Histamine Receptor Research Articles

Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells

BackgroundAlthough immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC.MethodsWe assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment.ResultsHRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy.ConclusionsHRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.

PREPARATION AND EVALUATION OF LAFUTIDINE NANOEMULSION AS ORAL DELIVERY SYSTEM

Objective: Lafutidine is a histamine (H2) receptor antagonist utilized for the treatment of gastric ulcer. Its oral bioavailability is low due to poor water solubility and an extensive first-pass hepatic. So, the present work aims to formulate and characterize of an oil in water (o/w) nanoemulsion of lafutidine as oral liquid dosage form and this could enhance drug solubility and improve its bioavailability. Methods: The pseudo-ternary phase diagrams were constructed via titration method. The diagram plots derived from oil, various ratios of surfactant and co-surfactant (S mix), and double distilled water. The selected optimized lafutidine nanoemulsions formula was determined via a variety of investigational studies like particle size, polydispersity index (PDI), zeta potential, pH, drug content and an in vitro drug release. Results: Characterization studies revealed that the optimum formula of nanoemulsions was (NE5), which consist of 0.2% of lafutidine, 30 % of surfactant and co-surfactant (S mix) (3:1), which mean (22.5%of tween 20:7.5% of polyethylene glycol 200 (PEG 200), 10% of peppermint oil and 59.4% of double distilled water. The optimized formula exhibited droplets size (62.56-96.2 nm), PDI (0.11), good pH value (7.1), zeta potential (-32.2 mV), high drug content (99.2%), in vitro release of lafutidine was significantly higher (P<0.05) for NE5. Scanning probe microscopy (SPM) revealed that the droplets size of NE5 was in nano-scale. Conclusion: It is possible to conclude that the optimized formula (NE5) was promised formula of nanoemulsion for increasing the orally delivered lafutidine bioavailability.

Development of simultaneous determination of dopamine 2, histamine 1, and muscarinic acetylcholine receptor occupancies by antipsychotics using liquid chromatography with tandem mass spectrometry

Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D2), histamine 1 (H1), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 μg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 μg/kg raclopride, 10 μg/kg doxepin, and 30 μg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D2, H1, and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70–95%, 19–43%, and 12–45%, respectively, at an olanzapine dose range of 3–10 mg/kg. These results suggest that simultaneous determination of in vivo D2, H1, and mACh receptor occupancy is possible using LC-MS/MS.

Role of Histamine in the Regulation of Calcium and Actin Dynamics in Collecting Duct Cells

Background. Histamine is a nitrogen-based molecule that has established involvement in allergic reactions and immune responses. The levels of histamine are increased in renal pathologies, such as nephrotic syndrome, diabetic nephropathy, acute renal failure, and end stage kidney disease. We have previously shown that all 4 histamine receptors (HR1 to HR4) are abundant in the kidney, and histamine exposure can affect levels of intracellular Ca2+ in the collecting ducts. Calcium signaling is an important regulator of actin cytoskeleton dynamics in these cells, and thus, affects their structure and integrity; however, there is a gap in knowledge regarding the role that histamine may play in this mechanism. In this study, we hypothesized that histamine exposure induces Ca2+ release and leads to reorganization of F-actin cytoskeleton in the cortical collecting duct cells. Methods. Immunofluorescent staining of cultured cells, in combination with the Western blotting, were utilized to characterize the renal expression of HRs and enzymes of the histaminergic system (HiS). The effects of histamine were tested in cultured mouse cortical collecting duct cells (mpkCCD). Functional live confocal imaging was used to detect changes in intracellular Ca2+ level (Fluo 8, 490/525 nm). Actin cytoskeleton rearrangements were assessed by F-actin staining with rhodamine-phalloidin. Images were analyzed in FIJI (NIH). Differences between the groups were assessed with 1-way ANOVA; p < 0.05 was considered significant. Results. IHC and Western blotting showed that all four HRs as well as HiS components are expressed in the mpkCCD cells. Acute application of histamine (100 uM) led to an increase in intracellular Ca2+ level which was predominantly regulated by extracellular influx, with a minor component of intracellular store release. Next, we blocked HR1, HR2, HR3, HR4 with loratadine (5uM), ranitidine (10 uM), iodophenpropit (500 nM), and A943931 (100 nM), respectively, to discern the involvement of specific HRs. We demonstrated that HR1, HR3, HR4 but not HR2 are involved in mediating the influx of Ca2+ in response to histamine. When mpkCCD cells were incubated with 100 uM histamine for 4 hours, we observed formation of the F-actin stress-fibers in the submembrane space. Conclusions. We have shown that collecting duct cells express HRs as well as HiS enzymes, indicating presence of a fully functional HiS. Our data revealed that histamine exposure leads to an influx of Ca2+ in these cells, which is mediated via H1R, H3R, and H4R. Additionally, histamine induced actin cytoskeleton rearrangements, suggesting its role in maintenance of renal epithelial cell structure. Our findings highlight the relationship between histamine, calcium regulation, and actin cytoskeleton dynamics in the renal epithelial cells, offering insights into future therapeutic strategies. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Production of Histamine by Diverse Gut Bacteria Can Activate Intestinal HRH1 and Promote Calcium Mobilization

