotics, proton pump inhibitors, H2-receptor antagonists, and steroids on survival among ovarian cancer patients receiving PARP inhibitor therapy

The effect of antibiotics, proton pump inhibitors, H2-receptor antagonists, and steroids on survival among ovarian cancer patients receiving PARP inhibitor therapy

Proton pump inhibitor attenutes acidic microenvironment to improve the therapeutic effects of MSLN-CAR-T cells on the brain metastasis of solid tumors

Proton pump inhibitor attenutes acidic microenvironment to improve the therapeutic effects of MSLN-CAR-T cells on the brain metastasis of solid tumors

The Role of Cation Exchange Membrane Characteristics in CO2 Electrolysis to CO Using Acid Anolyte

Cation exchange membranes are considered a suitable option for zero-gap CO2 electrolysis due to their potential to avoid carbonation and improve carbon efficiency. However, the use of acidic anolytes remains an issue due to high hydrogen production. This study investigates Nafion® membranes (111, 112, 115, 211, and 212) with different thicknesses produced by extrusion or solution-cast processes in a zero-gap cell with an acidic anolyte containing K2SO4. Faradaic efficiencies for CO production (FECO) are higher with thinner membranes, regardless of the manufacturing process, reaching FECO around 75% at 50 mA cm⁻². Additionally, membranes with similar thicknesses (∼50.8 µm) but produced in different ways displayed flow field carbonation after 3 hours of electrolysis at 30°C and 50 mA cm⁻². Linear sweep voltammetry (LSV) in full and half-cell configurations shows limiting diffusion current (iL) relative to proton transport for all the employed membranes, no matter the thickness. In contrast, the iL for Nafion® 115, the thicker membrane, is suppressed, indicating that proton depletion is fast and the electrode surface alkalinization primarily results from water reduction in this case. A mechanistic analysis was performed to explain the behavior of the limiting currents in the cell with Ar- and CO2-feed, indicating that CO2 reduction aids in the consumption of H+ provided by the membrane, increasing the local pH at less negative potentials. Overall, thinner membranes exhibited higher values of FECO and energy efficiency for CO (EE%CO). However, solution-cast membranes are more prone to provide K+, leading to better performance than those prepared by extrusion.