Search Results (319)

Microglia, the brain’s resident innate immune cells, play a fundamental role in maintaining neural homeostasis and mediating responses to injury or infection. Upon activation, microglia undergo morphological and functional changes, including phenotypic switching between pro- and anti-inflammatory types and the release of different inflammatory mediators. These processes contribute to neuroprotection and the pathogenesis of various central nervous system (CNS) disorders. Mast cells, although sparsely located in the brain, exert a significant influence on neuroinflammation through their interactions with microglia. Through degranulation and secretion of different mediators, mast cells disrupt the blood–brain barrier and modulate microglial responses, including alteration of microglial phenotypes. Notably, mast cell-derived factors, such as histamine, interleukins, and tryptase, activate microglia through various pathways including protease-activated receptor 2 and purinergic receptors. These interactions amplify inflammatory cascades via various signaling pathways. Previous studies have revealed an exceedingly complex crosstalk between mast cells and microglia suggesting a bidirectional regulation of CNS immunity, implicating their cooperation in both neurodegenerative progression and repair mechanisms. Here, we review some of the diverse communication pathways involved in this complex interplay. Understanding this crosstalk may offer novel insights into the cellular dynamics of neuroinflammation and highlight potential therapeutic targets for a variety of CNS disorders. Full article

Background: Allergic rhinitis (AR) is a prevalent allergic disorder characterized by a complex pathogenesis. Drawing on traditional Chinese medicine theory and contemporary pharmacological principles, this study developed an inhalation-based herbal formulation, ZHW, to explore a novel non-invasive therapeutic approach. Objective: To investigate the therapeutic effects of ZHW on AR and elucidate its underlying mechanisms and potential targets through an integrated analysis of network pharmacology and proteomics. Materials and Methods: The volatile components of ZHW were analyzed by gas chromatography–mass spectrometry (GC-MS). The mouse model of AR was induced by OVA sensitization. The therapeutic efficacy of ZHW was assessed based on nasal symptom scores, histopathological examination, and inflammatory cytokine levels. Furthermore, the underlying mechanisms and potential targets of ZHW were investigated through integrated network pharmacology and proteomics analyses. Results: GC-MS analysis identified 39 bioactive compounds in ZHW. Inhalation treatment with ZHW demonstrated significant anti-allergic effects in OVA-sensitized mice, as evidenced by (1) reduced sneezing frequency and nasal rubbing behaviors; (2) decreased serum levels of IL-4, histamine, and OVA-specific IgE; (3) attenuated IL-4 concentrations in both nasal lavage fluid and lung tissue; (4) diminished nasal mucosal thickening; and (5) suppression of inflammatory cell infiltration. Integrated network pharmacology and proteomics analyses indicated that ZHW’s therapeutic effects were mediated through the modulation of multiple pathways, including the PI3K-Akt signaling pathway, the B cell receptor signaling pathway, oxidative phosphorylation, and the FcεRI signaling pathway. Key molecular targets involved Rac1, MAPK1, and SYK. Molecular docking simulations revealed strong binding affinities between ZHW’s primary bioactive constituents (linalool, levomenthol, linoleic acid, Linoelaidic acid, and n-Valeric acid cis-3-hexenyl ester) and these target proteins. Conclusions: The herbal formulation ZHW demonstrates significant efficacy in alleviating allergic rhinitis symptoms through multi-target modulation of key signaling pathways, including PI3K-Akt- and FcεRI-mediated inflammatory responses. These findings substantiate ZHW’s therapeutic potential as a novel, non-invasive treatment for AR and provide a strong basis for the development of new AR therapies. Future clinical development will require systematic safety evaluation to ensure optimal therapeutic outcomes. Full article

It was unknown whether hyperthermia increased the efficacy of histamine to raise the force of cardiac contractions via human H1-histamine receptors. To that end, we measured the force in isolated human atrial preparations (HAPs) excised from the right atrium of patients who underwent cardiac surgery due to severe two- or three-vessel coronary heart disease. For comparison, we also measured the force in paced (1 Hz) left and spontaneously beating right atrial preparations of transgenic mice overexpressing cardiac human H1-histamine receptors (H1-TG). Histamine (100 µM) was less efficient in raising the force in left atrial preparations from H1 TG mouse atria under hyperthermia than under hypothermia. Oppositely, histamine was more efficient in augmenting force during hyperthermia than during hypothermia in isolated electrically stimulated (1 Hz) HAPs. In sum, the contractile response to activation of H1-histamine receptor in H1-TG mice and in HAPs are opposite with regard to hyperthermia dependence. In patients with fever, histamine might thus be important, to preserve cardiac contractile function as a compensatory mechanism. Full article