Background: Histamine is a biogenic amine that impacts several physiological processes, including allergic reactions, neurotransmitter activity and immune regulation. Bacteria uptake L-histidine and convert it into histamine via the activity of histidine decarboxylase enzymes. Histamine can also be produced by host cells such as enterochromaffn-like cells, mast cells and neurons. We hypothesized that a diverse group of bacteria would be capable of generating histamine. We predicted that histamine producing bacteria in the gut would activate intestinal epithelial histamine receptors and promote gut health. Methods and Results: To investigate how widespread histamine production is across bacterial species, we examined 102,018 annotated genomes in the Integrated Microbiome Genome Database. We found 3,679 bacterial genomes (3.6%) possessed histidine decarboxylase. We found histidine decarboxylase in bacteria belonged to 9 phyla: Bacillota, Bacteroidota, Actinomycetota, Pseudomonadota, Lentisphaerota, Fusobacteriota, Armatimonadota, Cyanobacteriota, and Verrucomicrobiota. Although the majority of the identified bacteria were aquatic and terrestrial in origin, ~14% of the bacteria were from the human gut microbiota. We confirmed the ability of several gut bacteria to generate histamine in a chemically defined bacterial growth medium using liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics. Briefly, histamine and histidine quantification is performed using authentic analytical and stable-label deuterated internal standard compounds that are used to produce calibration curves that span a linear dynamic range of 0.977-1,000 ng/mL. We found higher concentrations of histamine produced by gut-associated Klebsiella aerogenes, Fusobacterium varium, Clostridium perfringens, Limosilactobacillus reuteri and Morganella morganii. To address the question if bacterial-derived histamine could activate intestinal epithelial histamine receptors in the gut, we examined histamine receptors in publicly available single cell RNAseq datasets. We found that HRH1 was expressed in all cell types of the small and large intestine. We did not observe any expression of HRH2, HRH3 or HRH4 in the gut epithelium. We confirmed this finding in human intestinal organoids derived from duodenum, jejunum, ileum and colon. HRH1 activation in airway epithelial cells is known to signal through MAPK and promote pro-inflammatory cytokine release. Using GCaMP6S transduced organoids, we found that multiple concentrations of histamine stimulated robust calcium mobilization. However, histamine did not alter the levels of phosphorylated MAPK members p38, JNK, ERK, CREB or AKT and did not stimulate the release of any of the 18 epithelial specific cytokines we examined. Conclusions: Our work reveals that gut bacteria are capable of generating histamine, and histamine in the gut can activate epithelial HRH1 to drive calcium signaling and other downstream signals. K01 DK123195 (M Engevik) K01 DK121869 (A Engevik F32 DK130288 (K Engevik) APS Postdoctoral Fellowship (K Engevik). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prevalence and factors associated with inappropriate continuation of stress ulcer prophylaxis at discharge

Stress ulcer prophylaxis is started in the critical care unit to decrease the risk of upper gastrointestinal ulcers in critically ill persons and to decrease mortality caused by stress ulcer...

