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Gehlhaar P, Schaper-Gerhardt K, Gutzmer R, Hasler F, Röhn TA, Werfel T, Mommert S. Histamine and TH2 cytokines regulate the biosynthesis of cysteinyl-leukotrienes and expression of their receptors in human mast cells. Inflamm Res 2025; 74:32. [PMID: 39890627 PMCID: PMC11785601 DOI: 10.1007/s00011-024-01974-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/28/2024] [Accepted: 11/25/2024] [Indexed: 02/03/2025] Open
Abstract
INTRODUCTION In skin lesions of atopic dermatitis (AD), a chronic inflammatory skin disease, mast cells beyond other immune cells are present in increasing numbers. Upon activation, mast cells release a plethora of mediators, in particular histamine and leukotrienes, as well as chemokines and cytokines, which modulate the immune response of cells in their microenvironment and may influence mast cells in an autocrine loop. This study investigated the effects of histamine and TH2 cytokines on the biosynthesis of cysteinyl leukotrienes (CysLTs) as well as CysLT receptor expression on human mast cells from healthy volunteers and patients with AD. METHODS Human mast cells were generated from CD34+ progenitor cells from peripheral blood. The cultured mast cells were stimulated with IL-4, IL-13, histamine and different histamine receptor selective ligands. Expression of enzymes in the biosynthesis of leukotrienes and expression of CysLT receptors were quantified by real-time PCR. The release of CysLTs was measured by ELISA. RESULTS Mast cells from AD patients showed higher expression of 5-Lipoxygenase (5-LO) and 5-Lipoxygenase activating protein (FLAP) compared to mast cells from healthy volunteers at baseline and in presence of histamine and TH2 cytokines. Expression of leukotriene C4 synthase (LTC4S), the biosynthesis of CysLTs, and mRNA expression of both CysLT receptors were induced by histamine and TH2 cytokines in mast cells from healthy volunteers and AD patients. CONCLUSION We provide evidence that in an acute allergic situation histamine and TH2 cytokines may activate the biosynthesis of pro-allergic cysteinyl leukotrienes and up-regulation of CysLT receptor expression in human mast cells. This suggests a novel mechanism for sustaining mast cell activation through a possible autocrine signalling loop under these conditions.
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Affiliation(s)
- Patricia Gehlhaar
- Department of Dermatology and Allergy, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Katrin Schaper-Gerhardt
- Department of Dermatology and Allergy, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
- Department of Dermatology, Johannes Wesling Medical Center, Ruhr University Bochum, Minden, Germany
| | - Ralf Gutzmer
- Department of Dermatology and Allergy, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
- Department of Dermatology, Johannes Wesling Medical Center, Ruhr University Bochum, Minden, Germany
| | - Franziska Hasler
- Immunology Disease Area, Novartis BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Till A Röhn
- Immunology Disease Area, Novartis BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Thomas Werfel
- Department of Dermatology and Allergy, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Susanne Mommert
- Department of Dermatology and Allergy, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
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Polakovičová S, Líška J, Varga I, Gálfiová P. Morphology of the Human Pineal Gland Studied by Freeze-Fracturing in Scanning Electron Microscopy. Life (Basel) 2024; 14:1617. [PMID: 39768325 PMCID: PMC11678662 DOI: 10.3390/life14121617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/11/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
The human pineal gland is the largest producer of the hormone melatonin. Pineal acervuli (brain sand), calcified concretions in the pineal gland, have long been studied because of their association with ageing, melatonin production, and neurological disorders. The solid inorganic matter of the hydroxyapatite crystals often renders sample sectioning impossible, to the extent that the sections lose value. Technically, freeze-fracturing has revealed the detailed structure and cell relationships without tissue damage. In our electron microscopic study, samples of the human pineal gland were obtained during autopsy from 20 donors with mean age 69 years. Samples underwent freeze-fracturing and standard histological procedures, and were analysed by scanning electron microscopy (SEM) in high vacuum. Based on our results, freeze-fracturing enabled identification of a mulberry-like acervulus topography. The acervuli were situated in specific "nest-like" structures, which were surrounded by pinealocytes, interstitial cells, and nerve fibres. A fractured surface of the intrapineal acervuli exhibited a regular lamellar structure. Freeze-fracturing the pineal gland and imaging by SEM enabled complex structural analysis. This approach permits viewing the surface acervuli spherical and internal lamellar architecture. Our results confirmed that the parenchyma of this small but important gland contains two types of acervuli, depending on their size: non-aggregated and aggregated. We propose to include these forms of acervuli in the new edition of the Terminologica Histologica. In conclusion, pineal gland freeze-fracturing by SEM is suitable for complex structural analysis. Our description of our methods can be a guide for other scientists who want to study the pineal gland with electron microscopy methods.
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Affiliation(s)
| | | | - Ivan Varga
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University in Bratislava, Špitálska Street 24, 813 72 Bratislava, Slovakia
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Tiligada E, Stefanaki C, Ennis M, Neumann D. Opportunities and challenges in the therapeutic exploitation of histamine and histamine receptor pharmacology in inflammation-driven disorders. Pharmacol Ther 2024; 263:108722. [PMID: 39306197 DOI: 10.1016/j.pharmthera.2024.108722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/31/2024] [Accepted: 09/13/2024] [Indexed: 09/26/2024]
Abstract
Inflammation-driven diseases encompass a wide array of pathological conditions characterised by immune system dysregulation leading to tissue damage and dysfunction. Among the myriad of mediators involved in the regulation of inflammation, histamine has emerged as a key modulatory player. Histamine elicits its actions through four rhodopsin-like G-protein-coupled receptors (GPCRs), named chronologically in order of discovery as histamine H1, H2, H3 and H4 receptors (H1-4R). The relatively low affinity H1R and H2R play pivotal roles in mediating allergic inflammation and gastric acid secretion, respectively, whereas the high affinity H3R and H4R are primarily linked to neurotransmission and immunomodulation, respectively. Importantly, however, besides the H4R, both H1R and H2R are also crucial in driving immune responses, the H2R tending to promote yet ill-defined and unexploited suppressive, protective and/or resolving processes. The modulatory action of histamine via its receptors on inflammatory cells is described in detail. The potential therapeutic value of the most recently discovered H4R in inflammatory disorders is illustrated via a selection of preclinical models. The clinical trials with antagonists of this receptor are discussed and possible reasons for their lack of success described.
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Affiliation(s)
- Ekaterini Tiligada
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
| | - Charikleia Stefanaki
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; University Research Institute of Maternal and Child Health and Precision Medicine, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Madeleine Ennis
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Belfast, UK
| | - Detlef Neumann
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
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Pehar M, Hewitt M, Wagner A, Sandhu JK, Khalili A, Wang X, Cho JY, Sim VL, Kulka M. Histamine stimulates human microglia to alter cellular prion protein expression via the HRH2 histamine receptor. Sci Rep 2024; 14:25519. [PMID: 39462031 PMCID: PMC11513956 DOI: 10.1038/s41598-024-75982-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Although the cellular prion protein (PrPC) has been evolutionarily conserved, the role of this protein remains elusive. Recent evidence indicates that PrPC may be involved in neuroinflammation and the immune response in the brain, and its expression may be modified via various mechanisms. Histamine is a proinflammatory mediator and neurotransmitter that stimulates numerous cells via interactions with histamine receptors 1-4 (HRH1-4). Since microglia are the innate immune cells of the central nervous system, we hypothesized that histamine-induced stimulation regulates the expression of PrPC in human-derived microglia. The human microglial clone 3 (HMC3) cell line was treated with histamine, and intracellular calcium levels were measured via a calcium flux assay. Cytokine production was monitored by enzyme-linked immunosorbent assay (ELISA). Western blotting and quantitative reverse transcription-polymerase chain reaction were used to determine protein and gene expression of HRH1-4. Flow cytometry and western blotting were used to measure PrPC expression levels. Fluorescence microscopy was used to examine Iba-1 and PrPC localization. HMC3 cells stimulated by histamine exhibited increased intracellular calcium levels and increased release of IL-6 and IL-8, while also modifying PrPC localization. HMC3 stimulated with histamine for 6 and 24 hours exhibited increased surface PrPC expression. Specifically, we found that stimulation of the HRH2 receptor was responsible for changes in surface PrPC. Histamine-induced increases in surface PrPC were attenuated following inhibition of the HRH2 receptor via the HRH2 antagonist ranitidine. These changes were unique to HRH2 activation, as stimulation of HRH1, HRH3, or HRH4 did not alter surface PrPC. Prolonged stimulation of HMC3 decreased PrPC expression following 48 and 72 hours of histamine stimulation. HMC3 cells can be stimulated by histamine to undergo intracellular calcium influx. Surface expression levels of PrPC on HMC3 cells are altered by histamine exposure, primarily mediated by HRH2. While histamine exposure also increases release of IL-6 and IL-8 in these cells, this cytokine release is not fully dependent on PrPC levels, as IL-6 release is only partially reduced and IL-8 release is unchanged under the conditions of HRH2 blockade that prevent PrPC changes. Overall, this suggests that PrPC may play a role in modulating microglial responses.
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Affiliation(s)
- Marcus Pehar
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada
| | - Melissa Hewitt
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - Ashley Wagner
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
| | - Jagdeep K Sandhu
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - Aria Khalili
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Xinyu Wang
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Jae-Young Cho
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada
- Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada
| | - Valerie L Sim
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Marianna Kulka
- Quantum and Nanotechnologies Research Centre, National Research Council Canada, Edmonton, AB, Canada.
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
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Acharya S, Liao S, Jung WJ, Kang YS, Moghaddam VA, Feitosa MF, Wojczynski MK, Lin S, Anema JA, Schwander K, Connell JO, Province MA, Brent MR. A methodology for gene level omics-WAS integration identifies genes influencing traits associated with cardiovascular risks: the Long Life Family Study. Hum Genet 2024; 143:1241-1252. [PMID: 39276247 PMCID: PMC11485042 DOI: 10.1007/s00439-024-02701-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 08/15/2024] [Indexed: 09/16/2024]
Abstract
The Long Life Family Study (LLFS) enrolled 4953 participants in 539 pedigrees displaying exceptional longevity. To identify genetic mechanisms that affect cardiovascular risks in the LLFS population, we developed a multi-omics integration pipeline and applied it to 11 traits associated with cardiovascular risks. Using our pipeline, we aggregated gene-level statistics from rare-variant analysis, GWAS, and gene expression-trait association by Correlated Meta-Analysis (CMA). Across all traits, CMA identified 64 significant genes after Bonferroni correction (p ≤ 2.8 × 10-7), 29 of which replicated in the Framingham Heart Study (FHS) cohort. Notably, 20 of the 29 replicated genes do not have a previously known trait-associated variant in the GWAS Catalog within 50 kb. Thirteen modules in Protein-Protein Interaction (PPI) networks are significantly enriched in genes with low meta-analysis p-values for at least one trait, three of which are replicated in the FHS cohort. The functional annotation of genes in these modules showed a significant over-representation of trait-related biological processes including sterol transport, protein-lipid complex remodeling, and immune response regulation. Among major findings, our results suggest a role of triglyceride-associated and mast-cell functional genes FCER1A, MS4A2, GATA2, HDC, and HRH4 in atherosclerosis risks. Our findings also suggest that lower expression of ATG2A, a gene we found to be associated with BMI, may be both a cause and consequence of obesity. Finally, our results suggest that ENPP3 may play an intermediary role in triglyceride-induced inflammation. Our pipeline is freely available and implemented in the Nextflow workflow language, making it easily runnable on any compute platform ( https://nf-co.re/omicsgenetraitassociation ).
