Pantoprazole and riluzole target H+/K+-ATPases and pH-sensitive K+ channels in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer type. PDAC is characterized by fibrotic, hypoxic, and presumably acidic tumor microenvironment (TME). Acidic TME is an important player in tumor development, progression, aggressiveness, and chemoresistance. The dysregulation of ductal ion transporters/channels might contribute to extracellular pH (pHe) acidification and PDAC progression. Our aim was to test whether H+/K+-ATPases and pH-sensitive K+ channels contribute to these processes and could be targeted by clinically approved drugs. We used human pancreatic cancer cells adapted to various pHe conditions and grown in monolayers and spheroids. First, we created cells expressing pHoran4 at the outer plasma membrane and showed that pantoprazole, the H+/K+-ATPase inhibitor, alkalinized pHe. Second, we used FluoVolt to monitor the membrane voltage (Vm) and showed that riluzole hyperpolarized Vm, most likely by opening of pH-sensitive K+ channels such as TREK-1. Third, we show that pantoprazole and riluzole inhibited cell proliferation and viability of monolayers and spheroids of cancer cells adapted to various pHe conditions. Most importantly, combination of the two drugs had significantly larger inhibitory effects on PDAC cell survival. We propose that co-targeting H+/K+-ATPases and pH-sensitive K+ channels by re-purposing of pantoprazole and riluzole could provide novel acidosis-targeted therapies of PDAC.

Vonoprazan a novel potassium competitive acid blocker; another leap forward.

Introduction: The eradication rate of Helicobacter pylori (H. pylori) has decreased due to antibiotics resistance and inadequate acid suppression. Vonoprazan is a novel potassium-competitive acid blocker (P-CAB), which has a rapid and sustained acid inhibitory effect and may be more effective than conventional proton pump inhibitors (PPIs) in H. pylori eradication. Aim: to study the efficacy and safety of vonoprazan as a component of first-line H. pylori eradication treatment compared with conventional PPI-based therapy. Material and methods: This randomised (one to one) non-blinded study was conducted on 400 consecutive proven H. pylori infected patients, of whom 200 received vonoprazan-based triple therapy, while 200 patients received PPI-based triple therapy for 14 days. The study outcomes were evaluated as eradication rate and adverse events in both patient groups. Results: The eradication rate was 86% in the vonoprazan group and 74.5% in the PPI group. The vonoprazan eradication rate was significantly higher than that of PPIs (p = 0.004). There was no significant difference regarding adverse events between both patient groups. Conclusions: Vonoprazan-based therapy was more effective than PPI-based therapy as a first-line H. pylori eradication treatment. Vonoprazan was generally safe and well tolerated.

The Assessment of the Association of Proton Pump Inhibitor Usage with Chronic Kidney Disease Progression through a Process Mining Approach.

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.

Chemical cross-linking and mass spectrometry enabled systems-level structural biology.

Structural information on protein-protein interactions (PPIs) is essential for improved understanding of regulatory interactome networks that confer various physiological and pathological responses. Additionally, maladaptive PPIs constitute desirable therapeutic targets due to inherently high disease state specificity. Recent advances in chemical cross-linking strategies coupled with mass spectrometry (XL-MS) have positioned XL-MS as a promising technology to not only elucidate the molecular architecture of individual protein assemblies, but also to characterize proteome-wide PPI networks. Moreover, quantitative in vivo XL-MS provides a new capability for the visualization of cellular interactome dynamics elicited by drug treatments, disease states, or aging effects. The emerging field of XL-MS based complexomics enables unique insights on protein moonlighting and protein complex remodeling. These techniques provide complimentary information necessary for in-depth structural interactome studies to better comprehend how PPIs mediate function in living systems.

Structural basis of the Integrator complex assembly and association with transcription factors.

Integrator is a multi-subunit protein complex responsible for premature transcription termination of coding and non-coding RNAs. This is achieved via two enzymatic activities, RNA endonuclease and protein phosphatase, acting on the promoter-proximally paused RNA polymerase Ⅱ (RNAPⅡ). Yet, it remains unclear how Integrator assembly and recruitment are regulated and what the functions of many of its core subunits are. Here, we report the structures of two human Integrator sub-complexes: INTS10/13/14/15 and INTS5/8/10/15, and an integrative model of the fully assembled Integrator bound to the RNAPⅡ paused elongating complex (PEC). An in silico protein-protein interaction screen of over 1,500 human transcription factors (TFs) identified ZNF655 as a direct interacting partner of INTS13 within the fully assembled Integrator. We propose a model wherein INTS13 acts as a platform for the recruitment of TFs that could modulate the stability of the Integrator's association at specific loci and regulate transcription attenuation of the target genes.