Histamine Receptors Are Altered in Colorectal Cancer

Background: Histamine is an endogenous amine that acts on a wide variety of cell types throughout the body. Its activity is mediated by four distinct receptors: HRH1, HRH2, HRH3 and HRH4. Each of these receptors induces a distinct signaling cascade that has diverse output. Histamine has been postulated to influence cancer progression, but little is known about the distribution of histamine receptors in the gut epithelium or its exact role in colorectal cancer. The aim of this study was to define the distribution of histamine receptors in the colonic epithelium in the setting of health and cancer. Methods & Results: We utilized publicly available single cell sequencing databases to examine the distribution of histamine receptors in the normal colon. We found that HRH1 was highly expressed in all colonic epithelial cells. Interestingly, HRH2, HRH3 and HRH4 were not expressed in any cell type in the colon. To confirm these findings, we grew human colonic organoids and found by qPCR analysis that HRH1 was the only receptor present in this epithelial specific system. In the setting of cancer, we found that HRH1 was elevated in colorectal cancer tumors compared to normal controls. Immunostaining of a tissue array confirmed that colon cancer tissue specimens had higher concentrations of immune associated HRH1; suggesting that immune cells were contributing to the higher levels of HRH1 observed in tumors. Single cell RNAseq data demonstrated that macrophages and monocytes had the highest expression of HRH1 among immune cells. Examination of immune infiltration and HRH1 expression in the Cancer Genome Atlas revealed a positive correlation between monocyte and macrophage HRH1 expression. Conclusions: These data suggest that HRH1 is the only receptor expressed in the colonic epithelium and that in cancer, infiltration of monocytes and macrophages harboring HRH1 elevate overall expression levels of this receptor in tumors. DDRC Pilot and Feasibility Award (Amy Engevik) Career Development Award (K01) (Amy Engevik) DK121869-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Liposomal Nanocarriers of Preassembled Glycocalyx Restore Venular Permeability in Sepsis: Assessed Quantitatively with a Novel Microchamber System

Background: The endothelial glycocalyx (EG), covering the luminal side of endothelial cells, regulates vascular permeability and senses wall shear stress. In sepsis, EG undergoes degradation leading to increased permeability and edema formation. We hypothesized that restoring EG integrity using liposomal nanocarriers of preassembled glycocalyx (LNPG) will restore normal venular permeability in a lipopolysaccharide (LPS)-induced sepsis model of mice. Methods: To test this hypothesis, we designed a unique perfusion microchamber in which the vascular permeability of isolated and cannulated mice mesenteric venules could be assessed by measuring the concentration of Evans blue dye (EBD) by fluorescent spectroscopy in microliter-samples of extravascular solution (ES). Results: Histamine-induced time- and dose-dependent increases in EBD in the ES could be measured, confirming the sensitivity of the microchamber system. Notably, the histamine-induced increase in permeability was significantly attenuated by histamine receptor (H1) antagonist, triprolidine hydrochloride. Subsequently, mice were treated with LPS, or LPS + LNPG. Compared to control mice, venules from LPS-treated mice showed a significant increased permeability, which was significantly reduced by LNPG administration. Moreover, in the presence of wall shear stress, intraluminal administration of LNPG significantly reduced the permeability in isolated venules from LPS-treated mice. Conclusion: Our newly developed microchamber system can quantitatively measure the permeability of isolated venules. LPS-induced sepsis increases permeability of venules that is attenuated by in vivo LNPG administration, which is also reestablished endothelial vasomotor responses to shear stress. Thus, LNPG presents a promising therapeutic potential for restoring EG function and thereby mitigating the increased permeability in sepsis. Support: National Institute of Health [grant number: HL144528, Dong Sun] and the Uehara Memorial Foundation [grant number: 202241049, Shinya Ishiko) and Hungarian Academy of Sciences Post-Covid 2021-34 (AK) and MIT of Hungary, National Research, Development, and Innovation Fund, OTKA K 132596 (AK). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