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Affiliation(s)
- Sandeep Acharya
- Division of Computational and Data Sciences, Washington University, St Louis, MO, USA
| | - Shu Liao
- Department of Computer Science and Engineering, Washington University, St Louis, MO, USA
| | - Wooseok J Jung
- Department of Computer Science and Engineering, Washington University, St Louis, MO, USA
| | - Yu S Kang
- Department of Computer Science and Engineering, Washington University, St Louis, MO, USA
| | - Vaha Akbary Moghaddam
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO, USA
| | - Mary F Feitosa
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO, USA
| | - Mary K Wojczynski
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO, USA
| | - Shiow Lin
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO, USA
| | - Jason A Anema
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO, USA
| | - Karen Schwander
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO, USA
| | - Jeff O Connell
- Department of Medicine, University of Maryland, Baltimore, MD, USA
| | - Michael A Province
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO, USA
| | - Michael R Brent
- Department of Computer Science and Engineering, Washington University, St Louis, MO, USA.
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Jin BH, Hong T, Yoo BW, Kim CO, Kim D, Kim YN, Park MS. Pharmacokinetics, pharmacodynamics, and safety of izuforant, an H4R inhibitor, in healthy subjects: A phase I single and multiple ascending dose study. Clin Transl Sci 2024; 17:e70032. [PMID: 39432406 PMCID: PMC11493102 DOI: 10.1111/cts.70032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 08/21/2024] [Accepted: 09/05/2024] [Indexed: 10/23/2024] Open
Abstract
Izuforant is a selective, and potent histamine H4 receptor (H4R) antagonist developed to treat atopic dermatitis (AD). There is an unmet medical need for therapeutic agents to control inflammation and pruritus. Izuforant is a strong candidate for this task based on the findings of non-clinical studies showing that inhibition of the histamine-mediated signaling pathway via H4R by izuforant results in decreased pruritus and inflammation. This study aimed to evaluate the clinical pharmacokinetic (PK) and pharmacodynamic (PD) profiles of izuforant. Dose-block-randomized, double-blind, placebo-controlled, single- and multiple ascending dose studies were conducted in 64 healthy volunteers. For the single ascending dose (SAD) study, 10-600 mg izuforant was administered to the designated groups. For the multiple ascending dose (MAD) study, 100-400 mg izuforant was administered to three groups. The clinical pharmacokinetic (PK) profile of izuforant was evaluated using plasma and urine concentrations. Blood sampling for the PD assay, which measured imetit-induced eosinophil shape changes (ESC), was also conducted. A one-compartment PK model described the distribution and elimination profiles of izuforant. An imetit-induced ESC inhibition test was established and validated for PD evaluation as a measure of the H4R antagonistic effect. ESC inhibition was observed even at doses as low as 10 mg; however, this inhibition became stronger and lasted longer as the dose increased. All izuforant doses were well tolerated, and no discontinuations due to adverse events (AE) or deaths were reported.
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Affiliation(s)
- Byung Hak Jin
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
- Department of Pharmaceutical Medicine and Regulatory Science, Colleges of Medicine and PharmacyYonsei UniversityIncheonSouth Korea
| | - Taegon Hong
- Clinical Trial CenterSeoul Bumin HospitalSeoulSouth Korea
| | - Byung Won Yoo
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
| | - Choon Ok Kim
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
| | - Dasohm Kim
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
- Department of Pharmaceutical Medicine and Regulatory Science, Colleges of Medicine and PharmacyYonsei UniversityIncheonSouth Korea
| | - Youn Nam Kim
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
| | - Min Soo Park
- Department of Clinical Pharmacology, Severance HospitalYonsei University College of MedicineSeoulSouth Korea
- Department of Pharmaceutical Medicine and Regulatory Science, Colleges of Medicine and PharmacyYonsei UniversityIncheonSouth Korea
- Department of PediatricsYonsei University College of MedicineSeoulSouth Korea
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Engevik KA, Hazzard A, Puckett B, Hoch KM, Haidacher SJ, Haag AM, Spinler JK, Versalovic J, Engevik MA, Horvath TD. Phylogenetically diverse bacterial species produce histamine. Syst Appl Microbiol 2024; 47:126539. [PMID: 39029335 DOI: 10.1016/j.syapm.2024.126539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 05/02/2024] [Accepted: 07/16/2024] [Indexed: 07/21/2024]
Abstract
Histamine is an important biogenic amine known to impact a variety of patho-physiological processes ranging from allergic reactions, gut-mediated anti-inflammatory responses, and neurotransmitter activity. Histamine is found both endogenously within specialized host cells and exogenously in microbes. Exogenous histamine is produced through the decarboxylation of the amino acid L-histidine by bacterial-derived histidine decarboxylase enzymes. To investigate how widespread histamine production is across bacterial species, we examined 102,018 annotated genomes in the Integrated Microbial Genomes Database and identified 3,679 bacterial genomes (3.6 %) which possess the enzymatic machinery to generate histamine. These bacteria belonged to 10 phyla: Bacillota, Bacteroidota, Actinomycetota, Pseudomonadota, Lentisphaerota, Fusobacteriota, Armatimonadota, Cyanobacteriota, Thermodesulfobacteriota, and Verrucomicrobiota. The majority of the identified bacteria were terrestrial or aquatic in origin, although several bacteria originated in the human gut microbiota. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics to confirm our genome discoveries correlated with L-histidine-to-histamine conversion in a chemically defined bacterial growth medium by a cohort of select environmental and human gut bacteria. We found that environmental microbes Vibrio harveyi, Pseudomonas fluorescens and Streptomyces griseus generated considerable levels of histamine (788 - 8,730 ng/mL). Interestingly, we found higher concentrations of histamine produced by gut-associated Fusobacterium varium, Clostridium perfringens, Limosilactobacillus reuteri and Morganella morganii (8,510--82,400 ng/mL). This work expands our knowledge of histamine production by diverse microbes.
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Affiliation(s)
- Kristen A Engevik
- Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Amber Hazzard
- Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, SC USA; Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Brenton Puckett
- Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, SC USA; Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Kathleen M Hoch
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Department of Pathology, Texas Children's Hospital, Houston, TX, USA
| | - Sigmund J Haidacher
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Department of Pathology, Texas Children's Hospital, Houston, TX, USA
| | - Anthony M Haag
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Department of Pathology, Texas Children's Hospital, Houston, TX, USA
| | - Jennifer K Spinler
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Department of Pathology, Texas Children's Hospital, Houston, TX, USA
| | - James Versalovic
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Department of Pathology, Texas Children's Hospital, Houston, TX, USA
| | - Melinda A Engevik
- Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, SC USA; Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Thomas D Horvath
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Department of Pathology, Texas Children's Hospital, Houston, TX, USA.
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Abbasifard M, Bagherzadeh K, Khorramdelazad H. The story of clobenpropit and CXCR4: can be an effective drug in cancer and autoimmune diseases? Front Pharmacol 2024; 15:1410104. [PMID: 39070795 PMCID: PMC11272485 DOI: 10.3389/fphar.2024.1410104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 06/25/2024] [Indexed: 07/30/2024] Open
Abstract
Clobenpropit is a histamine H3 receptor antagonist and has developed as a potential therapeutic drug due to its ability to inhibit CXCR4, a chemokine receptor involved in autoimmune diseases and cancer pathogenesis. The CXCL12/CXCR4 axis involves several biological phenomena, including cell proliferation, migration, angiogenesis, inflammation, and metastasis. Accordingly, inhibiting CXCR4 can have promising clinical outcomes in patients with malignancy or autoimmune disorders. Based on available knowledge, Clobenpropit can effectively regulate the release of monocyte-derived inflammatory cytokine in autoimmune diseases such as juvenile idiopathic arthritis (JIA), presenting a potential targeted target with possible advantages over current therapeutic approaches. This review summarizes the intricate interplay between Clobenpropit and CXCR4 and the molecular mechanisms underlying their interactions, comprehensively analyzing their impact on immune regulation. Furthermore, we discuss preclinical and clinical investigations highlighting the probable efficacy of Clobenpropit for managing autoimmune diseases and cancer. Through this study, we aim to clarify the immunomodulatory role of Clobenpropit and its advantages and disadvantages as a novel therapeutic opportunity.
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Affiliation(s)
- Mitra Abbasifard
- Department of Internal Medicine, School of Medicine, Ali-Ibn Abi-Talib Hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Kowsar Bagherzadeh
- Eye Research Center, The Five Senses Health Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Acharya S, Liao S, Jung WJ, Kang YS, Moghaddam VA, Feitosa M, Wojczynski M, Lin S, Anema JA, Schwander K, Connell JO, Province M, Brent MR. Multi-omics Integration Identifies Genes Influencing Traits Associated with Cardiovascular Risks: The Long Life Family Study. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.03.04.24303657. [PMID: 38496585 PMCID: PMC10942516 DOI: 10.1101/2024.03.04.24303657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
The Long Life Family Study (LLFS) enrolled 4,953 participants in 539 pedigrees displaying exceptional longevity. To identify genetic mechanisms that affect cardiovascular risks in the LLFS population, we developed a multi-omics integration pipeline and applied it to 11 traits associated with cardiovascular risks. Using our pipeline, we aggregated gene-level statistics from rare-variant analysis, GWAS, and gene expression-trait association by Correlated Meta-Analysis (CMA). Across all traits, CMA identified 64 significant genes after Bonferroni correction (p ≤ 2.8×10-7), 29 of which replicated in the Framingham Heart Study (FHS) cohort. Notably, 20 of the 29 replicated genes do not have a previously known trait-associated variant in the GWAS Catalog within 50 kb. Thirteen modules in Protein-Protein Interaction (PPI) networks are significantly enriched in genes with low meta-analysis p-values for at least one trait, three of which are replicated in the FHS cohort. The functional annotation of genes in these modules showed a significant over-representation of trait-related biological processes including sterol transport, protein-lipid complex remodeling, and immune response regulation. Among major findings, our results suggest a role of triglyceride-associated and mast-cell functional genes FCER1A, MS4A2, GATA2, HDC, and HRH4 in atherosclerosis risks. Our findings also suggest that lower expression of ATG2A, a gene we found to be associated with BMI, may be both a cause and consequence of obesity. Finally, our results suggest that ENPP3 may play an intermediary role in triglyceride-induced inflammation. Our pipeline is freely available and implemented in the Nextflow workflow language, making it easily runnable on any compute platform (https://nf-co.re/omicsgenetraitassociation).
