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Keywords = proton-pumping Complex I

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19 pages, 552 KiB  
Review
Current and Emerging Therapies for Eosinophilic Esophagitis (EoE): A Comprehensive Review
by Brooke G. Musburger, Maria Gonzalez Echeandia, Elias L. Suskind, David L. Suskind, Hengqi Betty Zheng and Dominique Mark
Pharmaceutics 2025, 17(6), 753; https://doi.org/10.3390/pharmaceutics17060753 - 7 Jun 2025
Viewed by 1800
Abstract
Eosinophilic Esophagitis (EoE) is a chronic, immune-mediated disorder that is characterized by symptoms of esophageal dysfunction and the presence of increased eosinophils in the esophageal mucosa. It is becoming increasingly prevalent among children and adults and its pathogenesis arises from the complex interaction [...] Read more.
Eosinophilic Esophagitis (EoE) is a chronic, immune-mediated disorder that is characterized by symptoms of esophageal dysfunction and the presence of increased eosinophils in the esophageal mucosa. It is becoming increasingly prevalent among children and adults and its pathogenesis arises from the complex interaction of genetic predisposition and environmental triggers, both which contribute to esophageal inflammation. Current societal guidelines recommend the use of proton pump inhibitors, topical steroids, and dietary interventions such as elimination diets as first-line treatments, however, the recent approval of Dupliumab has provided an additional therapeutic avenue. There are a number of investigational biologic agents targeting other immune pathways which are making their way through the pipeline of pharmacologic options in treating this chronic disorder. Full article
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24 pages, 1096 KiB  
Article
Association Between Antimicrobials and Pump Proton Inhibitors Consumption with the Incidence of Nosocomial Clostridiodes difficile Infection in High Complexity Hospitals in Costa Rica
by Cristina Fernández-Barrantes, Allan Ramos-Esquivel, Luis Esteban Hernández-Soto, Manuel Ramírez-Cardoce, Luis David Garro-Zamora, José Castro Cordero and Santiago Grau
Antibiotics 2025, 14(4), 350; https://doi.org/10.3390/antibiotics14040350 - 28 Mar 2025
Viewed by 726
Abstract
Background: Exposure to antimicrobials and Proton Pump Inhibitors (PPIs) are modifiable risk factors for nosocomial Clostridiodes difficile infection (CDI). We investigated the association between these agents and nosocomial CDI over five years. Methods: Nosocomial CDI from January 2017 to December 2021 [...] Read more.
Background: Exposure to antimicrobials and Proton Pump Inhibitors (PPIs) are modifiable risk factors for nosocomial Clostridiodes difficile infection (CDI). We investigated the association between these agents and nosocomial CDI over five years. Methods: Nosocomial CDI from January 2017 to December 2021 were included. Consumption trends were analyzed using a simple linear regression model. A correlation analysis was performed using Spearman’s test in two ways: without a time interval and with 1-month interval matching. An interrupted time-series method to evaluate the impact of three key temporal breakpoints on CDI incidence rate was performed using the Poisson regression model. Results: A downward trend for cephalexin, ceftriaxone, clindamycin, gentamicin, macrolides, metronidazole, and penicillin sodium was identified. In contrast, an upward trend was recognized for amoxicillin, ceftazidime/avibactam, ertapenem, fluconazole, ketoconazole, levofloxacin, and tigecycline. Among the antimicrobials that showed a positive association between consumption and the incidence of CDI are clindamycin and cephalosporins after immediate consumption. Moreover, macrolides and metronidazole presented a positive correlation, in both immediate and delayed consumption. PPIs consumption did not show changes and was not associated with nosocomial CDI incidence. The interrupted time series analysis showed no changes at the breakpoints selected. Conclusions: Consumption of clindamycin, cephalosporins, and macrolides showed positive association with CDI, despite having a downtrend in consumption. Specific events, such as the COVID-19 pandemic and the implementation of ASP, have had no correlation with CDI. Further analysis is required in Latin America to advance our understanding of risk factors associated with CDI. Full article
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15 pages, 4376 KiB  
Article
Proton Pump Inhibitor Use and Its Association with Lung Cancer Likelihood and Mortality: A Nationwide Nested Case–Control Study in Korea
by Mi Jung Kwon, Ho Suk Kang, Hyo Geun Choi, Joo-Hee Kim, Ji Hee Kim, Woo Jin Bang, Dae Myoung Yoo, Na-Eun Lee, Kyeong Min Han, Nan Young Kim, Sangkyoon Hong and Hong Kyu Lee
Cancers 2025, 17(5), 877; https://doi.org/10.3390/cancers17050877 - 4 Mar 2025
Viewed by 1058
Abstract
Background/Objectives: Proton pump inhibitors (PPIs) are widely used for acid-related gastrointestinal disorders, but their potential association with lung cancer risk and mortality remains underexplored and debated. This study sought to investigate the association between PPI use and lung cancer likelihood and mortality, focusing [...] Read more.