H3 Receptor Expression in the Spinal Trigeminal Nucleus Caudalis in a Rat Model of Allergic Rhinitis

Background: Allergic rhinitis is one of the most frequently observed allergic diseases. Although antihistamine medication is an effective symptomatic treatment for this disease, it is not suffcient enough to improve quality of life, requiring an additional treatment. Excessive sneezing is a typical symptom of allergic rhinitis in response to immunological release of histamine, and we hypothesized that this could be due to characteristic changes on the reflex pathway, particularly a nucleus receiving nasal trigeminal afferents, the spinal trigeminal nucleus caudalis (Sp5C), via a histamine mechanism(s). In the present study, we created an allergic rhinitis model by conventional methods, harvesting brainstem tissues to perform immunohistochemistry for histamine receptor subtype 3 (H3R) in Sp5C. Methods: Male Fisher 344 rats (8 weeks old) were sensitized and nasally challenged to Ovalbumin. After the Ovalbumin challenge into the nasal cavity, the number of sneezing was visually counted for 13 min and repeated for 7 days. After that, animals were euthanized, brainstems were extracted, and immunohistochemistry were performed with various antibodies, including anti-H3R and -GFAP. In some animals, to identify the subregion within Sp5C where nasal trigeminal afferents are transmitted from the nasal mucosa, capsaicin (0.3mM), a potent nociceptive substance, was administered into the nasal cavity and then immunohistochemistry of c-Fos expression was performed. Quantitative analysis was performed by area of fluorescent staining. Results: Intranasal administration of capsaicin markedly increased c-Fos expression in Sp5C compared to non-administration control, confirming the subregion of Sp5C receiving nasal afferent information. The allergic rhinitis model rats showed a significant increase in sneezing frequency in response to Ovalbumin nasal challenge compared to non-sensitized rats challenged with Ovalbumin or saline (56.8±3.9 vs. 16.6±1.6 vs. 23.7±3.2 [sneezes during a total observation period]; p<0.001). The expression pattern of H3Rs was punctate and co-stained with GFAP in many cases. Both H3 receptor and GFAP expressions were significantly decreased in allergic model rats compared to control rats (control vs. allergic; 21.2±1.2 vs.6.4±0.5 [%] in H3Rs, p<0.001; 16.2±0.5 vs.10.9±0.8 [%] in GFAP, p<0.001). No difference in DAPI staining was observed (14.5±0.8 vs.13.7±0.5 [%], p=0.223), suggesting similar population of cells in data analyzed from both groups. Discussion: These results may suggest that Sp5C is part of the sneezing reflex pathway and that a decrease in H3Rs, including those on astrocytes, is involved in worsening clinical symptoms of allergic rhinitis such as excessive sneezing. This research was supported by KAKENHI, Grant-in-Aid for challenging Exploratory Research # 21K19182. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Insight into the solution thermodynamic properties of cimetidine form A and form B based on experiments and molecular simulations

Cimetidine (CIM) is an antagonist of the type II histamine receptors, and act as a significant agent in the treatment of stomach ulcers. In this work, the effect of polymorphism and solvent type on the thermodynamic properties of CIM was investigated based on experimental results and molecular simulations. The solubility data of two polymorphs for CIM (forms A and B) in organic solvents were measured and correlated with four thermodynamic models. It could be found that the solubility of CIM form A is higher compared to form B. In addition, molecular simulations were adopted to investigate the mechanism of the solubility and stability of the two forms. Hirshfeld surface analysis shows that strong H···N interaction contributes to better stability of form B. Meanwhile, molecular electrostatic potential surface and radial distribution function results indicate that the solubility behavior is significantly influenced by the intensity of the solute–solvent interactions. Finally, the dissolution thermodynamic properties, including the enthalpy change, the Gibbs energy change, and the entropy change, were calculated and the results show that the dissolution process of CIM is endothermic, entropy-driven and spontaneous.