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Affiliation(s)
- Sandeep Acharya
- Division of Computational and Data Sciences, Washington University, St Louis, MO
| | - Shu Liao
- Department of Computer Science and Engineering, Washington University, St Louis, MO
| | - Wooseok J Jung
- Department of Computer Science and Engineering, Washington University, St Louis, MO
| | - Yu S Kang
- Department of Computer Science and Engineering, Washington University, St Louis, MO
| | - Vaha A Moghaddam
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO
| | - Mary Feitosa
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO
| | - Mary Wojczynski
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO
| | - Shiow Lin
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO
| | - Jason A Anema
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO
| | - Karen Schwander
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO
| | - Jeff O Connell
- Department of Medicine, University of Maryland, Baltimore, MD
| | - Mike Province
- Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO
| | - Michael R Brent
- Department of Computer Science and Engineering, Washington University, St Louis, MO
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Fiorani M, Del Vecchio LE, Dargenio P, Kaitsas F, Rozera T, Porcari S, Gasbarrini A, Cammarota G, Ianiro G. Histamine-producing bacteria and their role in gastrointestinal disorders. Expert Rev Gastroenterol Hepatol 2023; 17:709-718. [PMID: 37394958 DOI: 10.1080/17474124.2023.2230865] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 06/22/2023] [Indexed: 07/04/2023]
Abstract
INTRODUCTION Gut microbiota produces thousands of metabolites, which have a huge impact on the host health. Specific microbial strains are able to synthesize histamine, a molecule with a crucial role in many physiologic and pathologic mechanisms of the host. This function is mediated by the histidine decarboxylase enzyme (HDC) that converts the amino acid histidine to histamine. AREAS COVERED This review summarizes the emerging data on histamine production by gut microbiota, and the effect of bacterial-derived histamine in different clinical contexts, including cancer, irritable bowel syndrome, and other gastrointestinal and extraintestinal pathologies. This review will also outline the impact of histamine on the immune system and the effect of probiotics that can secrete histamine. Search methodology: we searched the literature on PubMed up to February 2023. EXPERT OPINION The potential of modulating gut microbiota to influence histamine production is a promising area of research, and although our knowledge of histamine-secreting bacteria is still limited, recent advances are exploring their diagnostic and therapeutical potential. Diet, probiotics, and pharmacological treatments directed to the modulation of histamine-secreting bacteria may in the future potentially be employed in the prevention and management of several gastrointestinal and extraintestinal disorders.
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Affiliation(s)
- Marcello Fiorani
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Livio Enrico Del Vecchio
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Pasquale Dargenio
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesco Kaitsas
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Tommaso Rozera
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Serena Porcari
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Giovanni Cammarota
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Gianluca Ianiro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
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Olejarz-Maciej A, Mogilski S, Karcz T, Werner T, Kamińska K, Kupczyk J, Honkisz-Orzechowska E, Latacz G, Stark H, Kieć-Kononowicz K, Łażewska D. Trisubstituted 1,3,5-Triazines as Histamine H 4 Receptor Antagonists with Promising Activity In Vivo. Molecules 2023; 28:molecules28104199. [PMID: 37241939 DOI: 10.3390/molecules28104199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Pain is a very unpleasant experience that makes life extremely uncomfortable. The histamine H4 receptor (H4R) is a promising target for the treatment of inflammatory and immune diseases, as well as pain. H4R ligands have demonstrated analgesic effects in a variety of pain models, including inflammatory pain. Continuing the search for active H4R ligands among the alkyl derivatives of 1,3,5-triazine, we obtained 19 new compounds in two series: acyclic (I) and aliphatic (II). In vitro pharmacological evaluation showed their variable affinity for H4R. The majority of compounds showed a moderate affinity for this receptor (Ki > 100 nM), while all compounds tested in ß-arrestin and cAMP assays showed antagonistic activity. The most promising, compound 6, (4-(cyclopentylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine; Ki = 63 nM) was selected for further in vitro evaluation: blood-brain barrier permeability (PAMPA assay; Pe = 12.26 × 10-6 cm/s) and toxicity tests (HepG2 and SH-5YSY cells; no toxicity up to 50 µM). Next, compound 6 tested in vivo in a carrageenan-induced inflammatory pain model showed anti-inflammatory and analgesic effects (strongest at 50 mg/kg i.p.). Furthermore, in a histamine- and chloroquine-induced pruritus model, compound 6 at a dose of 25 mg/kg i.p. and 50 mg/kg i.p., respectively, reduced the number of scratch bouts. Thus, compound 6 is a promising ligand for further studies.
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Affiliation(s)
- Agnieszka Olejarz-Maciej
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Szczepan Mogilski
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Tadeusz Karcz
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Tobias Werner
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany
| | - Katarzyna Kamińska
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Jarosław Kupczyk
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Ewelina Honkisz-Orzechowska
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Gniewomir Latacz
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany
| | - Katarzyna Kieć-Kononowicz
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Dorota Łażewska
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
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12
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Facheris P, Jeffery J, Del Duca E, Guttman-Yassky E. The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment. Cell Mol Immunol 2023; 20:448-474. [PMID: 36928371 PMCID: PMC10203371 DOI: 10.1038/s41423-023-00992-4] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/21/2023] [Indexed: 03/18/2023] Open
Abstract
Atopic dermatitis (AD) is the most common inflammatory skin disease, and it is considered a complex and heterogeneous condition. Different phenotypes of AD, defined according to the patient age at onset, race, and ethnic background; disease duration; and other disease characteristics, have been recently described, underlying the need for a personalized treatment approach. Recent advancements in understanding AD pathogenesis resulted in a real translational revolution and led to the exponential expansion of the therapeutic pipeline. The study of biomarkers in clinical studies of emerging treatments is helping clarify the role of each cytokine and immune pathway in AD and will allow addressing the unique immune fingerprints of each AD subset. Personalized medicine will be the ultimate goal of this targeted translational research. In this review, we discuss the changes in the concepts of both the pathogenesis of and treatment approach to AD, highlight the scientific rationale behind each targeted treatment and report the most recent clinical efficacy data.
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Affiliation(s)
- Paola Facheris
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Humanitas Clinical and Research Center, Department of Dermatology, Rozzano, Milano, Italy
| | - Jane Jeffery
- Duke University School of Medicine, Durham, NC, USA
| | - Ester Del Duca
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Emma Guttman-Yassky
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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13
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Rische CH, Thames AN, Krier-Burris RA, O’Sullivan JA, Bochner BS, Scott EA. Drug delivery targets and strategies to address mast cell diseases. Expert Opin Drug Deliv 2023; 20:205-222. [PMID: 36629456 PMCID: PMC9928520 DOI: 10.1080/17425247.2023.2166926] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 11/10/2022] [Accepted: 01/06/2023] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Current and developing mast cell therapeutics are reliant on small molecule drugs and biologics, but few are truly selective for mast cells. Most have cellular and disease-specific limitations that require innovation to overcome longstanding challenges to selectively targeting and modulating mast cell behavior. This review is designed to serve as a frame of reference for new approaches that utilize nanotechnology or combine different drugs to increase mast cell selectivity and therapeutic efficacy. AREAS COVERED Mast cell diseases include allergy and related conditions as well as malignancies. Here, we discuss the targets of existing and developing therapies used to treat these disease pathologies, classifying them into cell surface, intracellular, and extracellular categories. For each target discussed, we discuss drugs that are either the current standard of care, under development, or have indications for potential use. Finally, we discuss how novel technologies and tools can be used to take existing therapeutics to a new level of selectivity and potency against mast cells. EXPERT OPINION There are many broadly and very few selectively targeted therapeutics for mast cells in allergy and malignant disease. Combining existing targeting strategies with technology like nanoparticles will provide novel platforms to treat mast cell disease more selectively.
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Affiliation(s)
- Clayton H. Rische
- Northwestern University McCormick School of Engineering, Department of Biomedical Engineering, Evanston, IL, USA
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
| | - Ariel N. Thames
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
- Northwestern University McCormick School of Engineering, Department of Chemical and Biological Engineering, Evanston, IL, USA
| | - Rebecca A. Krier-Burris
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
| | - Jeremy A. O’Sullivan
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
| | - Bruce S. Bochner
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
| | - Evan A. Scott
- Northwestern University McCormick School of Engineering, Department of Biomedical Engineering, Evanston, IL, USA
- Northwestern University Feinberg School of Medicine, Department of Microbiolgy-Immunology, Chicago, IL, USA
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14
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Buzoianu AD, Sharma A, Muresanu DF, Feng L, Huang H, Chen L, Tian ZR, Nozari A, Lafuente JV, Wiklund L, Sharma HS. Nanodelivery of Histamine H3/H4 Receptor Modulators BF-2649 and Clobenpropit with Antibodies to Amyloid Beta Peptide in Combination with Alpha Synuclein Reduces Brain Pathology in Parkinson's Disease. ADVANCES IN NEUROBIOLOGY 2023; 32:55-96. [PMID: 37480459 DOI: 10.1007/978-3-031-32997-5_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/24/2023]
Abstract
Parkinson's disease (PD) in military personnel engaged in combat operations is likely to develop in their later lives. In order to enhance the quality of lives of PD patients, exploration of novel therapy based on new research strategies is highly warranted. The hallmarks of PD include increased alpha synuclein (ASNC) and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) leading to brain pathology. In addition, there are evidences showing increased histaminergic nerve fibers in substantia niagra pars compacta (SNpc), striatum (STr), and caudate putamen (CP) associated with upregulation of histamine H3 receptors and downregulation of H4 receptors in human brain. Previous studies from our group showed that modulation of potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist induces neuroprotection in PD brain pathology. Recent studies show that PD also enhances amyloid beta peptide (AβP) depositions in brain. Keeping these views in consideration in this review, nanowired delivery of monoclonal antibodies to AβP together with ASNC and H3/H4 modulator drugs on PD brain pathology is discussed based on our own observations. Our investigation shows that TiO2 nanowired BF-2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of monoclonal antibodies (mAb) to AβP and ASNC induced superior neuroprotection in PD-induced brain pathology. These observations are the first to show the modulation of histaminergic receptors together with antibodies to AβP and ASNC induces superior neuroprotection in PD. These observations open new avenues for the development of novel drug therapies for clinical strategies in PD.
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Affiliation(s)
- Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania
- "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Lianyuan Feng
- Department of Neurology, Bethune International Peace Hospital, Zhongshan, Hebei Province, China
| | - Hongyun Huang
- Beijing Hongtianji Neuroscience Academy, Beijing, China
| | - Lin Chen
- Department of Neurosurgery, Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA
| | - Ala Nozari
- Anesthesiology & Intensive Care, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA
| | - José Vicente Lafuente
- LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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15
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Mochizuki H, Suyama S, Youm SY, Ho PS, Shimoi A. Characteristics of histamine H 4 receptor agonist-induced allergic conjunctivitis model in Guinea pigs. J Pharmacol Toxicol Methods 2023; 119:107203. [PMID: 35842185 DOI: 10.1016/j.vascn.2022.107203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 01/03/2023]
Abstract
Histamine is strongly associated with the onset of allergic conjunctivitis. The most recent cloned histamine H4 receptor antagonist is highly expected as a new therapeutic drug candidate. As a model for a therapeutic drug targeting the histamine H4 receptor, a mouse model in which conjunctivitis symptoms are induced by instilling 4-methylhistamine, a histamine H4 receptor agonist, has been reported. However, the affinity of the H4 receptor for histamine varies in species, and it is known that the histamine binding affinity for the guinea pig H4 receptor is closer to that for human receptor than mice receptor. In this paper, we investigated a possibility that a guinea pig model would become a drug efficacy evaluation model with higher evaluation accuracy than the mouse model. As a result, hyperemia was observed in the conjunctivae and iris of guinea pigs after instillation of 4-methylhistamine and specifically suppressed by the histamine H4 receptor antagonist. Unlikely to the previously reported mouse model, however, none of edema, increased vascular permeability or scratching behavior was observed, suggesting that there may be differences between mice and guinea pigs not only in the binding affinity of histamine to the H4 receptor but also in the biological reaction to 4-methylhistamine. Although the symptoms of allergic conjunctivitis do not appear comprehensively in the guinea pig model, results of this study indicated a possibility that this model can be used as a simple screening model in the early stages of drug development.