Background/Objectives: Proton pump inhibitors (PPIs) are widely used for acid-related gastrointestinal disorders, but their potential association with lung cancer risk and mortality remains underexplored and debated. This study sought to investigate the association between PPI use and lung cancer likelihood and mortality, focusing on the impact of PPI exposure history and duration. Methods: This study utilized data from 6795 lung cancer patients, 27,180 matched controls, and 4257 deceased and 2538 surviving lung cancer patients from the Korean National Health Insurance Service’s Health Screening Cohort (2002–2019). Propensity score overlap weighting and logistic regression models were applied to assess the correlations between PPI usage history and duration with lung cancer risk and mortality, while standardized differences ensured balanced baseline characteristics. Results: Overall, PPI use was modestly associated, with a 19% increased likelihood of lung cancer occurrence (95% confidence intervals (CI): 1.12–1.26). Interestingly, prolonged PPI use (≥30 days) was linked to a 13% reduction in lung cancer incidence (95% CI: 0.80–0.94), particularly in subgroups such as older adults (≥70 years), individuals with gastroesophageal reflux disease (GERD) or hypertension, and those with low alcohol consumption. Conversely, overall PPI usage was linked with a 36% increased mortality likelihood among lung cancer patients (95% CI: 1.20–1.55), with prolonged use further correlating with a 27% higher mortality risk (95% CI: 1.05–1.53), especially in high-risk subgroups, including smokers, underweight individuals, and those with hypercholesterolemia or GERD. Conclusions: These findings may suggest a complex and context-dependent relationship between PPI use and lung cancer outcomes, emphasizing the need for individualized risk assessments and careful prescribing practices. Full article
(This article belongs to the Special Issue New Era of Cancer Research: From Large-Scale Cohorts to Big-Data)
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33 pages, 3109 KiB  
Review
Medication Exposure and Risk of Dementia and Alzheimer’s Disease
by Niti Sharma, Seong Soo A. An and Sang Yun Kim
Int. J. Mol. Sci. 2024, 25(23), 12850; https://doi.org/10.3390/ijms252312850 - 29 Nov 2024
Cited by 1 | Viewed by 6015
Abstract
Alzheimer’s disease (AD), a complex neurodegenerative disease (ND), is the most predominant cause of dementia among the elderly. Generally, elderly people have multiple chronic health conditions, like hypertension, arthritis, diabetes, insomnia, bowel problems, and depression. Although prescribed medications have beneficial therapeutic compositions, some [...] Read more.
Alzheimer’s disease (AD), a complex neurodegenerative disease (ND), is the most predominant cause of dementia among the elderly. Generally, elderly people have multiple chronic health conditions, like hypertension, arthritis, diabetes, insomnia, bowel problems, and depression. Although prescribed medications have beneficial therapeutic compositions, some may have side effects that could hinder cognitive function or worsen cognitive decline. Hence, we should evaluate those medications to guarantee their safety. In the present mechanistic review, we discussed frequently used categories of medication (analgesics, anticholinergics, benzodiazepines, proton pump inhibitors, and statins), concerning their possible involvement in increasing AD and dementia risks. This review summarized the results of various observational studies, meta-analyses, randomized case–control studies, and systematic reviews. As the results were contradictory, it was difficult to ascertain the clear associations between medication usage and increased risks of dementia or AD. The blood-based biomarkers (BBMs) offer a low-cost and accessible alternative for early diagnosis of AD. Systematic reviews combined with meta-analysis would be crucial tools for accurately assessing and summarizing the efficacy of health interventions, yet randomized clinical trials have always been the best way to help with clinical care decisions. Thus, an open discussion is necessary to help individuals determine whether the advantages of utilizing medications outweigh the possible drawbacks. Full article
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24 pages, 1503 KiB  
Article
The Effects of Omeprazole on the Neuron-like Spiking of the Electrical Potential of Proteinoid Microspheres
by Panagiotis Mougkogiannis and Andrew Adamatzky
Molecules 2024, 29(19), 4700; https://doi.org/10.3390/molecules29194700 - 4 Oct 2024
Cited by 1 | Viewed by 1572
Abstract
This study examines a new approach to hybrid neuromorphic devices by studying the impact of omeprazole–proteinoid complexes on Izhikevich neuron models. We investigate the influence of these metabolic structures on five specific patterns of neuronal firing: accommodation, chattering, triggered spiking, phasic spiking, and [...] Read more.