Molecular Determinant Underlying Selective Coupling of Primary G-Protein by Class A GPCRs.

G-protein-coupled receptors (GPCRs) transmit downstream signals predominantly via G-protein pathways. However, the conformational basis of selective coupling of primary G-protein remains elusive. Histamine receptors H2R and H3R couple with Gs- or Gi-proteins respectively. Here, three cryo-EM structures of H2R-Gs and H3R-Gi complexes are presented at a global resolution of 2.6-2.7 Å. These structures reveal the unique binding pose for endogenous histamine in H3R, wherein the amino group interacts with E2065.46 of H3R instead of the conserved D1143.32 of other aminergic receptors. Furthermore, comparative analysis of the H2R-Gs and H3R-Gi complexes reveals that the structural geometry of TM5/TM6 determines the primary G-protein selectivity in histamine receptors. Machine learning (ML)-based structuromic profiling and functional analysis of class A GPCR-G-protein complexes illustrate that TM5 length, TM5 tilt, and TM6 outward movement are key determinants of the Gs and Gi/o selectivity among the whole Class A family. Collectively, the findings uncover the common structural geometry within class A GPCRs that determines the primary Gs- and Gi/o-coupling selectivity.

Label-free cell phenotypic profiling of histamine H4R receptor and discovery of non-competitive H4R antagonist from natural products

Histamine 4 receptor (H4R), the most recently identified subtype of histamine receptor, primarily induces inflammatory reactions upon activation. Several H4R antagonists have been developed for the treatment of inflammatory bowel disease (IBD) and atopic dermatitis (AD), but their use has been limited by adverse side effects, such as a short half-life and toxicity. Natural products, as an important source of anti-inflammatory agents, offer minimal side effects and reduced toxicity. This work aimed to identify novel H4R antagonists from natural products. An H4R target-pathway model deconvoluted downstream Gi and MAPK signaling pathways was established utilizing cellular label-free integrative pharmacology (CLIP), on which 148 natural products were screened. Cryptotanshinone was identified as selective H4R antagonist, with an IC50 value of 11.68 ± 1.30 μM, which was verified with Fluorescence Imaging Plate Reader (FLIPR) and Cellular Thermal Shift (CTS) assays. The kinetic binding profile revealed the noncompetitive antagonistic property of cryptotanshinone. Two allosteric binding sites of H4R were predicted using SiteMap, Fpocket and CavityPlus. Subsequent molecular docking and dynamics simulation indicated that cryptotanshinone interacts with H4R at a pocket formed by the outward interfaces between TM3/4/5, potentially representing a new allosteric binding site for H4R. Overall, this study introduced cryptotanshinone as a novel H4R antagonist, offering promise as a new hit for drug design of H4R antagonist. Additionally, this study provided a novel screening model for the discovery of H4R antagonists.

Exposure to DEP Modifies the Human Umbilical Artery Vascular Resistance Contributing to Hypertension in Pregnancy.

Hypertensive disorders in pregnancy (HDP) are the most prevalent diseases during pregnancy. In addition to the already identified risk factors, exposure to environmental contaminants has been also considered a new one. Phthalates, which are classified as priority environmental pollutants due to their ubiquitousness and endocrine disrupting properties, have been implicated in HDP in some epidemiological studies. Nevertheless, phthalates' vascular impacts still need to be clarified. Thus, we aimed to understand the connection between phthalates exposure and the occurrence of gestational hypertension, as well as the pathway involved in the pathological vascular effects. We investigated diethyl phthalate's (DEP) effect on the vascular reactivity of the human umbilical arteries (HUAs) from normotensive and hypertensive pregnant women. Both DEP's nongenomic (within minutes effect) and genomic (24 h exposure to DEP) actions were evaluated, as well as the contribution of cyclic guanosine monophosphate and Ca2+ channel pathways. The results show that short-term exposure to DEP interferes with serotonin and histamine receptors, while after prolonged exposure, DEP seems to share the same vasorelaxant mechanism as estrogens, through the NO/sGC/cGMP/PKG signaling pathway, and to interfere with the L-type Ca2+ channels. Thus, the vascular effect induced by DEP is similar to that observed in HUA from hypertensive pregnancies, demonstrating that the development of HDP may be a consequence of DEP exposure.