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Affiliation(s)
- Hidemi Mochizuki
- Ina Research Inc., 2148-188 Nishiminowa, Ina, Nagano 399-4501, Japan.
| | - Susumu Suyama
- Ina Research Inc., 2148-188 Nishiminowa, Ina, Nagano 399-4501, Japan.
| | - So-Young Youm
- JW Pharmaceutical Corporation, 2477, Nambusunhwan-ro, Seocho-gu, Seoul, 137-864, Republic of Korea.
| | - Pil-Su Ho
- JW Pharmaceutical Corporation, 2477, Nambusunhwan-ro, Seocho-gu, Seoul, 137-864, Republic of Korea.
| | - Akihito Shimoi
- Ina Research Inc., 2148-188 Nishiminowa, Ina, Nagano 399-4501, Japan.
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Poto R, Criscuolo G, Marone G, Brightling CE, Varricchi G. Human Lung Mast Cells: Therapeutic Implications in Asthma. Int J Mol Sci 2022; 23:14466. [PMID: 36430941 PMCID: PMC9693207 DOI: 10.3390/ijms232214466] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/15/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
Mast cells are strategically located in different compartments of the lung in asthmatic patients. These cells are widely recognized as central effectors and immunomodulators in different asthma phenotypes. Mast cell mediators activate a wide spectrum of cells of the innate and adaptive immune system during airway inflammation. Moreover, these cells modulate the activities of several structural cells (i.e., fibroblasts, airway smooth muscle cells, bronchial epithelial and goblet cells, and endothelial cells) in the human lung. These findings indicate that lung mast cells and their mediators significantly contribute to the immune induction of airway remodeling in severe asthma. Therapies targeting mast cell mediators and/or their receptors, including monoclonal antibodies targeting IgE, IL-4/IL-13, IL-5/IL-5Rα, IL-4Rα, TSLP, and IL-33, have been found safe and effective in the treatment of different phenotypes of asthma. Moreover, agonists of inhibitory receptors expressed by human mast cells (Siglec-8, Siglec-6) are under investigation for asthma treatment. Increasing evidence suggests that different approaches to depleting mast cells show promising results in severe asthma treatment. Novel treatments targeting mast cells can presumably change the course of the disease and induce drug-free remission in bronchial asthma. Here, we provide an overview of current and promising treatments for asthma that directly or indirectly target lung mast cells.
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Affiliation(s)
- Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
| | - Gjada Criscuolo
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO), Center of Excellence (CoE), 80131 Naples, Italy
- Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (CNR), 80131 Naples, Italy
| | - Chris E. Brightling
- Department of Respiratory Sciences, Leicester NIHR BRC, Institute for Lung Health, University of Leicester, Leicester LE1 7RH, UK
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO), Center of Excellence (CoE), 80131 Naples, Italy
- Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (CNR), 80131 Naples, Italy
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Bando K, Tanaka Y, Takahashi T, Sugawara S, Mizoguchi I, Endo Y. Histamine acts via H4-receptor stimulation to cause augmented inflammation when lipopolysaccharide is co-administered with a nitrogen-containing bisphosphonate. Inflamm Res 2022; 71:1603-1617. [DOI: 10.1007/s00011-022-01650-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 06/22/2022] [Accepted: 09/14/2022] [Indexed: 11/28/2022] Open
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18
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Antwi-Adjei M, Yeboah KO, Oppong-Kyekyeku J, Osafo N. Inflammation Modulating Activity of the Hydroethanol Stem Bark Extract of Bombax costatum in Murine Models. SCIENTIFICA 2022; 2022:6882147. [PMID: 36046123 PMCID: PMC9424023 DOI: 10.1155/2022/6882147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 06/29/2022] [Accepted: 07/26/2022] [Indexed: 06/15/2023]
Abstract
Bombax costatum (Bombacaceae) is traditionally used as a decoction of the leaves, stem, and root to treat headaches, fever, and oedema that may be associated with inflammatory conditions. Thus, the aim of this study was to evaluate the effect of 70%v/v ethanolic extract of the stem bark of Bombax costatum on acute and chronic inflammation. The effect of Bombax costatum extract (10, 50, 100 mg kg-1, p.o) was studied in prostaglandin E2-induced paw oedema in Sprague-Dawley rats (n = 5). Subsequently, the effect of the extract on clonidine and haloperidol-induced catalepsy was also investigated in ICR mice (n = 5). Finally, the ability of the extract to inhibit chronic inflammation was studied using a rat adjuvant-induced arthritis model. Pre-emptive and therapeutic administration of the extract at all doses significantly suppressed the formation of oedema following prostaglandin E 2 administration. As a measure of indirect antihistaminic effect, treatment with the extract suppressed clonidine-induced catalepsy but not haloperidol-induced catalepsy. Moreover, Bombax costatum extract significantly inhibited joint inflammation and damage following injection of complete Freund's adjuvant. Treatment with the extract also inhibited the onset of polyarthritis; thus, suppressing the systemic spread of joint inflammation from ipsilateral limbs to contralateral limbs. In conclusion, the hydroethanol extract of the stem bark of Bombax costatum inhibits both acute and chronic inflammation.
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Affiliation(s)
| | - Kofi Oduro Yeboah
- Department of Pharmacology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - James Oppong-Kyekyeku
- Department of Pharmaceutical Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Newman Osafo
- Department of Pharmacology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
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19
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Kraus FBT, Topalov NE, Deuster E, Hysenaj I, Mayr D, Chelariu-Raicu A, Beyer S, Kolben T, Burges A, Mahner S, Trillsch F, Jeschke U, Czogalla B. Expression pattern and prognostic potential of histamine receptors in epithelial ovarian cancer. J Cancer Res Clin Oncol 2022; 149:2501-2511. [PMID: 35751684 PMCID: PMC10129941 DOI: 10.1007/s00432-022-04114-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/06/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE Despite recent advances in the treatment of ovarian cancer (OC), long-term remissions remain scarce. For a targeted approach, prognostic markers are indispensable for predicting survival and treatment response. Given their association with multiple hallmarks of cancer, histamine receptors (HR) are emerging as promising candidates. Here, we investigate their expression pattern and prognostic value in OC. METHODS Specimens of 156 epithelial OC patients were collected during cytoreductive surgery at the Department of Obstetrics and Gynecology, LMU, between 1990 and 2002 and combined in a tissue microarray. Immunohistochemical staining of the HR H1, H2, H3 and H4 was quantified by an immunoreactive score and linked with clinico-pathological data by Spearman's correlation. Via ROC curve analysis, optimal cut-off values for potential prognostic markers were defined. Overall survival (OS) was visualized in Kaplan-Maier curves and significances determined by log-rank testing. A Cox regression model was applied for multivariate analysis. RESULTS HR H3 and H4 expression was restricted to the cytosol of OC cells, while H1 was also present in the nucleus. A significant association between HR H1, H3 and H4 expression with several clinico-pathological parameters was revealed. In addition, HR H1 and H3 expression correlated positively, HR H4 expression negatively with OS. In addition, HR H3 was identified as independent prognostic marker for OS. HR H2 expression had no prognostic value. CONCLUSIONS HR H1, H3 and H4 could serve as potential predictors for OS of OC patients. Further research is warranted to elucidate their pathophysiologic role and their predictive and therapeutic potential in OC.
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Affiliation(s)
- Fabian B T Kraus
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany.
| | - Nicole E Topalov
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - E Deuster
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - I Hysenaj
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - D Mayr
- Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - A Chelariu-Raicu
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - S Beyer
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - T Kolben
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - A Burges
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - S Mahner
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - F Trillsch
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
| | - U Jeschke
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany.,Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
| | - B Czogalla
- Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
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20
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Zhou B, Li J, Liu R, Zhu L, Peng C. The Role of Crosstalk of Immune Cells in Pathogenesis of Chronic Spontaneous Urticaria. Front Immunol 2022; 13:879754. [PMID: 35711438 PMCID: PMC9193815 DOI: 10.3389/fimmu.2022.879754] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/02/2022] [Indexed: 12/15/2022] Open
Abstract
Chronic spontaneous urticaria (CSU) is defined as recurrent episodes of spontaneous wheal development and/or angioedema for more than six weeks and at least twice a week. The core link in the pathogenesis of CSU is the activation of mast cells, T cells, eosinophils, and other immune cells infiltrating around the small venules of the lesion. Increased vascular permeability, vasodilatation, and recruitment of inflammatory cells directly depend on mast cell mediators’ release. Complex regulatory systems tightly influence the critical roles of mast cells in the local microenvironment. The bias toward Th2 inflammation and autoantibodies derived from B cells, histamine expressed by basophils, and initiation of the extrinsic coagulation pathway by eosinophils or monocytes exerts powerful modulatory influences on mast cells. Cell-to-cell interactions between mast cells and eosinophils/T cells also are regulators of their function and may involve CSU’s pathomechanism. This review summarizes up-to-date knowledge regarding the crosstalk between mast cells and other immune cells, providing the impetus to develop new research concepts and treatment strategies for CSU.
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Affiliation(s)
- Bingjing Zhou
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Runqiu Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lei Zhu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Cong Peng,
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21
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Li L, Liu R, Peng C, Chen X, Li J. Pharmacogenomics for the efficacy and side effects of antihistamines. Exp Dermatol 2022; 31:993-1004. [PMID: 35538735 DOI: 10.1111/exd.14602] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 05/01/2022] [Accepted: 05/09/2022] [Indexed: 11/27/2022]
Abstract
Antihistamines, especially H1 antihistamines, are widely used in the treatment of allergic diseases such as urticaria and allergic rhinitis, mainly for reversing elevated histamine and anti-allergic effects. Antihistamines are generally safe, but some patients experience adverse reactions, such as cardiotoxicity, central inhibition, and anticholinergic effects. There are also individual differences in antihistamine efficacy in clinical practice. The concept of individualized medicine has been deeply rooted in people's minds since it was put forward. Pharmacogenomics is the study of the role of inheritance in individual variations in drug response. In recent decades, pharmacogenomics has been developing rapidly, which provides new ideas for individualized medicine. Polymorphisms in the genes encoding metabolic enzymes, transporters, and target receptors have been shown to affect the efficacy of antihistamines. In addition, recent evidence suggests that gene polymorphisms influence urticaria susceptibility and antihistamine therapy. Here, we summarize current reports in this area, aiming to contribute to future research in antihistamines and clinical guidance for antihistamines use in individualized medicine.
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Affiliation(s)
- Liqiao Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Runqiu Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jie Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
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22
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Tavener SK, Jewell DE, Panickar KS. The Increase in Circulating Levels of Pro-Inflammatory Chemokines, Cytokines, and Complement C5 in Canines with Impaired Kidney Function. Curr Issues Mol Biol 2022; 44:1664-1676. [PMID: 35723372 PMCID: PMC9164022 DOI: 10.3390/cimb44040114] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic low-grade inflammation is a key contributor to the progression of kidney disease. The release of cytokines and other pro-inflammatory proteins may further contribute to detrimental kidney health by increasing interstitial edema and renal fibrosis. The aim of the present study was to investigate the inflammatory markers in canines who developed renal disease naturally and were diagnosed with renal disease either during life or following necropsy, as assessed by a veterinarian. RNA was isolated from canine blood obtained at necropsy and stored as bioarchived samples from ten canines with renal disease (9.6−14.7 yr) and ten controls (10.1−14.8 yr). At the time of death, the mean blood creatinine concentration and BUN were elevated in dogs with renal disease compared to control (both p < 0.01). Samples were assessed for changes in gene expression using the Canine cytokine RT2 Profiler PCR Array for inflammation. There was a significant increase in C-C Motif Chemokine Ligand 16 (CCL16), C-X-C Motif Chemokine Ligand 5 (CXCL5), Interleukin 16 (IL-16), and Complement Component 5 (C5) (all p < 0.05 vs. con). In addition, there was also a statistically non-significant increase in 49 genes and a down-regulation in 35 genes from a panel of total 84 genes. Pro-inflammatory genes including CCL16, CXCL5, IL-16, and C5 can all contribute to renal inflammation and fibrosis through different signaling pathways and may lead to a progressive impairment of kidney function. Blockade of their activation may be important in ameliorating the initiation and/or the progression of renal disease.