This study examines a new approach to hybrid neuromorphic devices by studying the impact of omeprazole–proteinoid complexes on Izhikevich neuron models. We investigate the influence of these metabolic structures on five specific patterns of neuronal firing: accommodation, chattering, triggered spiking, phasic spiking, and tonic spiking. By combining omeprazole, a proton pump inhibitor, with proteinoids, we create a unique substrate that interfaces with neuromorphic models. The Izhikevich neuron model is used because it is computationally efficient and can accurately simulate the various behaviours of cortical neurons. The results of our simulations show that omeprazole–proteinoid complexes have the ability to affect neuronal dynamics in different ways. This suggests that they could be used as adjustable components in bio-inspired computer systems. We noticed a notable alteration in the frequency of spikes, patterns of bursts, and rates of adaptation, especially in chattering and triggered spiking behaviours. The findings indicate that omeprazole–proteinoid complexes have the potential to serve as adaptable elements in neuromorphic systems, presenting novel opportunities for information processing and computation that have origins in neurobiological principles. This study makes a valuable contribution to the expanding field of biochemical neuromorphic devices and establishes a basis for the development of hybrid bio-synthetic computational systems. Full article
(This article belongs to the Topic Recent Advances in Chemical Artificial Intelligence)
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12 pages, 2635 KiB  
Article
Alternative Oxidase Alleviates Mitochondrial Oxidative Stress during Limited Nitrate Reduction in Arabidopsis thaliana
by Daisuke Otomaru, Natsumi Ooi, Kota Monden, Takamasa Suzuki, Ko Noguchi, Tsuyoshi Nakagawa and Takushi Hachiya
Biomolecules 2024, 14(8), 989; https://doi.org/10.3390/biom14080989 - 11 Aug 2024
Cited by 1 | Viewed by 2168
Abstract
The conversion of nitrate to ammonium, i.e., nitrate reduction, is a major consumer of reductants in plants. Previous studies have reported that the mitochondrial alternative oxidase (AOX) is upregulated under limited nitrate reduction conditions, including no/low nitrate or when ammonium is the sole [...] Read more.
The conversion of nitrate to ammonium, i.e., nitrate reduction, is a major consumer of reductants in plants. Previous studies have reported that the mitochondrial alternative oxidase (AOX) is upregulated under limited nitrate reduction conditions, including no/low nitrate or when ammonium is the sole nitrogen (N) source. Electron transfer from ubiquinone to AOX bypasses the proton-pumping complexes III and IV, thereby consuming reductants efficiently. Thus, upregulated AOX under limited nitrate reduction may dissipate excessive reductants and thereby attenuate oxidative stress. Nevertheless, so far there is no firm evidence for this hypothesis due to the lack of experimental systems to analyze the direct relationship between nitrate reduction and AOX. We therefore developed a novel culturing system for A. thaliana that manipulates shoot activities of nitrate reduction and AOX separately without causing N starvation, ammonium toxicity, or lack of nitrate signal. Using shoots processed with this system, we examined genome-wide gene expression and growth to better understand the relationship between AOX and nitrate reduction. The results showed that, only when nitrate reduction was limited, AOX deficiency significantly upregulated genes involved in mitochondrial oxidative stress, reductant shuttles, and non-phosphorylating bypasses of the respiratory chain, and inhibited growth. Thus, we conclude that AOX alleviates mitochondrial oxidative stress and sustains plant growth under limited nitrate reduction. Full article
(This article belongs to the Special Issue Nitrogen Signaling, Transport, and Function in Plants)
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16 pages, 4753 KiB  
Article
Application of Galenic Strategies for Developing Gastro-Resistant Omeprazole Formulation for Pediatrics
by Khadija Rouaz-El-Hajoui, Encarnación García-Montoya, Marc Suñé-Pou, Josep María Suñé-Negre and Pilar Pérez-Lozano
Children 2024, 11(8), 945; https://doi.org/10.3390/children11080945 - 5 Aug 2024
Cited by 2 | Viewed by 1901
Abstract
Objectives: This study addresses a critical need in pediatric pharmacotherapy by focusing on the development of an enteric formulation of omeprazole for pediatric use. Omeprazole, a widely used proton pump inhibitor, is essential for treating various gastrointestinal disorders in children. The main objective [...] Read more.