Vonoprazan causes symptomatic improvement in non-erosive gastroesophageal reflux disease: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of vonoprazan therapy as compared to conventional proton pump inhibitors (PPIs) or no vonoprazan for non-erosive esophagitis. METHODS: A thorough search was conducted across databases. The primary outcome was to determine the mean variance in the gastroesophageal reflux disease (GERD) score after vonoprazan treatment. Secondary outcomes comprised alterations in the scores for epigastric pain and post-prandial distress, the proportion of patients displaying improvement, and the occurrence of adverse events. Pooled mean differences and relative risks were determined utilizing random effects models. RESULTS: A total of 1,944 articles were screened and nine of them were included. As compared to PPI or no vonoprazan therapy, vonoprazan treatment led to a significant reduction in the GERD score [mean difference: -3.88 (95 % CI: -5.48, -2.28), p < 0.01, i2=95 %]. As compared to PPI or no vonoprazan therapy, vonoprazan treatment led to a significant reduction in the epigastric pain score [mean difference: -3.02 (95 % CI: -5.41, -0.63), p = 0.01, i2=75 %] and post-prandial distress score [mean difference: -2.82 (95 % CI: -3.51, -2.12), p < 0.01, i2=0 %] (all moderate GRADE evidence). Vonoprazan therapy was found to be safe. CONCLUSION: Treatment with vonoprazan could significantly improve symptoms in patients with non-erosive esophagitis or non-erosive GERD.

Proteome-wide assessment of human interactome as a source of capturing domain-motif and domain-domain interactions.

Protein-protein interactions (PPIs) play a crucial role in various biological processes by establishing domain-motif (DMI) and domain-domain interactions (DDIs). While the existence of real DMIs/DDIs is generally assumed, it is rarely tested; therefore, this study extensively compared high-throughput methods and public PPI repositories as sources for DMI and DDI prediction based on the assumption that the human interactome provides sufficient data for the reliable identification of DMIs and DDIs. Different datasets from leading high-throughput methods (Yeast two-hybrid [Y2H], Affinity Purification coupled Mass Spectrometry [AP-MS], and Co-fractionation-coupled Mass Spectrometry) were assessed for their ability to capture DMIs and DDIs using known DMI/DDI information. High-throughput methods were not notably worse than PPI databases and, in some cases, appeared better. In conclusion, all PPI datasets demonstrated significant enrichment in DMIs and DDIs (p-value <0.001), establishing Y2H and AP-MS as reliable methods for predicting these interactions. This study provides valuable insights for biologists in selecting appropriate methods for predicting DMIs, ultimately aiding in SLiM discovery.

A Case of Severe Proton Pump Inhibitor-Induced Hypomagnesemia Refractory to Continuous Oral and Intravenous Magnesium Replenishment.

Proton pump inhibitors (PPIs) are frequently used medications to treat a wide variety of gastrointestinal conditions. By irreversibly inhibiting the hydrogen-potassium ATPase pump, they remarkably reduce gastric acid secretion. However, chronic PPI intake can result in serious complications, including severe hypomagnesemia. The following case report presents a severe case of refractory PPI-induced hypomagnesemia (PPIH), resistant to continuous oral and intravenous magnesium replacement, in a 70-year-old male patient, with a long history of PPI use due to persistent epigastric pain. Upon each of the 10 admissions to the hospital, he presented with severe signs and symptoms of hypomagnesemia, such as nausea, muscle fasciculation, diffuse cramps, weakness, neuromuscular irritability, and ECG disturbances, including non-specific T-wave abnormalities. In fact, PPIH has been reported for the first time in 2006. It is believed that the excessive, chronic intake of PPIs can disturb the normal functioning of the transient receptor potential melastatin 6/7 (TRPM 6/7), which is the main pathway of active intestinal magnesium absorption, leading to hypomagnesemia. PPIH is typically characterized by stubborn resistance to oral and intravenous magnesium replenishment but usually resolves after PPI withdrawal. Hence, despite being among the safest and most commonly prescribed drugs, PPI intake should be closely monitored when prolonged usage is planned. Additionally, continuous follow-up and regular assessment of serum magnesium levels are crucial to avoid the occurrence of PPIH and to prevent its potentially deleterious complications, including life-threatening arrhythmias.

A comprehensive review on potential drug-drug interactions of proton pump inhibitors with antidiabetic drugs metformin and DPP-4 inhibitors.