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Affiliation(s)
- Selena K. Tavener
- Science & Technology Center, Hill’s Pet Nutrition, Inc., Topeka, KS 66617, USA;
| | - Dennis E. Jewell
- Department of Grain Science & Industry, Kansas State University, Manhattan, KS 66506, USA;
| | - Kiran S. Panickar
- Science & Technology Center, Hill’s Pet Nutrition, Inc., Topeka, KS 66617, USA;
- Correspondence: ; Tel.: 1-(785)-286-8002
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23
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Antwi S, Oduro-Mensah D, Asiedu-Larbi J, Oduro-Mensah E, Quasie O, Lewis C, Darko-Obiri D, Ocloo A, Okine LK. Prophylactic or therapeutic administration of Holarrhena floribunda hydro ethanol extract suppresses complete Freund's adjuvant-induced arthritis in Sprague-Dawley rats. J Inflamm (Lond) 2022; 19:3. [PMID: 35248062 PMCID: PMC8897772 DOI: 10.1186/s12950-022-00301-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 01/31/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND A hydro ethanol extract of the stem bark of Holarrhena floribunda (HFE) has been shown to be effective in the management of acute inflammation. This study was to evaluate usefulness of the extract for the management of chronic inflammation in a murine model. METHODS Arthritis was induced in Sprague-Dawley rats using Complete Freund's Adjuvant. Anti-arthritic effect of the extract was evaluated in prophylactic and therapeutic treatment models at doses of 50, 200 and 500 mg/kg. Parameters assessed included oedema, serology of inflammatory response, bone tissue histology and haematology. Data were analysed by ANOVA and Tukey's multiple comparisons post hoc test. RESULTS HFE at 50-500 mg/kg dose-dependently [P ≥ 0.0354 (prophylactic) and P ≥ 0.0001 (therapeutic) inhibited swelling of the injected paw upon prophylactic [≤ 81.26% (P < 0.0001) or therapeutic [≤ 67.92% (P < 0.01) administration - and prevented spread of arthritis to the contralateral paw. The inflammation alleviation activity was further demonstrated by decrease in arthritis score, radiologic score and erythrocyte sedimentation rate. HFE at all doses significantly reduced serum interleukin (IL)-1α (P < 0.0197), and 500 mg/kg HFE reduced IL-6 (P = 0.0032). In contrast, serum concentrations of IL-10, protein kinase A and cyclic adenosine monophosphate were enhanced (P ≤ 0.0436). HFE consistently showed better prophylactic than therapeutic activity. CONCLUSION HFE strongly suppressed Complete Freund's Adjuvant-induced arthritis and modulated regulators of inflammation, including IL-1α, - 6 and - 10. Taken together, the data suggest that HFE has potential for use as an agent for modulation of the inflammatory response.
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Affiliation(s)
- Stephen Antwi
- Department of Pharmacology/Toxicology, Centre for Plant Medicine Research, P. O. Box 73, Mampong, Akuapem, Ghana
- Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Daniel Oduro-Mensah
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 54, Accra, Ghana.
- West African Centre for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana.
| | - Jerry Asiedu-Larbi
- Department of Pharmacology/Toxicology, Centre for Plant Medicine Research, P. O. Box 73, Mampong, Akuapem, Ghana
| | | | - Olga Quasie
- Department of Pharmacology/Toxicology, Centre for Plant Medicine Research, P. O. Box 73, Mampong, Akuapem, Ghana
| | - Clara Lewis
- Clinical Research Department, Centre for Plant Medicine Research, P. O. Box 73, Mampong, Akuapem, Ghana
| | - David Darko-Obiri
- Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Augustine Ocloo
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 54, Accra, Ghana
- West African Centre for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
| | - Laud Kenneth Okine
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 54, Accra, Ghana
- West African Centre for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana
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24
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Resolvin D2 and Resolvin D1 Differentially Activate Protein Kinases to Counter-Regulate Histamine-Induced [Ca2+]i Increase and Mucin Secretion in Conjunctival Goblet Cells. Int J Mol Sci 2021; 23:ijms23010141. [PMID: 35008563 PMCID: PMC8745650 DOI: 10.3390/ijms23010141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/02/2021] [Accepted: 12/17/2021] [Indexed: 11/20/2022] Open
Abstract
Resolvin (Rv) D2 and RvD1 are biosynthesized from docosahexaenoic acid (DHA) and promote resolution of inflammation in multiple organs and tissues, including the conjunctiva. Histamine is a mediator produced by mast cells in the conjunctiva during the allergic response. We determined the interaction of RvD2 with histamine and its receptor subtypes in cultured conjunctival goblet cells and compared them with RvD1 by measuring intracellular [Ca2+] and mucous secretion. Treatment with RvD2 significantly blocked the histamine-induced [Ca2+]i increase as well as secretion. RvD2 and RvD1 counter-regulate different histamine receptor subtypes. RvD2 inhibited the increase in [Ca2+]i induced by the activation of H1, H3, or H4 receptors, whereas RvD1 inhibited H1 and H3 receptors. RvD2 and RvD1 also activate distinct receptor-specific protein kinases to counter-regulate the histamine receptors, probably by phosphorylation. Thus, our data suggest that the counter-regulation of H receptor subtypes by RvD2 and RvD1 to inhibit mucin secretion are separately regulated.
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25
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Guo CJ, Grabinski NS, Liu Q. Peripheral Mechanisms of Itch. J Invest Dermatol 2021; 142:31-41. [PMID: 34838258 DOI: 10.1016/j.jid.2021.10.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 10/15/2021] [Accepted: 10/26/2021] [Indexed: 12/30/2022]
Abstract
Itch is a universally experienced sensation, and chronic itch can be as diabolically debilitating as pain. Recent advances have not only identified the neuronal itch sensing circuitry, but also have uncovered the intricate interactions between skin and immune cells that work together with neurons to identify itch-inducing irritants. In this review, we will summarize the fundamental mechanisms of acute itch detection in the skin, as well as highlight the recent discoveries relating to this topic.
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Affiliation(s)
- Changxiong J Guo
- Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Nathaniel S Grabinski
- Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Qin Liu
- Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
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26
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Verta R, Gurrieri M, Borga S, Benetti E, Pollicino P, Cavalli R, Thurmond RL, Chazot PL, Pini A, Rosa AC, Grange C. The Interplay between Histamine H 4 Receptor and the Kidney Function: The Lesson from H 4 Receptor Knockout Mice. Biomolecules 2021; 11:biom11101517. [PMID: 34680152 PMCID: PMC8533779 DOI: 10.3390/biom11101517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/30/2021] [Accepted: 10/13/2021] [Indexed: 01/15/2023] Open
Abstract
Previous studies implicated the histamine H4 receptor in renal pathophysiology. The aim here is to elucidate the role of this receptor on renal function using H4 receptor knockout mice (H4R-/-). Healthy and diabetic H4R-/- mice compared to their C57BL/6J wild-type counterpart for renal function and the expression of crucial tubular proteins. H4R-/- and wild-type mice, matched for ages, showed comparable weight gain curves reaching similar median weight at the end of the study. However, H4R-/- mice displayed a higher basal glycemia. H4R-/- mice showed a lower urine 24 h outflow, and albumin-to-creatinine ratio (ACR) compared to wild-type mice. Consistently, H4R-/- mice presented a higher expression of megalin and a lower basal expression of the sodium-hydrogen exchanger (NHE)3 and aquaporin (AQP)2. According to these basal differences, diabetic H4R-/- mice developed more severe hyperglycemia and a higher 24 h urine volume, but a lower increase in ACR and decrease in urine pH were observed. These events were paralleled by a reduced NHE3 over-expression and megalin loss in diabetic H4R-/- mice. The AQP1 and AQP7 patterns were also different between H4R-/- and wild-type diabetic mice. The collected results highlight the role of the histamine H4 receptor in the control of renal reabsorption processes, particularly albumin uptake.
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Affiliation(s)
- Roberta Verta
- Department of Biotechnology and Health Sciences, University of Turin, C.So Dogliotti 14, 10126 Turin, Italy;
| | - Maura Gurrieri
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
| | - Sara Borga
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
| | - Elisa Benetti
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
| | - Paolo Pollicino
- Direzione Ricerca e Terza Missione, University of Turin, Via Bogino 9 Torino, 10123 Turin, Italy;
| | - Roberta Cavalli
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
| | - Robin L. Thurmond
- Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA;
| | - Paul L. Chazot
- Department of Biosciences and Wolfson Research Institute, Durham University, South Road, Durham DH1 3LE, UK;
| | - Alessandro Pini
- Department of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy;
| | - Arianna Carolina Rosa
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (M.G.); (S.B.); (E.B.); (R.C.)
- Correspondence: ; Tel.: +39-011-6707955
| | - Cristina Grange
- Department of Medical Sciences, University of Turin, C.So Dogliotti 14, 10126 Turin, Italy;
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Mast Cells Modulate the Immune Response and Redox Status of the Gastrointestinal Tract in Induced Venom Pathogenesis. Inflammation 2021; 45:509-527. [PMID: 34608585 DOI: 10.1007/s10753-021-01562-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 09/06/2021] [Accepted: 09/07/2021] [Indexed: 10/20/2022]
Abstract
The pathogenesis of Androctonus autralis hector (Aah) scorpion venom involved cellular and molecular mechanisms resulting in multi-organ dysfunction. However, little is reported about the effects of venom on the gastrointestinal axis. Mast cells (MCs) are known to play a crucial role in modulating immune response of the gut. This study aims to investigate the involvement of this cell type in venom-induced gastric and intestinal disorders in a time course (3 and 24h). The obtained results revealed that Aah scorpion venom induced inflammatory cell infiltration as shown by the increase of the myeloperoxidase and eosinophil peroxidase activities. Overexpression of the c-kit receptor (CD117) severely imbalanced the redox status with depletion of antioxidant systemic accompanied by gastrointestinal tissue damage. Moreover, an increased level of lactate dehydrogenase in the serum was correlated with tissue injuries. Pharmacological inhibition of MCs targeting tyrosine kinase (TK) reduces the generation of reactive oxygen species and normalizes catalase, and gluthation S-transferase activities to their physiological levels. In addition, histopathological alterations were restored after pretreatment with c-kit receptor inhibitor associated with a considerable reduction of MC density. Interestingly, obtained results indicate that MCs might be involved in gastric modulation and intestinal inflammation through c-kit signaling following sub-cutaneous Aah venom injection.