Evaluation of Urtica dioica Phytochemicals against Therapeutic Targets of Allergic Rhinitis Using Computational Studies.

Allergic rhinitis (AR) is a prevalent inflammatory condition affecting millions globally, with current treatments often associated with significant side effects. To seek safer and more effective alternatives, natural sources like Urtica dioica (UD) are being explored. However, UD's mechanism of action remains unknown. Therefore, to elucidate it, we conducted an in silico evaluation of UD phytochemicals' effects on known therapeutic targets of allergic rhinitis: histamine receptor 1 (HR1), neurokinin 1 receptor (NK1R), cysteinyl leukotriene receptor 1 (CLR1), chemoattractant receptor-homologous molecule expressed on type 2 helper T cells (CRTH2), and bradykinin receptor type 2 (BK2R). The docking analysis identified amentoflavone, alpha-tocotrienol, neoxanthin, and isorhamnetin 3-O-rutinoside as possessing a high affinity for all the receptors. Subsequently, molecular dynamics (MD) simulations were used to analyze the key interactions; the free energy of binding was calculated through Generalized Born and Surface Area Solvation (MMGBSA), and the conformational changes were evaluated. Alpha-tocotrienol exhibited a high affinity while also inducing positive conformational changes across all targets. Amentoflavone primarily affected CRTH2, neoxanthin targeted NK1R, CRTH2, and BK2R, and isorhamnetin-3-O-rutinoside acted on NK1R. These findings suggest UD's potential to treat AR symptoms by inhibiting these targets. Notably, alpha-tocotrienol emerges as a promising multi-target inhibitor. Further in vivo and in vitro studies are needed for validation.

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model.

The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.

Gastritis and peptic ulcers are associated with the lower levels of plasma lipids: possible involvement of histamine

Background: Histamine receptors are involved to regulate lipid metabolism, so the hypothesis will arise that pathological states with abnormal histamine levels are associated with altered plasma lipids. Objectives: To study the profile of plasma lipids in patients with gastritis and peptic ulcer (GPU). Methods: In a case-control study, 70 dyspeptic patients were selected according to clinical criteria and using gastroduodenoscopy and compared with sex and age matched normal subjects. Results: There were no significant differences in age, sex, and the prevalence of hypertension and diabetes between two groups. But allergy, the familial history of allergy and dyspeptic and H. pylori infection were more prevalent in case group compared with controls. The levels of the indices of inflammation and body hydration were the same in two groups. Patients with dyspeptic compared with the controls had the lower concentrations of serum triglyceride (139.2±44.3 vs. 153.4±91.3), p≤0.553), total cholesterol (174.6±32.4 vs. 192.8±52.0, p≤0.073, LDLc (93.4±20.2 vs. 105.4±32.2, p≤0.015) and NonHDLc (130.2±38.1 vs. 159.2±42.2, p≤0.008). The level of HDL had not a significant change (43.4±7.8 vs. 43.5±12.7, p≤0.930). Dyspeptic state had negative significant correlation with total cholesterol, LDLc and NonHDLc but not HDLc. Neither the markers of inflammation nor the indices of body hydration had significant correlation with GPU. Conclusions: The GPU patients relative to normal group had the lower levels of serum lipids. The hypolipemic effects may be attributed to increased level of histamine in GPU patients.

Cimetidine Attenuates Therapeutic Effect of Anti-PD-1 and Anti-PD-L1 and Modulates Tumor Microenvironment in Colon Cancer.