A drug interaction is a condition in which two or more drugs are taken at the same time. Type 2 diabetes mellitus is a significant contributor to polypharmacy. Proton pump inhibitors (PPIs) are often prescribed in combination with metformin or DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin) or a combined dose of metformin and DPP-4 inhibitor to treat gastritis in diabetic patients. This review article mainly focused on evaluating the potential drug-drug interactions (DDIs) between PPIs (i.e. esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) with metformin and PPIs with DPP-4 inhibitors. The findings demonstrated the existence of pharmacokinetic and pharmacodynamic DDIs between the aforementioned PPIs with metformin and DPP-4 inhibitors, which could impact the biological activities (i.e., hypoglycemia) of these drugs. Moreover, this review suggested that esomeprazole could be the best drug in the PPI group to be prescribed simultaneously with metformin and DPP-4 inhibitors, as most of the antidiabetic drugs of this study did not show any interaction with esomeprazole. The findings of this study also revealed that both antidiabetic drugs and PPIs could have positive interactions as PPIs have the potential to lessen the gastrointestinal side effects of metformin and DPP-4 inhibitors. To achieve the greatest therapeutic impact with the fewest side effects, careful dose control of these drugs is required. So, more extensive research on both human and animal subjects are needed to ascertain the veracity of this hypothesis.

Harnessing the predicted maize pan-interactome for putative gene function prediction and prioritization of candidate genes for important traits.

The recent assembly and annotation of the 26 maize nested association mapping population founder inbreds have enabled large-scale pan-genomic comparative studies. These studies have expanded our understanding of agronomically important traits by integrating pan-transcriptomic data with trait-specific gene candidates from previous association mapping results. In contrast to the availability of pan-transcriptomic data, obtaining reliable protein-protein interaction (PPI) data has remained a challenge due to its high cost and complexity. We generated predicted PPI networks for each of the 26 genomes using the established STRING database. The individual genome-interactomes were then integrated to generate core- and pan-interactomes. We deployed the PPI clustering algorithm ClusterONE to identify numerous PPI clusters that were functionally annotated using gene ontology (GO) functional enrichment, demonstrating a diverse range of enriched GO terms across different clusters. Additional cluster annotations were generated by integrating gene coexpression data and gene description annotations, providing additional useful information. We show that the functionally annotated PPI clusters establish a useful framework for protein function prediction and prioritization of candidate genes of interest. Our study not only provides a comprehensive resource of predicted PPI networks for 26 maize genomes but also offers annotated interactome clusters for predicting protein functions and prioritizing gene candidates. The source code for the Python implementation of the analysis workflow and a standalone web application for accessing the analysis results are available at https://github.com/eporetsky/PanPPI.

MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells by binding ITGB4/LAMB3 to activate the AKT signaling pathway.

Colorectal cancer (CRC) is one of the most lethal cancers. Single-cell RNA sequencing (scRNA-seq) and protein-protein interactions (PPIs) have enabled the systematic study of CRC. In our research, the activation of the AKT pathway in CRC was analyzed by KEGG using single-cell sequencing data from the GSE144735 dataset. The correlation and PPIs of MDFI and ITGB4/LAMB3 were examined. The results were verified in the TCGA and CCLE and further tested by coimmunoprecipitation experiments. The effect of MDFI on the AKT pathway via ITGB4/LAMB3 was validated by knockdown and lentiviral overexpression experiments. The effect of MDFI on oxaliplatin/fluorouracil sensitivity was probed by colony formation assay and CCK8 assay. We discovered that MDFI was positively associated with ITGB4/LAMB3. In addition, MDFI was negatively associated with oxaliplatin/fluorouracil sensitivity. MDFI upregulated the AKT pathway by directly interacting with LAMB3 and ITGB4 in CRC cells, and enhanced the proliferation of CRC cells via the AKT pathway. Finally, MDFI reduced the sensitivity of CRC cells to oxaliplatin and fluorouracil. In conclusion, MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells, partially through the activation of the AKT signaling pathway by the binding to ITGB4/LAMB3. Our findings provide a possible molecular target for CRC therapy.

Virtual Screening of Peptide Libraries: The Search for Peptide-Based Therapeutics Using Computational Tools.