Background/Objectives: Hallucinogenic substances such as psilocybin, psilocin, ergometrine, ergotamine, and lysergic acid diethylamide (LSD) have been demonstrated to enhance the force of contraction (FOC), in part due to the phosphorylation of phospholamban in human atrial preparations via 5-HT₄ serotonin receptors and/or H₂ histamine receptors. However, whether psilocybin or psilocin acts at isolated mammalian ventricular preparations and whether they increase protein phosphorylation in the mammalian ventricle remains to be elucidated. Methods: To this end, the FOC and phospholamban phosphorylation in isolated perfused hearts from transgenic mice with cardiomyocyte-specific overexpression of either human 5-HT₄ receptors (5-HT₄-TG) or human H₂ receptors (H₂-TG) and their wild-type littermates (WT) were examined. Furthermore, the ergot alkaloids ergometrine, ergotamine, and LSD were used as references. Results: Psilocybin and psilocin enhanced the FOC to 137% and to 152%, respectively, and elevated the phospholamban phosphorylation in isolated perfused hearts from 5-HT₄-TG. In H₂-TG hearts, psilocybin and psilocin increased the FOC to a much lesser extent but had no effect on the phospholamban phosphorylation. In contrast, LSD increased the FOC and phosphorylation state of phospholamban in isolated hearts of both 5-HT₄-TG and H₂-TG. On the other hand, ergometrine and ergotamine increased the FOC only in H₂-TG. Ergometrine increased the phosphorylation state of phospholamban in perfused hearts from H₂-TG, but not from 5-HT₄-TG. Ergotamine failed to increase the phospholamban phosphorylation in both H₂-TG and 5-HT₄-TG. Psilocybin, psilocin, ergotamine, ergometrine, and LSD were unable to increase FOC and phospholamban phosphorylation in perfused hearts from WT. Conclusions: The increase in the phosphorylation state of phospholamban could provide a partial explanation for the positive inotropic effects and the relaxant effects of not only psilocybin and psilocin but also ergometrine and LSD in the isolated hearts of the animals used in this study. Full article

Influenza is still a chronic global health threat, inducing a sustained search for effective antiviral therapeutics. Computational methods have played a pivotal role in developing small molecule therapeutics. In this study, we applied a combined in silico and in vitro approach to explore the potential anti-influenza activity of cyproheptadine, a clinically used histamine H1 receptor antagonist. Virtual screening based on the average quasivalence number (AQVN) and electron–ion interaction potential (EIIP) descriptors suggests similarities between cyproheptadine and several established anti-influenza agents. The subsequent ligand-based pharmacophore screening of a focused H1 antagonist library was aligned with the bioinformatics prediction, and further experimental in vitro evaluation of cyproheptadine demonstrated its anti-influenza activity. These findings provide proof of concept for cyproheptadine’s in silico-predicted antiviral potential and underscore the value of integrating computational predictions with experimental validation. The results of the current study provide a preliminary proof of concept for the predicted anti-influenza potential based on computational analysis and emphasize the utility of integrating in silico screening with experimental validation in the early stages of drug repurposing efforts. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder marked by intricate interplay among skin barrier dysfunction, immune dysregulation, and microbial dysbiosis. While therapeutic advancements targeting T helper 2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have yielded promising outcomes, a significant proportion of patients still experience inadequate relief, particularly from persistent pruritus. Achieving minimal disease activity remains an unmet clinical priority and a cornerstone of effective AD management. This review provides an in-depth analysis of current therapeutic approaches and integrates findings from recent biologic studies, with a particular focus on innovative strategies under active investigation. These approaches include targeting components of the innate immune system, such as thymic stromal lymphopoietin (TSLP) and IL-1 family cytokines; the adaptive immune system, including OX40-OX40L interactions and Th17- and Th22-related cytokines; and mechanisms associated with pruritus, such as IL-31, histamine receptors, and neurokinin 1 receptor. Emerging insights underscore the transformative potential of personalized therapeutic regimens tailored to the distinct endotypes and severity of AD. Advances in deciphering the pathogenesis of AD are unlocking unprecedented opportunities for precision medicine, offering renewed hope for improved outcomes in this multifaceted and heterogeneous condition. Full article