Histamine modulates immunity by binding to histamine receptor 2 (H2R). Cimetidine, an H2R antagonist that inhibits gastric acid secretion and treats gastrointestinal ulcers, interferes with histamine-mediated immunomodulation and may have anticancer activity. This study examined cimetidine's effect on the anticancer effect of anti-PD-L1 in colon cancer. The MTT assay, colony formation assay, and DNA histograms assessed cell viability, clonogenicity, and cell cycle distribution, respectively. Flow cytometry measured H2R and PD-L1 expression and estimated specific immune cell lineages. For the in vivo study, tumor cells were subcutaneously implanted into the right flank of BALB/c mice. Cimetidine had no significant effect on CT26 cell viability, clonogenicity, or cell cycle distribution. It also did not affect H2R and PD-L1 expression levels in CT26 cells. In vivo, anti-PD-1 and anti-PD-L1 suppressed CT26 tumor growth, whereas cimetidine showed mild antitumor activity. In the combined experiment, cimetidine significantly attenuated anti-PD-1 and anti-PD-L1' antitumor effects without major toxicity. In the tumor microenvironment, anti-PD-L1 increased CD3+ T, CD4+ T, and CD8+ T cells and M1 macrophages. Combined treatment with cimetidine reversed this. Cimetidine also reversed anti-PD-1 and anti-PD-L1's decrease in circulating and tumor-associated neutrophils. Cimetidine attenuated anti-PD-L1's antitumor effect and modulated the tumor microenvironment in colon cancer.

A Comprehensive Review on Peptic Ulcer

Abstract: Up to 10% people in the world are affected by a chronic condition known as peptic ulcer. Peptic ulcer development is influenced by the pH of gastric juice and a decline in mucosal defenses. Protonpump inhibitors, histamine (H2) receptor antagonists, prostaglandin analogues and sucralfate have all been used to treat peptic ulcer disease. There has been a continuing search for an appropriate, palliative, and curative agent for the treatment of peptic ulcer disease using natural materials of plant and animal origin due to the complexity, cost, and toxicity of these medications. The goal of this review was to examine medicinal plants, phytochemicals, pathways, and research models that have been applied to the treatment of PUD in order to assess the potential contribution of natural substances to the development of herbal treatments for PUD. A literature search was used to find information utilising electronic databases such as Web of Science, Google Scholar, PubMed, Sci Finder, Reaxys, and Cochrane.

Novel Carbon Nanotubes/Gold Nanoparticles Modified Carbon Paste Electrochemical Sensor for Antazoline Determination in Aqueous Humor

Antazoline (ANT) is a H1 histamine receptor antagonist having anticholinergic properties used to decrease nasal congestion. It is found in eye drops usually in combination with either tetryzoline (TET) or xylometazoline (XLO). In this work, a novel electrochemical sensor based on carbon paste electrode (CPE) is developed for simple, rapid, sensitive, and selective determination of antazoline in pure form, different pharmaceutical formulations and in presence of aqueous humor. CPE is modified with nanoparticles multiwalled carbon nanotube (MWCNT) composite and further decorated with gold nanoparticles using amperometric electrodeposition technique to attain Au-NP@MWCNT/CPE for enhancing sensor sensitivity. Linearity is divided into two linear segments and found to be 2 × 10–7 − 2 × 10−6 (1st Linear segment) and 2 × 10–6 − 2 × 10−5 (2nd Linear segment) with limit of detection and quantification of 1.77 × 10−7 and 5.37 × 10−7, respectively. High sensitivity, selectivity, and reproducibility of the modified electrode towards determination of antazoline have promoted its applicability in different dosage forms and in rabbit aqueous humor. This method has noticeable potential applications in quality control, pharmacokinetic studies, and routine determination of antazoline drug in binary pharmaceutical formulations.

Stereo Selectivity of Histaminic Receptors Play an Important Role of Anti-histaminic Activity

The histamine is a natural compound derived from histidine and amino acid which act on different histaminic receptors (H1, H2, H3 and H4), each receptor combined with histamine and give the different actions especially H1 and H2 receptors. The action of each depends on the specificity of the receptors, e.g., the compounds which act on H1 receptor are similar to each other but different than the compounds which act on H2 receptor (due to the difference between two receptors from the area and stereo of the receptors).