Over the last few decades, we have witnessed growing interest from both academic and industrial laboratories in peptides as possible therapeutics. Bioactive peptides have a high potential to treat various diseases with specificity and biological safety. Compared to small molecules, peptides represent better candidates as inhibitors (or general modulators) of key protein-protein interactions. In fact, undruggable proteins containing large and smooth surfaces can be more easily targeted with the conformational plasticity of peptides. The discovery of bioactive peptides, working against disease-relevant protein targets, generally requires the high-throughput screening of large libraries, and in silico approaches are highly exploited for their low-cost incidence and efficiency. The present review reports on the potential challenges linked to the employment of peptides as therapeutics and describes computational approaches, mainly structure-based virtual screening (SBVS), to support the identification of novel peptides for therapeutic implementations. Cutting-edge SBVS strategies are reviewed along with examples of applications focused on diverse classes of bioactive peptides (i.e., anticancer, antimicrobial/antiviral peptides, peptides blocking amyloid fiber formation).

Protein-protein interaction network-based integration of GWAS and functional data for blood pressure regulation analysis.

BACKGROUND: It is valuable to analyze the genome-wide association studies (GWAS) data for a complex disease phenotype in the context of the protein-protein interaction (PPI) network, as the related pathophysiology results from the function of interacting polyprotein pathways. The analysis may include the design and curation of a phenotype-specific GWAS meta-database incorporating genotypic and eQTL data linking to PPI and other biological datasets, and the development of systematic workflows for PPI network-based data integration toward protein and pathway prioritization. Here, we pursued this analysis for blood pressure (BP) regulation. METHODS: The relational scheme of the implemented in Microsoft SQL Server BP-GWAS meta-database enabled the combined storage of: GWAS data and attributes mined from GWAS Catalog and the literature, Ensembl-defined SNP-transcript associations, and GTEx eQTL data. The BP-protein interactome was reconstructed from the PICKLE PPI meta-database, extending the GWAS-deduced network with the shortest paths connecting all GWAS-proteins into one component. The shortest-path intermediates were considered as BP-related. For protein prioritization, we combined a new integrated GWAS-based scoring scheme with two network-based criteria: one considering the protein role in the reconstructed by shortest-path (RbSP) interactome and one novel promoting the common neighbors of GWAS-prioritized proteins. Prioritized proteins were ranked by the number of satisfied criteria. RESULTS: The meta-database includes 6687 variants linked with 1167 BP-associated protein-coding genes. The GWAS-deduced PPI network includes 1065 proteins, with 672 forming a connected component. The RbSP interactome contains 1443 additional, network-deduced proteins and indicated that essentially all BP-GWAS proteins are at most second neighbors. The prioritized BP-protein set was derived from the union of the most BP-significant by any of the GWAS-based or the network-based criteria. It included 335 proteins, with ~ 2/3 deduced from the BP PPI network extension and 126 prioritized by at least two criteria. ESR1 was the only protein satisfying all three criteria, followed in the top-10 by INSR, PTN11, CDK6, CSK, NOS3, SH2B3, ATP2B1, FES and FINC, satisfying two. Pathway analysis of the RbSP interactome revealed numerous bioprocesses, which are indeed functionally supported as BP-associated, extending our understanding about BP regulation. CONCLUSIONS: The implemented workflow could be used for other multifactorial diseases.

Potential effects of the most prescribed drugs on the microbiota-gut-brain-axis: A review.

The link between drug-induced dysbiosis and its influence on brain diseases through gut-residing bacteria and their metabolites, named the microbiota-gut-brain axis (MGBA), remains largely unexplored. This review investigates the effects of commonly prescribed drugs (metformin, statins, proton-pump-inhibitors, NSAIDs, and anti-depressants) on the gut microbiota, comparing the findings with altered bacterial populations in major brain diseases (depression, multiple sclerosis, Parkinson's and Alzheimer's). The report aims to explore whether drugs can influence the development and progression of brain diseases via the MGBA. Central findings indicate that all explored drugs induce dysbiosis. These dysbiosis patterns were associated with brain disorders. The influence on brain diseases varied across different bacterial taxa, possibly mediated by direct effects or through bacterial metabolites. Each drug induced both positive and negative changes in the abundance of bacteria, indicating a counterbalancing effect. Moreover, the above-mentioned drugs exhibited similar effects, suggesting that they may counteract or enhance each other's effects on brain diseases when taken together by comorbid patients. In conclusion, the interplay of bacterial species and their abundances may have a greater impact on brain diseases than individual drugs or bacterial strains. Future research is needed to better understand drug-induced dysbiosis and the implications for brain disease pathogenesis, with the potential to develop more effective therapeutic options for patients with brain-related diseases.

Commonly asked questions about transcriptional activation domains.