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28
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Sarasola MDLP, Táquez Delgado MA, Nicoud MB, Medina VA. Histamine in cancer immunology and immunotherapy. Current status and new perspectives. Pharmacol Res Perspect 2021; 9:e00778. [PMID: 34609067 PMCID: PMC8491460 DOI: 10.1002/prp2.778] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/25/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer is the second leading cause of death globally and its incidence and mortality are rapidly increasing worldwide. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer. Immunotherapy comes to the forefront of cancer treatments, resulting in impressive and durable responses but only in a fraction of patients. Thus, understanding the characteristics and profiles of immune cells in the tumor microenvironment (TME) is a necessary step to move forward in the design of new immunomodulatory strategies that can boost the immune system to fight cancer. Histamine produces a complex and fine-tuned regulation of the phenotype and functions of the different immune cells, participating in multiple regulatory responses of the innate and adaptive immunity. Considering the important actions of histamine-producing immune cells in the TME, in this review we first address the most important immunomodulatory roles of histamine and histamine receptors in the context of cancer development and progression. In addition, this review highlights the current progress and foundational developments in the field of cancer immunotherapy in combination with histamine and pharmacological compounds targeting histamine receptors.
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Affiliation(s)
- María de la Paz Sarasola
- Laboratory of Tumor Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Mónica A Táquez Delgado
- Laboratory of Tumor Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Melisa B Nicoud
- Laboratory of Tumor Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Vanina A Medina
- Laboratory of Tumor Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
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29
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Höring C, Conrad M, Söldner CA, Wang J, Sticht H, Strasser A, Miao Y. Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations. Int J Mol Sci 2021; 22:10047. [PMID: 34576210 PMCID: PMC8467750 DOI: 10.3390/ijms221810047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/15/2021] [Accepted: 09/15/2021] [Indexed: 01/29/2023] Open
Abstract
G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H2 and H4 receptors (H2R and H4R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H2R and H4R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H2R and H4R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H2R and H4R from the mini-G protein recruitment assays using HEK293T cells. Compared to H2R-mGs expressing cells, histamine responses were weaker (pEC50, Emax) for H2R-mGsi and -mGsq. By contrast, the H4R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H2R to mGs and H4R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H2R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H4R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H2R function in the brain, as well as of the pharmacological potential of H4R selective drugs.
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Affiliation(s)
- Carina Höring
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany
| | - Marcus Conrad
- Bioinformatik, Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Fahrstraße 17, 91054 Erlangen, Germany
| | - Christian A Söldner
- Bioinformatik, Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Fahrstraße 17, 91054 Erlangen, Germany
| | - Jinan Wang
- Department of Computational Biology and Molecular Biosciences, University of Kansas, Lawrence, KS 66047, USA
| | - Heinrich Sticht
- Bioinformatik, Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Fahrstraße 17, 91054 Erlangen, Germany
- Erlangen National High Performance Computing Center (NHR@FAU), Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91058 Erlangen, Germany
| | - Andrea Strasser
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany
| | - Yinglong Miao
- Department of Computational Biology and Molecular Biosciences, University of Kansas, Lawrence, KS 66047, USA
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Shulpekova YO, Nechaev VM, Popova IR, Deeva TA, Kopylov AT, Malsagova KA, Kaysheva AL, Ivashkin VT. Food Intolerance: The Role of Histamine. Nutrients 2021; 13:3207. [PMID: 34579083 PMCID: PMC8469513 DOI: 10.3390/nu13093207] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 12/16/2022] Open
Abstract
Histamine is a natural amine derived from L-histidine. Although it seems that our knowledge about this molecule is wide and diverse, the importance of histamine in many regulatory processes is still enigmatic. The interplay between different types of histamine receptors and the compound may cause ample effects, including histamine intoxication and so-called histamine intolerance or non-allergic food intolerance, leading to disturbances in immune regulation, manifestation of gastroenterological symptoms, and neurological diseases. Most cases of clinical manifestations of histamine intolerance are non-specific due to tissue-specific distribution of different histamine receptors and the lack of reproducible and reliable diagnostic markers. The diagnosis of histamine intolerance is fraught with difficulties, in addition to challenges related to the selection of a proper treatment strategy, the regular course of recovery, and reduced amelioration of chronic symptoms due to inappropriate treatment prescription. Here, we reviewed a history of histamine uptake starting from the current knowledge about its degradation and the prevalence of histamine precursors in daily food, and continuing with the receptor interactions after entering and the impacts on the immune, central nervous, and gastrointestinal systems. The purpose of this review is to build an extraordinarily specific method of histamine cycle assessment in regard to non-allergic intolerance and its possible dire consequences that can be suffered.
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Affiliation(s)
- Yulia O. Shulpekova
- Department of Internal Diseases Propedeutics, Sechenov University, 119121 Moscow, Russia; (Y.O.S.); (V.M.N.); (I.R.P.); (V.T.I.)
| | - Vladimir M. Nechaev
- Department of Internal Diseases Propedeutics, Sechenov University, 119121 Moscow, Russia; (Y.O.S.); (V.M.N.); (I.R.P.); (V.T.I.)
| | - Irina R. Popova
- Department of Internal Diseases Propedeutics, Sechenov University, 119121 Moscow, Russia; (Y.O.S.); (V.M.N.); (I.R.P.); (V.T.I.)
| | - Tatiana A. Deeva
- Department of Biological Chemistry, Sechenov University, 119991 Moscow, Russia;
| | - Arthur T. Kopylov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 123098 Moscow, Russia; (A.T.K.); (A.L.K.)
| | - Kristina A. Malsagova
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 123098 Moscow, Russia; (A.T.K.); (A.L.K.)
| | - Anna L. Kaysheva
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 123098 Moscow, Russia; (A.T.K.); (A.L.K.)
| | - Vladimir T. Ivashkin
- Department of Internal Diseases Propedeutics, Sechenov University, 119121 Moscow, Russia; (Y.O.S.); (V.M.N.); (I.R.P.); (V.T.I.)
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Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets. Biomolecules 2021; 11:biom11081232. [PMID: 34439898 PMCID: PMC8392479 DOI: 10.3390/biom11081232] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 02/07/2023] Open
Abstract
High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy. However, due to the complexity of the pathophysiological roles of histamine and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into clinical settings.
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Ma X, Verweij EWE, Siderius M, Leurs R, Vischer HF. Identification of TSPAN4 as Novel Histamine H 4 Receptor Interactor. Biomolecules 2021; 11:1127. [PMID: 34439793 PMCID: PMC8394291 DOI: 10.3390/biom11081127] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 12/20/2022] Open
Abstract
The histamine H4 receptor (H4R) is a G protein-coupled receptor that is predominantly expressed on immune cells and considered to be an important drug target for various inflammatory disorders. Like most GPCRs, the H4R activates G proteins and recruits β-arrestins upon phosphorylation by GPCR kinases to induce cellular signaling in response to agonist stimulation. However, in the last decade, novel GPCR-interacting proteins have been identified that may regulate GPCR functioning. In this study, a split-ubiquitin membrane yeast two-hybrid assay was used to identify H4R interactors in a Jurkat T cell line cDNA library. Forty-three novel H4R interactors were identified, of which 17 have also been previously observed in MYTH screens to interact with other GPCR subtypes. The interaction of H4R with the tetraspanin TSPAN4 was confirmed in transfected cells using bioluminescence resonance energy transfer, bimolecular fluorescence complementation, and co-immunoprecipitation. Histamine stimulation reduced the interaction between H4R and TSPAN4, but TSPAN4 did not affect H4R-mediated G protein signaling. Nonetheless, the identification of novel GPCR interactors by MYTH is a starting point to further investigate the regulation of GPCR signaling.
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Affiliation(s)
| | | | | | | | - Henry F. Vischer
- Division of Medicinal Chemistry, Faculty of Science, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands; (X.M.); (E.W.E.V.); (M.S.); (R.L.)
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Hersey M, Hashemi P, Reagan LP. Integrating the monoamine and cytokine hypotheses of depression: Is histamine the missing link? Eur J Neurosci 2021; 55:2895-2911. [PMID: 34265868 DOI: 10.1111/ejn.15392] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 06/26/2021] [Accepted: 07/06/2021] [Indexed: 12/28/2022]
Abstract
Psychiatric diseases, like depression, largely affect the central nervous system (CNS). While the underlying neuropathology of depressive illness remains to be elucidated, several hypotheses have been proposed as molecular underpinnings for major depressive disorder, including the monoamine hypothesis and the cytokine hypothesis. The monoamine hypothesis has been largely supported by the pharmaceuticals that target monoamine neurotransmitters as a treatment for depression. However, these antidepressants have come under scrutiny due to their limited clinical efficacy, side effects, and delayed onset of action. The more recent, cytokine hypothesis of depression is supported by the ability of immune-active agents to induce "sickness behaviour" akin to that seen with depression. However, treatments that more selectively target inflammation have yielded inconsistent antidepressive results. As such, neither of these hypotheses can fully explain depressive illness pathology, implying that the underlying neuropathological mechanisms may encompass aspects of both theories. The goal of the current review is to integrate these two well-studied hypotheses and to propose a role for histamine as a potential unifying factor that links monoamines to cytokines. Additionally, we will focus on stress-induced depression, to provide an updated perspective of depressive illness research and thereby identify new potential targets for the treatment of major depressive disorder.
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Affiliation(s)
- Melinda Hersey
- Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, USA.,Department of Chemistry & Biochemistry, University of South Carolina, Columbia, South Carolina, USA
| | - Parastoo Hashemi
- Department of Chemistry & Biochemistry, University of South Carolina, Columbia, South Carolina, USA.,Department of Bioengineering, Imperial College, London, UK
| | - Lawrence P Reagan
- Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, USA.,WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA
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Carthy E, Ellender T. Histamine, Neuroinflammation and Neurodevelopment: A Review. Front Neurosci 2021; 15:680214. [PMID: 34335160 PMCID: PMC8317266 DOI: 10.3389/fnins.2021.680214] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/18/2021] [Indexed: 12/16/2022] Open
Abstract
The biogenic amine, histamine, has been shown to critically modulate inflammatory processes as well as the properties of neurons and synapses in the brain, and is also implicated in the emergence of neurodevelopmental disorders. Indeed, a reduction in the synthesis of this neuromodulator has been associated with the disorders Tourette's syndrome and obsessive-compulsive disorder, with evidence that this may be through the disruption of the corticostriatal circuitry during development. Furthermore, neuroinflammation has been associated with alterations in brain development, e.g., impacting synaptic plasticity and synaptogenesis, and there are suggestions that histamine deficiency may leave the developing brain more vulnerable to proinflammatory insults. While most studies have focused on neuronal sources of histamine it remains unclear to what extent other (non-neuronal) sources of histamine, e.g., from mast cells and other sources, can impact brain development. The few studies that have started exploring this in vitro, and more limited in vivo, would indicate that non-neuronal released histamine and other preformed mediators can influence microglial-mediated neuroinflammation which can impact brain development. In this Review we will summarize the state of the field with regard to non-neuronal sources of histamine and its impact on both neuroinflammation and brain development in key neural circuits that underpin neurodevelopmental disorders. We will also discuss whether histamine receptor modulators have been efficacious in the treatment of neurodevelopmental disorders in both preclinical and clinical studies. This could represent an important area of future research as early modulation of histamine from neuronal as well as non-neuronal sources may provide novel therapeutic targets in these disorders.