Objectives: This study addresses a critical need in pediatric pharmacotherapy by focusing on the development of an enteric formulation of omeprazole for pediatric use. Omeprazole, a widely used proton pump inhibitor, is essential for treating various gastrointestinal disorders in children. The main objective is to design a compounding formula that can be prepared in hospital pharmacy services without the need for industrial equipment, which is often unavailable in these settings. Methods: The research applied different galenic strategies to overcome the challenges of omeprazole’s instability in acidic environments and its complex pharmacokinetic and physicochemical properties. The experiments were conducted sequentially, employing salting out, ionic gelation, and matrix granulation strategies. Based on the results obtained, the control conditions and parameters for the various trials were established. Results: Among the techniques used, wet granulation proved to be the most promising, achieving a gastro-resistance level of 44%. In contrast, the ionic gelation and salting-out techniques did not yield satisfactory results. Conclusions: The findings of this study underscore the need to adopt alternative formulation strategies to ensure the stability of omeprazole. This goal requires a multidisciplinary approach and continuous effort to design omeprazole formulations that meet quality standards and appropriate gastro-resistance requirements. Full article
(This article belongs to the Special Issue Advances in Pediatric Formulations Update)
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24 pages, 4736 KiB  
Article
Biophysical Analysis of a Minimalistic Kidney Model Expressing SGLT1 Reveals Crosstalk between Luminal and Lateral Membranes and a Plausible Mechanism of Isosmotic Transport
by Erik Hviid Larsen and Jens Nørkær Sørensen
Biomolecules 2024, 14(8), 889; https://doi.org/10.3390/biom14080889 - 23 Jul 2024
Cited by 1 | Viewed by 1353 | Correction
Abstract
We extended our model of the S1 tubular segment to address the mechanisms by which SGLT1 interacts with lateral Na/K pumps and tight junctional complexes to generate isosmotic fluid reabsorption via tubular segment S3. The strategy applied allowed for simulation of laboratory experiments. [...] Read more.
We extended our model of the S1 tubular segment to address the mechanisms by which SGLT1 interacts with lateral Na/K pumps and tight junctional complexes to generate isosmotic fluid reabsorption via tubular segment S3. The strategy applied allowed for simulation of laboratory experiments. Reproducing known experimental results constrained the range of acceptable model outputs and contributed to minimizing the free parameter space. (1) In experimental conditions, published Na and K concentrations of proximal kidney cells were found to deviate substantially from their normal physiological levels. Analysis of the mechanisms involved suggested insufficient oxygen supply as the cause and, indirectly, that a main function of the Na/H exchanger (NHE3) is to extrude protons stemming from mitochondrial energy metabolism. (2) The water path from the lumen to the peritubular space passed through aquaporins on the cell membrane and claudin-2 at paracellular tight junctions, with an additional contribution to water transport by the coupling of 1 glucose:2 Na:400 H2O in SGLT1. (3) A Na-uptake component passed through paracellular junctions via solvent drag in Na- and water-permeable claudin-2, thus bypassing the Na/K pump, in agreement with the findings of early studies. (4) Electrical crosstalk between apical rheogenic SGLT1 and lateral rheogenic Na/K pumps resulted in tight coupling of luminal glucose uptake and transepithelial water flow. (5) Isosmotic transport was achieved by Na-mediated ion recirculation at the peritubular membrane. Full article
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15 pages, 1950 KiB  
Article
The Assessment of the Association of Proton Pump Inhibitor Usage with Chronic Kidney Disease Progression through a Process Mining Approach
by Kaile Chen, Farhad Abtahi, Hong Xu, Carlos Fernandez-Llatas, Juan-Jesus Carrero and Fernando Seoane
Biomedicines 2024, 12(6), 1362; https://doi.org/10.3390/biomedicines12061362 - 19 Jun 2024
Cited by 1 | Viewed by 1829
Abstract
Previous studies have suggested an association between Proton Pump Inhibitors (PPIs) and the progression of chronic kidney disease (CKD). This study aims to assess the association between PPI use and CKD progression by analysing estimated glomerular filtration rate (eGFR) trajectories using a process [...] Read more.