Eukaryotic transcription factors activate gene expression with their DNA-binding domains and activation domains. DNA-binding domains bind the genome by recognizing structurally related DNA sequences; they are structured, conserved, and predictable from protein sequences. Activation domains recruit chromatin modifiers, coactivator complexes, or basal transcriptional machinery via structurally diverse protein-protein interactions. Activation domains and DNA-binding domains have been called independent, modular units, but there are many departures from modularity, including interactions between these regions and overlap in function. Compared to DNA-binding domains, activation domains are poorly understood because they are poorly conserved, intrinsically disordered, and difficult to predict from protein sequences. This review, organized around commonly asked questions, describes recent progress that the field has made in understanding the sequence features that control activation domains and predicting them from sequence.

Proton pump inhibitor prescribing patterns and utilization: A retrospective chart review analysis.

Introduction: Proton pump inhibitors (PPIs) show a high level of efficacy and a high safety profile, and they have been increasingly prescribed in recent years. However, recent pharmacoepidemiological evidence has shown that PPI use has been associated with health risks and complications. Objectives: This study aimed to assess the prescribing patterns of proton pump inhibitors and the prevalence of potential drug-drug interactions (DDIs) among patients who use PPIs. Method: This was a retrospective analysis of electronic health records from the Ministry of National Guard Hospitals in Riyadh from January 2019 to June 2022. All adult patients who used PPIs were included to assess the prescribing patterns and drug utilization, including the number of prescriptions, duration of prescriptions, number of doses, and prescription indications. Potential DDIs were assessed based on concurrent use, which is defined as taking an interacting drug parallel to PPIs. The assessment includes complete or partial overlapping, with at least one day of overlapping. Results: The total number of PPI prescriptions was 80,365 for a total of 9,930 patients with a mean age of 67.5. The majority of PPIs were prescribed in high doses (74%), without reporting appropriate indications (95%), and 17% were prescribed for long-term use. A total of 24,575 (33.6%) potential DDIs with PPIs were found. Conclusion: The results showed that the majority of the PPI prescriptions were made with a high number of doses, without reporting appropriate indications, with some having potential DDIs. This might result in exposing patients to an increasing number of health risks. The findings highlight the importance of implementing a stewardship program for PPI prescription with periodic reassessments of patients' needs for these medications.

Assessment of Awareness and Knowledge of Proton Pump Inhibitors Among the General Population in the Qassim Region, Saudi Arabia.

OBJECTIVE: This descriptive observational cross-sectional study aimed to assess the general population's awareness, attitudes, and behaviours towards proton pump inhibitor (PPI) usage, as well as their knowledge about associated side effects, in the Qassim region of Saudi Arabia. METHODS: An autonomous online survey was conducted from June 15, 2023, to September 1, 2023, using social media. The survey targeted adult residents of Qassim and collected a total of 1090 respondents. Data analysis employed descriptive statistics, chi-square tests, and probit regression using R version 4.3.1 (RStudio, Boston, MA). A significance level of p<0.05 was utilized to interpret the results. RESULTS: A total of 1050 samples, limited to residents of Qassim, were analyzed. Significant associations were observed between awareness of PPIs and factors such as side effects (adjOR = 1.19, 99% CI: 1.08-1.31), widespread PPI use (adjOR = 1.24, 99% CI: 1.12-1.38), PPI usage (adjOR = 2.47, 99% CI: 2.18-2.82), and optimal PPI timing (adjOR = 1.30, 99% CI: 1.13-1.50). Additionally, age, educational attainment, and employment in the medical field significantly influenced awareness gaps related to potential side effects, PPI prevalence, adherence to medical prescriptions, and optimal timing for PPI usage. CONCLUSION: The current study concludes that a significant portion of individuals in the Qassim region lack awareness regarding the potential side effects of PPI usage. Comprehensive healthcare education is required to bridge awareness gaps regarding PPIs and foster informed medication practices. By grasping the intricacies of individual perceptions, medical engagement, and demographic factors, healthcare providers and policymakers can collaboratively empower individuals in the Qassim region to make informed choices regarding their health and medication usage.

Esophagitis Dissecans Superficialis: A Case Report.

Esophagitis dissecans superficialis (EDS) is a rare esophageal lesion characterized by sloughing of the esophageal mucosa. Typically asymptomatic and histopathologically nonspecific, diagnosis relies on endoscopic appearance. We report a case of an 81-year-old female who presented with an 8-pound weight loss in two weeks. Upper endoscopy showed severe mucosal changes with sloughing in the lower esophagus, consistent with EDS. Histopathology confirmed the diagnosis. No offending agents were identified, and high-dose proton pump inhibitors (PPIs) were initiated, resulting in symptom improvement. EDS remains poorly understood; it is associated with medication use, esophageal motility disorders, and autoimmune conditions. EDS should be considered in unexplained weight loss cases, with treatment focused on the discontinuation of culprits and PPI therapy.