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Affiliation(s)
- Elliott Carthy
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Tommas Ellender
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
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Honda T, Nishio Y, Sakai H, Asagiri M, Yoshimura K, Inui M, Kuramasu A. Calcium/calmodulin-dependent regulation of Rac GTPases and Akt in histamine-induced chemotaxis of mast cells. Cell Signal 2021; 83:109973. [PMID: 33689810 DOI: 10.1016/j.cellsig.2021.109973] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 03/04/2021] [Accepted: 03/04/2021] [Indexed: 12/16/2022]
Abstract
Histamine induces chemotaxis of mast cells through the histamine H4 receptor. This involves the activation of small GTPases, Rac1 and Rac2, downstream of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Activation of the H4 receptor also results in phospholipase C (PLC)-mediated calcium mobilization; however, it is unclear whether the PLC‑calcium pathway interacts with the PI3K-Rac pathway. Here, we demonstrated that calcium mobilization regulates the PI3K-dependent activation of Rac GTPases through calmodulin. A PLC inhibitor (U73122) and an intracellular calcium chelator (BAPTA-AM) suppressed the histamine-induced activation of Rac, whereas the calcium ionophore ionomycin increased the active Rac GTPases, suggesting that intracellular calcium regulates the activation of Rac. The calmodulin antagonist (W-7) inhibited the histamine-induced activation of Rac and migration of mast cells, indicating that calmodulin mediates the effect of calcium. Inhibition of calcium/calmodulin signaling suppressed histamine-induced phosphorylation of Akt. The Akt inhibitor MK-2206 attenuated histamine-induced migration of mast cells. However, it did not suppress the activation of Rac GTPases. These results suggest that Rac GTPases and Akt play independent roles in the histamine-induced chemotaxis of mast cells. Our findings enable further elucidation of the molecular mechanism of histamine-induced chemotaxis of mast cells and help identify therapeutic targets for allergic and inflammatory conditions involving mast cell accumulation.
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Affiliation(s)
- Takeshi Honda
- Department of Pharmacology, Yamaguchi University Graduate School of Medicine, 1-1-1, Minamikogushi, Ube, Yamaguchi 755-8505, Japan
| | - Yusuke Nishio
- Department of Pharmacology, Yamaguchi University Graduate School of Medicine, 1-1-1, Minamikogushi, Ube, Yamaguchi 755-8505, Japan
| | - Hiroki Sakai
- Department of Pharmacology, Yamaguchi University Graduate School of Medicine, 1-1-1, Minamikogushi, Ube, Yamaguchi 755-8505, Japan
| | - Masataka Asagiri
- Department of Pharmacology, Yamaguchi University Graduate School of Medicine, 1-1-1, Minamikogushi, Ube, Yamaguchi 755-8505, Japan
| | - Kiyoshi Yoshimura
- Department of Clinical Immuno Oncology, Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, 6-11-11, Kitakarasuyama, Setagaya-ku, Tokyo 157-8577, Japan
| | - Makoto Inui
- Department of Pharmacology, Yamaguchi University Graduate School of Medicine, 1-1-1, Minamikogushi, Ube, Yamaguchi 755-8505, Japan
| | - Atsuo Kuramasu
- Department of Pharmacology, Yamaguchi University Graduate School of Medicine, 1-1-1, Minamikogushi, Ube, Yamaguchi 755-8505, Japan.
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The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut. Int J Mol Sci 2021; 22:ijms22116116. [PMID: 34204101 PMCID: PMC8200986 DOI: 10.3390/ijms22116116] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/31/2021] [Accepted: 06/03/2021] [Indexed: 02/07/2023] Open
Abstract
Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H1R) antagonists, which are used to control allergic inflammation, antagonists at H2R, which therapeutically decrease gastric acid release, and an antagonist at H3R, which is indicated to treat narcolepsy. Ligands at H4R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H4R ligands so far. Nevertheless, pre-clinically, H4R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H1R, H2R, and H3R do not provide an effect on inflammation, supporting the idea that H4R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H4R in inflammatory and inflammation-associated diseases of the gut.
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Samelisant (SUVN-G3031), a potent, selective and orally active histamine H3 receptor inverse agonist for the potential treatment of narcolepsy: pharmacological and neurochemical characterisation. Psychopharmacology (Berl) 2021; 238:1495-1511. [PMID: 33550481 DOI: 10.1007/s00213-021-05779-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
RATIONALE Samelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability. OBJECTIVES Pharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy. METHODS Samelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine. Sleep EEG studies were carried out in orexin knockout mice to study the effects of Samelisant (SUVN-G3031) on the sleep-wake cycle and cataplexy. RESULTS Samelisant (SUVN-G3031) has a similar binding affinity towards human (hH3R; Ki = 8.7 nM) and rat (rH3R; Ki = 9.8 nM) H3R indicating no inter-species differences. Samelisant (SUVN-G3031) displays inverse agonist activity and it exhibits very high selectivity towards H3R. Samelisant (SUVN-G3031) treatment in mice produced a dose-dependent increase in tele-methylhistamine levels indicating the activation of histaminergic neurotransmission. Apart from increasing the levels of histamine, Samelisant (SUVN-G3031) also modulates dopamine and norepinephrine levels in the cerebral cortex while it has no effects on dopamine levels in the striatum or nucleus accumbens. Treatment with Samelisant (SUVN-G3031; 10 and 30 mg/kg, p.o.) produced a significant increase in wakefulness with a concomitant decrease in NREM sleep in orexin knockout mice subjected to sleep EEG. Samelisant (SUVN-G3031) also produced a significant decrease in Direct REM sleep onset (DREM) episodes, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy. Modulation in cortical levels of histamine, norepinephrine and dopamine provides the neurochemical basis for wake-promoting and anticataplectic effects observed in orexin knockout mice. CONCLUSIONS Pre-clinical studies of Samelisant (SUVN-G3031) provide a strong support for utility in the treatment of sleep-related disorders related to EDS and is currently being evaluated in a phase 2 proof of concept study in the USA for the treatment of narcolepsy with and without cataplexy.
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Charitos IA, Castellaneta F, Santacroce L, Bottalico L. Historical Anecdotes and Breakthroughs of Histamine: From Discovery to Date. Endocr Metab Immune Disord Drug Targets 2021; 21:801-814. [PMID: 32727338 DOI: 10.2174/1871530320666200729150124] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/04/2020] [Accepted: 06/22/2020] [Indexed: 11/22/2022]
Abstract
AIM Investigating about the history of allergies and discovery of the histamine's role in the immune response through historical references, starting with ancient anecdotes, analysing the first immunization attempts on animals to understand its importance as the anaphylaxis mediator. Moreover, we shortly resume the most recent discoveries on mast cell role in allergic diseases throughout the latest updates on its antibody-independent receptors. METHODS Publications, including reviews, treatment guidelines, historical and medical books, on the topic of interest were found on Medline, PubMed, Web of Knowledge, Web of Science, Google Scholar, Elsevier's (EMBASE.comvarious internet museum archives. Texts from the National Library of Greece (Stavros Niarchos Foundation), from the School of Health Sciences of the National and Kapodistrian University of Athens (Greece). We selected key articles which could provide ahistorical and scientific insight into histamine molecule and its mechanism of action's discovery starting with Egyptian, Greek and Chinese antiquity to end with the more recent pharmacological and molecular discoveries. RESULTS Allergic diseases were described by medicine since ancient times, without exactly understanding the physio-pathologic mechanisms of immuno-mediated reactions and of their most important biochemical mediator, histamine. Researches on histamine and allergic mechanisms started at the beginning of the 20th century with the first experimental observations on animals of anaphylactic reactions. Histamine was then identified as their major mediator of many allergic diseases and anaphylaxis, but also of several physiologic body's functions, and its four receptors were characterized. Modern researches focus their attention on the fundamental role of the antibody-independent receptors of mast cells in allergic mechanisms, such as MRGPRX2, ADGRE2 and IL-33 receptor. CONCLUSION New research should investigate how to modulate immunity cells activity in order to better investigate possible multi-target therapies for host's benefits in preclinical and clinical studies on allergic diseases in which mast cells play a major role.
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Affiliation(s)
- Ioannis A Charitos
- CEDICLO - Interdepartmental Research Center for Pre-Latin, Latin and Oriental Rights and Culture Studies, University of Bari, Bari, Italy
| | | | - Luigi Santacroce
- CEDICLO - Interdepartmental Research Center for Pre-Latin, Latin and Oriental Rights and Culture Studies, University of Bari, Bari, Italy
| | - Lucrezia Bottalico
- CEDICLO - Interdepartmental Research Center for Pre-Latin, Latin and Oriental Rights and Culture Studies, University of Bari, Bari, Italy
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Sudarikova AV, Fomin MV, Yankelevich IA, Ilatovskaya DV. The implications of histamine metabolism and signaling in renal function. Physiol Rep 2021; 9:e14845. [PMID: 33932106 PMCID: PMC8087988 DOI: 10.14814/phy2.14845] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 03/31/2021] [Accepted: 03/31/2021] [Indexed: 01/18/2023] Open
Abstract
Inflammation is an essential part of the immune response; it has been found to be central to the disruption of kidney function in acute kidney injury, diabetic nephropathy, hypertension, and other renal conditions. One of the well‐known mediators of the inflammatory response is histamine. Histamine receptors are expressed throughout different tissues, including the kidney, and their inhibition has proven to be a viable strategy for the treatment of many inflammation‐associated diseases. Here, we provide an overview of the current knowledge regarding the role of histamine and its metabolism in the kidney. Establishing the importance of histamine signaling for kidney function will enable new approaches for the treatment of kidney diseases associated with inflammation.
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Affiliation(s)
| | - Mikhail V Fomin
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Irina A Yankelevich
- St. Petersburg State Chemical Pharmaceutical University, St. Petersburg, Russia.,Institute of Experimental Medicine, St. Petersburg, Russia
| | - Daria V Ilatovskaya
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
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40
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Duguay BA, Lu L, Arizmendi N, Unsworth LD, Kulka M. The Possible Uses and Challenges of Nanomaterials in Mast Cell Research. THE JOURNAL OF IMMUNOLOGY 2020; 204:2021-2032. [PMID: 32253270 DOI: 10.4049/jimmunol.1800658] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 12/19/2019] [Indexed: 11/19/2022]
Abstract
Mast cells are tissue-resident immune cells that are involved in inflammation and fibrosis but also serve beneficial roles, including tissue maintenance, angiogenesis, pathogen clearance, and immunoregulation. Their multifaceted response and the ability of their mediators to target multiple organs and tissues means that mast cells play important roles in numerous conditions, including asthma, atopic dermatitis, drug sensitivities, ischemic heart disease, Alzheimer disease, arthritis, irritable bowel syndrome, infections (parasites, bacteria and viruses), and cancer. As a result, mast cells have become an important target for drug discovery and diagnostic research. Recent work has focused on applying novel nanotechnologies to explore cell biology. In this brief review, we will highlight the use of nanomaterials to modify mast cell functions and will discuss the potential of these technologies as research tools for understanding mast cell biology.