Previous studies have suggested an association between Proton Pump Inhibitors (PPIs) and the progression of chronic kidney disease (CKD). This study aims to assess the association between PPI use and CKD progression by analysing estimated glomerular filtration rate (eGFR) trajectories using a process mining approach. We conducted a retrospective cohort study from 1 January 2006 to 31 December 2011, utilising data from the Stockholm Creatinine Measurements (SCREAM). New users of PPIs and H2 blockers (H2Bs) with CKD (eGFR < 60) were identified using a new-user and active-comparator design. Process mining discovery is a technique that discovers patterns and sequences in events over time, making it suitable for studying longitudinal eGFR trajectories. We used this technique to construct eGFR trajectory models for both PPI and H2B users. Our analysis indicated that PPI users exhibited more complex and rapidly declining eGFR trajectories compared to H2B users, with a 75% increased risk (adjusted hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.49 to 2.06) of transitioning from moderate eGFR stage (G3) to more severe stages (G4 or G5). These findings suggest that PPI use is associated with an increased risk of CKD progression, demonstrating the utility of process mining for longitudinal analysis in epidemiology, leading to an improved understanding of disease progression. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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17 pages, 698 KiB  
Review
Proton-Pump Inhibitors in Eosinophilic Esophagitis: A Review Focused on the Role of Pharmacogenetics
by Leticia Rodríguez-Alcolado, Pilar Navarro, Laura Arias-González, Elena Grueso-Navarro, Alfredo J. Lucendo and Emilio J. Laserna-Mendieta
Pharmaceutics 2024, 16(4), 487; https://doi.org/10.3390/pharmaceutics16040487 - 2 Apr 2024
Cited by 5 | Viewed by 4886
Abstract
Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to a double dosage of PPI. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In [...] Read more.
Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to a double dosage of PPI. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies—the only accurate method of assessing PPI response—efforts have been made to identify PPI responder patients. The clinical or endoscopic features and biomarkers evaluated so far, however, have not proven to be sufficient in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6. Here, we provide an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
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15 pages, 3789 KiB  
Review
Mitochondria at the Nanoscale: Physics Meets Biology—What Does It Mean for Medicine?
by Lev Mourokh and Jonathan Friedman
Int. J. Mol. Sci. 2024, 25(5), 2835; https://doi.org/10.3390/ijms25052835 - 29 Feb 2024
Cited by 5 | Viewed by 3941
Abstract
Mitochondria are commonly perceived as “cellular power plants”. Intriguingly, power conversion is not their only function. In the first part of this paper, we review the role of mitochondria in the evolution of eukaryotic organisms and in the regulation of the human body, [...] Read more.
Mitochondria are commonly perceived as “cellular power plants”. Intriguingly, power conversion is not their only function. In the first part of this paper, we review the role of mitochondria in the evolution of eukaryotic organisms and in the regulation of the human body, specifically focusing on cancer and autism in relation to mitochondrial dysfunction. In the second part, we overview our previous works, revealing the physical principles of operation for proton-pumping complexes in the inner mitochondrial membrane. Our proposed simple models reveal the physical mechanisms of energy exchange. They can be further expanded to answer open questions about mitochondrial functions and the medical treatment of diseases associated with mitochondrial disorders. Full article
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17 pages, 4824 KiB  
Article
Vacuolar Proton-Translocating ATPase May Take Part in the Drug Resistance Phenotype of Glioma Stem Cells
by Martina Giambra, Andrea Di Cristofori, Francesca Raimondo, Roberta Rigolio, Donatella Conconi, Gaia Chiarello, Silvia Maria Tabano, Laura Antolini, Gabriella Nicolini, Miriam Bua, Davide Ferlito, Giorgio Carrabba, Carlo Giorgio Giussani, Marialuisa Lavitrano and Angela Bentivegna
Int. J. Mol. Sci. 2024, 25(5), 2743; https://doi.org/10.3390/ijms25052743 - 27 Feb 2024
Cited by 3 | Viewed by 1995
Abstract
The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase [...] Read more.