Background/Objectives: The incidence of food allergies and other allergic diseases is rising. Emerging evidence links both antimicrobials and acid-suppressive therapy with gut dysbiosis, which is implicated in allergy development. We investigated the relationship between the use of acid-suppressive medications or antimicrobials in infancy and the risk of developing childhood allergic diseases. Methods: The US network in the TriNetX platform was used to identify patients prescribed proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H₂RAs), antimicrobials ≥1, or antimicrobials ≥3 times during their first year of life from October 2015 to January 2022. ICD-10 diagnoses were used to assess two-year outcomes of anaphylaxis, food allergy, and atopic dermatitis. A sub-analysis in gastroesophageal reflux (GERD) patients was also performed. Results: Risks of anaphylaxis and food allergy increased with the prescription of PPIs (risk ratio [95% CI], 2.49 [1.40–4.41], 5.33 [4.97–5.71]), H₂RAs (4.48 [3.43–5.86], 4.21 [4.01–4.41]), and antimicrobials ≥1 (2.41 [2.13–2.72], 1.90 [1.86–1.94]), or ≥3 times (3.69 [3.12–4.37], 2.79 [2.70–2.88]). Risk of atopic dermatitis was increased in both H₂RA (1.41 [1.35–1.48]) and antimicrobial groups (2.25 [2.22–2.28], 3.35 [3.29–3.41]), but not in the PPI group. In the GERD sub-analysis, anaphylaxis risk was not significantly different, food allergy risk was increased in both PPI (2.30 [2.08–2.53]) and H₂RA groups (1.77 [1.63–1.92]), and atopic dermatitis decreased in the PPI group (0.76 [0.67–0.85]) but slightly increased in the H₂RA group (1.11 [1.03–1.20]). Conclusions: Exposure to acid-suppressive or antimicrobial medications during infancy was associated with increased risk of food allergy and anaphylaxis in early childhood. In infants diagnosed with GERD, exposure to acid-suppressive medications was still associated with increased food allergy risk. Full article

We tried to synthesize the possibilities of predicting the response to clozapine treatment, which can significantly improve the efficacy of the active substance and reduce adverse reactions, and how the active substance acts at the D1 dopaminergic receptors D2, D3, D4, and D5, muscarinic M1, M2, M3, and M5, and the histamine and alpha 1 adrenergic receptor, as well as how it contributes to increased cerebral blood flow, the effect on ribosomal protein S6 function, or the effect on kynurenine 3-monooxygenase function. Clozapine is one of the most effective antipsychotics, and there is potential to improve performance by combining it with different compounds to limit adverse effects or by augmenting it with other antipsychotics (amisulpride, paliperidone), other active substances with different properties (minocycline, N-acetylcysteine, memantine), or alternative therapies (electroconvulsive therapy, repetitive transcranial magnetic stimulation). There are also significant steps in optimizing clozapine efficacy by predicting treatment response, which could be determined by testing the following: plasma levels of clozapine N-oxide and N-desmethylclozapine, serum levels of neurotrophins and glutamate, genetic testing, the polygenic risk score, morphometry, or even the identification and accurate determination of persistent negative symptoms. Full article

Background/Objectives: The nephrotoxicity of immune checkpoint inhibitors (ICIs) combined with proton pump inhibitors (PPIs) has been recognized but lacks a comprehensive analysis. We conducted an in-depth investigation of renal adverse events (rAEs) associated with ICIs and different acid-suppressing agents (ASAs)—including PPIs, histamine-2 receptor antagonists (H₂RAs), and potassium-competitive acid blockers (P-CABs)—using real-world data from the FDA’s Adverse Event Reporting System (FAERS). Methods: We analyzed rAE reports from the FAERS database covering Q1 2004 to Q1 2023. Disproportionality analysis was conducted to identify rAEs associated with ICI or ASA monotherapy or combination therapy. Univariate logistic regression was employed to explore influencing factors. Results: No eligible rAE reports were retrieved for H₂RAs and P-CABs. However, 6,775 reports in the ICI group, 54,055 reports in the PPI group, and 210 reports in the ICI–PPI combination therapy group were included in the final analysis. In PPI–ICI combination settings, tubulointerstitial nephritis had the highest reporting frequency and signal intensity; the overall risk of rAEs was significantly elevated compared to ICI or PPI monotherapy, with reporting odds ratios of 14. 65 (95% confidence interval [CI] 12.93–16.58) and 3.24 (95% CI 2.87–3.66), respectively; the median onset time was shortest at 21 days (interquartile range 5.5–135); and PD-1 monotherapy, omeprazole, and rabeprazole were associated with higher rAE risks. Conclusions: Our findings confirm that the combination of PPIs (but not other ASAs) with ICIs further increases the risk of various acute and chronic rAEs. Healthcare providers should exercise caution when managing patients on these therapies. Full article