The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy. Full article
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4 pages, 192 KiB  
Editorial
The Complex Interaction between Proton Pump Inhibitors and Cancer Treatment
by Hao Chen, Masaaki Kondo, Nobuyuki Horita, Kenichi Takahashi and Takeshi Kaneko
Cancers 2023, 15(22), 5346; https://doi.org/10.3390/cancers15225346 - 9 Nov 2023
Cited by 1 | Viewed by 1855
Abstract
We have read the article authored by Rizzo et al [...] Full article
(This article belongs to the Section Cancer Therapy)
22 pages, 1137 KiB  
Review
Mechanistic Insights into Eosinophilic Esophagitis: Therapies Targeting Pathophysiological Mechanisms
by Sara Massironi, Giacomo Mulinacci, Camilla Gallo, Alessandra Elvevi, Silvio Danese, Pietro Invernizzi and Edoardo Vespa
Cells 2023, 12(20), 2473; https://doi.org/10.3390/cells12202473 - 18 Oct 2023
Cited by 28 | Viewed by 5734
Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophilic infiltration of the esophagus. It arises from a complex interplay of genetic predisposition (susceptibility loci), environmental triggers (allergens and dietary antigens), and a dysregulated immune response, mainly mediated by type 2 T [...] Read more.
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophilic infiltration of the esophagus. It arises from a complex interplay of genetic predisposition (susceptibility loci), environmental triggers (allergens and dietary antigens), and a dysregulated immune response, mainly mediated by type 2 T helper cell (Th2)-released cytokines, such as interleukin (IL)-4, IL-5, and IL-13. These cytokines control eosinophil recruitment and activation as well as tissue remodeling, contributing to the characteristic features of EoE. The pathogenesis of EoE includes epithelial barrier dysfunction, mast cell activation, eosinophil degranulation, and fibrosis. Epithelial barrier dysfunction allows allergen penetration and promotes immune cell infiltration, thereby perpetuating the inflammatory response. Mast cells release proinflammatory mediators and promote eosinophil recruitment and the release of cytotoxic proteins and cytokines, causing tissue damage and remodeling. Prolonged inflammation can lead to fibrosis, resulting in long-term complications such as strictures and dysmotility. Current treatment options for EoE are limited and mainly focus on dietary changes, proton-pump inhibitors, and topical corticosteroids. Novel therapies targeting key inflammatory pathways, such as monoclonal antibodies against IL-4, IL-5, and IL-13, are emerging in clinical trials. A deeper understanding of the complex pathogenetic mechanisms behind EoE will contribute to the development of more effective and personalized therapeutic strategies. Full article
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10 pages, 1213 KiB  
Review
ATP12A Proton Pump as an Emerging Therapeutic Target in Cystic Fibrosis and Other Respiratory Diseases
by Michał Dębczyński, Giulia Gorrieri, Damian Mojsak, Floriana Guida, Federico Zara and Paolo Scudieri
Biomolecules 2023, 13(10), 1455; https://doi.org/10.3390/biom13101455 - 27 Sep 2023
Viewed by 2882
Abstract
ATP12A encodes the catalytic subunit of the non-gastric proton pump, which is expressed in many epithelial tissues and mediates the secretion of protons in exchange for potassium ions. In the airways, ATP12A-dependent proton secretion contributes to complex mechanisms regulating the composition and properties [...] Read more.
ATP12A encodes the catalytic subunit of the non-gastric proton pump, which is expressed in many epithelial tissues and mediates the secretion of protons in exchange for potassium ions. In the airways, ATP12A-dependent proton secretion contributes to complex mechanisms regulating the composition and properties of the fluid and mucus lining the respiratory epithelia, which are essential to maintain the airway host defense and the respiratory health. Increased expression and activity of ATP12A in combination with the loss of other balancing activities, such as the bicarbonate secretion mediated by CFTR, leads to excessive acidification of the airway surface liquid and mucus dysfunction, processes that play relevant roles in the pathogenesis of cystic fibrosis and other chronic inflammatory respiratory disorders. In this review, we summarize the findings dealing with ATP12A expression, function, and modulation in the airways, which led to the consideration of ATP12A as a potential therapeutic target for the treatment of cystic fibrosis and other airway diseases; we also highlight the current advances and gaps regarding the development of therapeutic strategies aimed at ATP12A inhibition. Full article
(This article belongs to the Collection Feature Papers in Molecular Genetics)
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