Current treatment options for Alzheimer’s disease target neurotransmitters following the disease onset, and they offer limited efficacy without slowing down the disease progression. There has been an increasing concern in recent years targeting the histamine H3 receptor (H3R) in treating cognitive disorders, including dementia. Preclinical studies have shown that antagonists of H3R or inverse agonists enhance the cognitive function in animal models with dementia by increasing the release of neurotransmitters associated with learning and memory. This review employed a systematic literature search across databases including PubMed, Scopus, Google Scholar, and ClinicalTrials.gov, selecting peer-reviewed studies. The results of this study illustrate the complex landscape of research on H3R modulators in dementia, highlighting both promising findings and ongoing challenges in translating preclinical discoveries into effective clinical interventions. Knowing the role of H3R in dementia and developing novel pharmacological interventions targeting these receptors represent a promising avenue for future research, leading to the development of new treatments for this devastating condition. Full article

Hypertension-induced cardiac remodeling is a complex process driven by interconnected molecular and cellular mechanisms that culminate in hypertensive myocardium, characterized by ventricular hypertrophy, fibrosis, impaired angiogenesis, and myocardial dysfunction. This review discusses the histomorphometric changes in capillary density, fibrosis, and mast cells in the hypertensive myocardium and delves into the roles of key regulatory systems, including the apelinergic system, vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathways, and nitric oxide (NO)/nitric oxide synthase (NOS) signaling in the pathogenesis of hypertensive heart disease (HHD). Capillary rarefaction, a hallmark of HHD, contributes to myocardial ischemia and fibrosis, underscoring the importance of maintaining vascular integrity. Targeting capillary density (CD) through antihypertensive therapy or angiogenic interventions could significantly improve cardiac outcomes. Myocardial fibrosis, mediated by excessive collagen deposition and influenced by fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta (TGF-β), plays a pivotal role in the structural remodeling of hypertensive myocardium. While renin–angiotensin–aldosterone system (RAAS) inhibitors show anti-fibrotic effects, more targeted therapies are needed to address fibrosis directly. Mast cells, though less studied in humans, emerge as critical regulators of cardiac remodeling through their release of pro-fibrotic mediators such as histamine, tryptase, and FGF-2. The apelinergic system emerges as a promising therapeutic target due to its vasodilatory, anti-fibrotic, and cardioprotective properties. The system counteracts the deleterious effects of the RAAS and has demonstrated efficacy in preclinical models of hypertension-induced cardiac damage. Despite its potential, human studies on apelin analogs remain limited, warranting further exploration to evaluate their clinical utility. VEGF signaling plays a dual role, facilitating angiogenesis and compensatory remodeling during the early stages of arterial hypertension (AH) but contributing to maladaptive changes when dysregulated. Modulating VEGF signaling through exercise or pharmacological interventions has shown promise in improving CD and mitigating hypertensive cardiac damage. However, VEGF inhibitors, commonly used in oncology, can exacerbate AH and endothelial dysfunction, highlighting the need for therapeutic caution. The NO/NOS pathway is essential for vascular homeostasis and the prevention of oxidative stress. Dysregulation of this pathway, particularly endothelial NOS (eNOS) uncoupling and inducible NOS (iNOS) overexpression, leads to endothelial dysfunction and nitrosative stress in hypertensive myocardium. Strategies to restore NO bioavailability, such as tetrahydrobiopterin (BH₄) supplementation and antioxidants, hold potential for therapeutic application but require further validation. Future studies should adopt a multidisciplinary approach to integrate molecular insights with clinical applications, paving the way for more personalized and effective treatments for HHD. Addressing these challenges will not only enhance the understanding of hypertensive myocardium but also improve patient outcomes and quality of life. Full article

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder that is defined by the reflux of gastric contents into the esophagus, and it results in symptoms such as esophageal inflammation, regurgitation, and indigestion. Although proton pump inhibitors (PPIs) and histamine-2 receptor antagonists are frequently employed to treat GERD, their prolonged administration is associated with adverse effects, necessitating the development of alternative therapeutic strategies. Natural products are now recognized as promising candidates for the management of GERD due to their bioactive compounds, which possess antioxidant, anti-inflammatory, and mucosal-protective properties. The potential of natural products in the treatment of GERD is comprehensively examined in this review, with a focus on their mechanisms of action, which include acid suppression, esophageal mucosal regeneration, anti-inflammatory activity, and gut microbiota modulation. Also, the efficacy and safety of key natural products, including flavonoids, polyphenols, plant-derived oils, herbal extracts, probiotics, and dietary components, in preclinical and clinical studies, are assessed. Additionally, this review addresses the barriers confronting the translation of natural therapies into clinical practice, such as regulatory obstacles, variability in bioavailability, and the need for dosage standardization. The integration of natural products into the management of GERD has the potential to enhance conventional therapies, providing a more comprehensive and secure approach for patients. Full article

Background: The four subtypes of G protein-coupled receptors (GPCRs) regulated by histamine play critical roles in various physiological and pathological processes, such as allergy, gastric acid secretion, cognitive and sleep disorders, and inflammation. Previous experimental structures of histamine receptors (HRs) with agonists and antagonists exhibited multiple conformations for the ligands and G protein binding. However, the structural basis for HR regulation and signaling remains elusive. Methods: We determined the cryo-electron microscopy (cryo-EM) structure of the H4R-histamine-Gi complex at 2.9 Å resolution, and predicted the models for all four HRs in the ligand-free apo and G protein subtype binding states using AlphaFold3 (AF3). Results: By comparing our H4R structure with the experimental HR structures and the computational AF3 models, we elucidated the distinct histamine binding modes and G protein interfaces, and proposed the essential roles of Y^6.51 and Q^7.42 in receptor activation and the intracellular loop 2 (ICL2) in G protein bias. Conclusions: Our findings deciphered the molecular mechanisms underlying the regulation of different HRs, from the extracellular ligand-binding pockets and transmembrane motifs to the intracellular G protein coupling interfaces. These insights are expected to facilitate selective drug discovery targeting HRs for diverse therapeutic purposes. Full article

Background: This study explored the prescribing patterns of proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs) across the UK during the COVID-19 pandemic, highlighting the dynamic relationship between emerging evidence, regulatory actions, and clinical practices. Methods: Using a repeated cross-sectional design, prescription data from July 2019 to May 2024 were analyzed across England, Scotland, Wales, and Northern Ireland. Segmented regression analysis was employed to assess trends before and after January 2022, reflecting the impact of emerging evidence on prescribing behaviors. Results: The results revealed a significant increase in famotidine prescriptions, from 57.56 to 303.31 per 100,000 population in England post-January 2022, reflecting early adoption of preliminary findings despite the lack of randomized controlled trial confirmation. Ranitidine prescriptions fell to near zero due to contamination concerns, while PPIs like omeprazole remained the most prescribed, with Wales reporting the highest post-2022 usage at 7445.71 per 100,000 population. Conclusions: Adherence to deprescribing guidelines was inconsistent, with a possibility that many PPI users lacked documented indications. Regional variations in prescribing trends highlighted differences in guideline implementation. These findings underscore the need for improved evidence dissemination and adherence to prescribing guidelines. Future research should include patient-level data and long-term evaluations to optimize healthcare practices. Full article

Objectives: Gastroesophageal reflux disease (GERD) is commonly encountered in adults and children. A subset of patients with GERD are refractory to acid suppressants, implicating other factors in the refluxate. Duodenogastric reflux (DGR) produces similar symptoms through reflux of non-acidic duodenal content and the cytotoxic effect of bile in the esophageal mucosa. Various methods have been utilized to detect DGR using a Bilitec device or Hepatobiliary scintigraphy, amongst the most common, each with their own limitations. We aimed to use combined multichannel intraluminal impedance and pH (MII-pH) monitoring with an additional gastric pH sensor to collect information about acidic and non-acidic gastroesophageal refluxes and to assess whether continuous gastric pH measurement in children provides indirect evidence of DGR for better understanding of the symptoms. Methods: From 2022 through 2023, clinically symptomatic pediatric patients scheduled for esophagogastroduodenoscopy (EGD) and MII-pH at Arnold Palmer Hospital for Children in the United States were included (n = 26). Exclusions included patients taking acid suppressants prior to the start of this study. The data were analyzed for subjects completing at least 18 h of the study protocol. Results: Subjects with a normal pH impedance (n = 5) showed a median non-meal gastric pH of 1.8. Subjects with an abnormal pH impedance (n = 21) showed a median non-meal gastric pH of 2.2. Of the 26 subjects enrolled, the duration of non-meal gastric pH 4.0–7.0 was positively correlated with non-acidic gastroesophageal refluxes. Although all acidic reflux events occurred at gastric pH < 4.0, there was no correlation between the duration of non-meal gastric pH < 4.0 and impedance changes or reflux index. Conclusions: The results showed daily variability in the non-meal gastric pH of pediatric patients and a statistically significant correlation between its duration at pH 4.0 to 7.0 and non-acidic refluxes suggestive of the implication of DGR. Further research is required to assess this association with gastroesophageal reflux and dyspeptic symptoms to investigate the diagnostic tools and therapeutic interventions, including the role of prokinetics and surface protective agents for DGR. Full article