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Affiliation(s)
- Brett A Duguay
- Nanotechnology Research Centre, National Research Council Canada, Edmonton, Alberta T6G 2M9, Canada
| | - Lei Lu
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan, People's Republic of China
| | - Narcy Arizmendi
- Nanotechnology Research Centre, National Research Council Canada, Edmonton, Alberta T6G 2M9, Canada
| | - Larry D Unsworth
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta T6G 1H9, Canada; and
| | - Marianna Kulka
- Nanotechnology Research Centre, National Research Council Canada, Edmonton, Alberta T6G 2M9, Canada.,Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
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Nicoud MB, Táquez Delgado MA, Sarasola MDLP, Vidal A, Speisky D, Cremaschi GA, Sterle HA, Medina VA. Impact of histamine H4 receptor deficiency on the modulation of T cells in a murine breast cancer model. Cancer Immunol Immunother 2020; 70:233-244. [PMID: 32700092 DOI: 10.1007/s00262-020-02672-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 07/11/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND The histamine H4 receptor (H4R) is preferentially expressed in immune cells and is a potential therapeutic target for inflammatory and autoimmune diseases. This study aimed at further exploring the role of H4R in the immunobiology of breast cancer. METHODS We used wild type (WT) and H4R deficient mice (KO) to evaluate whether H4R genotypes show a different distribution of T cell subsets in spleens, tumours and tumour draining lymph nodes (TDLN) in a syngeneic ErbB2-positive breast cancer model developed orthotopically with LM3 cells and its impact on tumour growth. RESULTS The presence of tumours had a differential impact on the distribution of T cells in TDLN from KO mice compared to WT ones. At day 21 post-inoculation (p.i.) of cells, despite no significant changes in the tumour weight, TDLN from KO mice showed a significantly increased proportion of CD8+ T cells compared to WT mice. At day 38 p.i. of cells a reduced tumour weight was evident in KO mice. This was accompanied by a decreased proportion of CD4+CD25+FoxP3+ regulatory T cells in TDLN of KO compared to WT mice. Tumour-bearing KO mice showed a better survival compared to WT mice. CONCLUSIONS H4R-mediated mechanisms may modulate the immune tumour microenvironment, promoting an immunosuppressive milieu. Results suggest that H4R could be explored as an immunotherapeutic target with potential benefit in combination with immunotherapy. Further preclinical and clinical studies are necessary to confirm this hypothesis.
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Affiliation(s)
- Melisa B Nicoud
- Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Mónica A Táquez Delgado
- Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - María de la Paz Sarasola
- Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Agustina Vidal
- Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Daniela Speisky
- Pathology Department, British Hospital, Buenos Aires, Argentina
| | - Graciela A Cremaschi
- Neuroimmunomodulation and Molecular Oncology Division, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Helena A Sterle
- Neuroimmunomodulation and Molecular Oncology Division, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Vanina A Medina
- Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.
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Schirmer B, Lindemann L, Bittkau KS, Isaev R, Bösche D, Juchem M, Seifert R, Neumann D. Mouse Colonic Epithelial Cells Functionally Express the Histamine H 4 Receptor. J Pharmacol Exp Ther 2020; 373:167-174. [PMID: 32029576 DOI: 10.1124/jpet.119.264408] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 02/03/2020] [Indexed: 12/19/2022] Open
Abstract
We hypothesized that, in mice, histamine via the histamine receptor subtype 4 (H4R) on colon epithelial cells affects epithelial barrier integrity, perturbing physiologic function of the colonic mucosa and thus aggravating the severity of colitis. To test this hypothesis, bone marrow-chimeric mice were generated from H4R knockout (H4R-/-) and wild-type (WT) BALB/cJ mice and subjected to the dextrane sodium sulfate (DSS)-induced acute colitis model. Clinical symptoms and pathohistological derangements were scored. Additionally, total RNA was extracted from either mouse whole-colon homogenates or primary cell preparations enriched for epithelial cells, and gene expression was analyzed by real-time quantitative polymerase chain reaction. The impact of the H4R on epithelial barrier function was assessed by measurement of transepithelial electrical resistence of organoid-derived two-dimensional monolayers from H4R-/- and WT mice using chopstick electrodes. Bone marrow-chimeric mice with genetic depletion of the H4R in nonhematopoietic cells exhibited less severe DSS-induced acute colitis symptoms compared with WT mice, indicating a functional proinflammatory expression of H4R in nonimmune cells of the colon. Analysis of H4R expression revealed the presence of H4R mRNA in colon epithelial cells. This expression could be confirmed and complemented by functional analyses in organoid-derived epithelial cell monolayers. Thus, we conclude that the H4R is functionally expressed in mouse colon epithelial cells, potentially modulating mucosal barrier integrity and intestinal inflammatory reactions, as was demonstrated in the DSS-induced colitis model, in which presence of the H4R on nonhematopoietic cells aggravated the inflammatory phenotype. SIGNIFICANCE STATEMENT: The histamine H4 receptor (H4R) is functionally expressed on mouse colon epithelial cells, thereby aggravating dextrane sodium sulfate-induced colitis in BALB/cJ mice. Histamine via the H4R reduces transepithelial electrical resistance of colon epithelial monolayers, indicating a function of H4R in regulation of epithelial barrier integrity.
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Affiliation(s)
- Bastian Schirmer
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
| | - Luisa Lindemann
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
| | | | - Rukijat Isaev
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
| | - Daniela Bösche
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
| | - Malte Juchem
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
| | - Roland Seifert
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
| | - Detlef Neumann
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
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Schirmer B, Rother T, Bruesch I, Bleich A, Werlein C, Jonigk D, Seifert R, Neumann D. Genetic Deficiency of the Histamine H 4-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice. Cancers (Basel) 2020; 12:cancers12040912. [PMID: 32276475 PMCID: PMC7226035 DOI: 10.3390/cancers12040912] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/05/2020] [Accepted: 04/06/2020] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC), a severe complication of inflammatory bowel diseases, is a common type of cancer and accounts for high mortality. CRC can be modeled in mice by application of the tumor promoter, azoxymethane (AOM), in combination with dextran sodium sulfate (DSS), which are able to induce colitis-like manifestations. Active colitis correlates with high mucosal concentrations of histamine, which, together with the histamine receptor subtype 4 (H4R), provide a pro-inflammatory function in a mouse colitis model. Here, we analyzed whether H4R is involved in the pathogenesis of AOM/DSS-induced CRC in mice. As compared to wild type (WT) mice, AOM/DSS-treated mice lacking H4R expression (TM) demonstrate ameliorated signs of CRC, i.e., significantly reduced loss of body weight, stiffer stool consistency, and less severe perianal bleeding. Importantly, numbers and diameters of tumors and the degree of colonic inflammation are dramatically reduced in TM mice as compared to WT mice. This is concomitant with a reduced colonic inflammatory response involving expression of cyclooxygenase 2 and the production of C-X-C motif chemokine ligand 1 (CXCL1) and CXCL2. We conclude that H4R is involved in the tumorigenesis of chemically-induced CRC in mice via cyclooxygenase 2 expression and, probably, CXCL1 and CXCL2 as effector molecules.
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Affiliation(s)
- Bastian Schirmer
- Institute of Pharmacology, Hannover Medical School, 30625 Hannover, Germany
| | - Tamina Rother
- Institute of Pharmacology, Hannover Medical School, 30625 Hannover, Germany
- Institute of Pathology and German Center of Lung Research (DZL), Partner site BREATH, Hannover Medical School, 30625 Hannover, Germany
| | - Inga Bruesch
- Institute of Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany
| | - Andre Bleich
- Institute of Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany
| | - Christopher Werlein
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Danny Jonigk
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Roland Seifert
- Institute of Pharmacology, Hannover Medical School, 30625 Hannover, Germany
| | - Detlef Neumann
- Institute of Pharmacology, Hannover Medical School, 30625 Hannover, Germany
- Correspondence: ; Tel.: +49-511-532-4082
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Alterations in histamine responses between juvenile and adult urinary bladder urothelium, lamina propria and detrusor tissues. Sci Rep 2020; 10:4116. [PMID: 32139747 PMCID: PMC7057986 DOI: 10.1038/s41598-020-60967-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/20/2020] [Indexed: 01/09/2023] Open
Abstract
Inflammatory mediators may have a role in various lower urinary tract disorders. Histamine is known to induce significant increases in both the tension and frequency of spontaneous phasic contractions in both urothelium with lamina propria (U&LP) and detrusor muscle via the activation of H1 receptor in juvenile animal models. However, it is unclear whether age affects these contractile responses to histamine. This study assessed the histamine receptor subtypes mediating contraction in juvenile and adult porcine bladders and compared the urothelium with lamina propria and detrusor responses to histamine. Isolated tissue bath studies were conducted using strips of porcine U&LP and detrusor obtained from juvenile (6 months) and adult (3 years) animals exposed to histamine receptor agonists and antagonists. Treatment with histamine (100 µM) in U&LP of juvenile animals caused increases in baseline tension by 47.84 ± 6.52 mN/g (p < 0.001, n = 51) and by 50.76 ± 4.10 mN/g (p < 0.001, n = 55) in adult animals. Furthermore, the frequency of spontaneous phasic contractions was significantly enhanced in response to histamine in U&LP of both juvenile and adult tissues (p < 0.001 for both age groups). Treatment with an H2 agonist in U&LP of juvenile animals decreased baseline tension by 13.97 ± 3.45 mN/g (n = 12, p < 0.05), but had no effect in adult animals. Inhibition of H1 receptors resulted in significantly reduced contractile responses of U&LP and detrusor to histamine in both juvenile and adult animals (p < 0.05). Treatment with an H2 receptor antagonist significantly enhanced contractions in juvenile preparations (n = 10, p < 0.05) but had no effect in adult preparations (n = 8). In detrusor, treatment with histamine (100 µM) in juvenile tissues showed a significantly higher increase in baseline tension of 19.10 ± 4.92 mN/g (n = 51) when compared to adult tissues exhibiting increases of 8.21 ± 0.89 mN/g (n = 56, p < 0.05). The increases in the baseline tension were significantly inhibited by the presence of H1 receptor antagonists in both juvenile and adult detrusor preparations. Treatment with either the H2 receptor antagonist or agonist in detrusor had no effect on both juvenile and adult tissues. Therefore, the histamine receptor system may play an essential role in the maintenance of bladder function or in bladder dysfunction observed in some lower urinary tract disorders.
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Pal S, Gasheva OY, Zawieja DC, Meininger CJ, Gashev AA. Histamine-mediated autocrine signaling in mesenteric perilymphatic mast cells. Am J Physiol Regul Integr Comp Physiol 2020; 318:R590-R604. [PMID: 31913658 PMCID: PMC7099465 DOI: 10.1152/ajpregu.00255.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 12/29/2019] [Accepted: 12/31/2019] [Indexed: 12/25/2022]
Abstract
Lymphatic vessels play a critical role in mounting a proper immune response by trafficking peripheral immune cells to draining lymph nodes. Mast cells (MCs) are well known for their roles in type I hypersensitivity reactions, but little is known about their secretory regulation in the lymphatic niche. MCs, as innate sensor and effector cells, reside close to mesenteric lymphatic vessels (MLVs), and their activation and ability to release histamine influences the lymphatic microenvironment in a histamine-NF-κB-dependent manner. Using an established experimental protocol involving surgical isolation of rat mesenteric tissue segments, including MLVs and surrounding perilymphatic tissues, we tested the hypothesis that perilymphatic mesenteric MCs possess histamine receptors (HRs) that bind and respond to the histamine released from these same MCs. Under various experimental conditions, including inflammatory stimulation by LPS, we measured histamine in mesenteric perilymphatic tissues, evaluated expression of histidine decarboxylase in MCs along with the degree of MC degranulation, assessed the functional status of HRs in MCs, and evaluated the ability of histamine itself to induce MC activation. Finally, we evaluated the importance of MCs and HR1 and -2 for MLV-directed trafficking of CD11b/c-positive cells during acute tissue inflammation. Our data indicate the existence of a functionally potent MC-histamine autocrine regulatory loop, the elements of which are crucially important for acute inflammation-induced trafficking of the CD11b/c-positive cells toward MLVs. This MC-histamine loop serves as a first-line cellular servo control system, playing a key role in the innate and adaptive immune response as well as NF-κB-mediated maintenance of body homeostasis.
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Affiliation(s)
- Sarit Pal
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas
| | - Olga Y Gasheva
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas
| | - David C Zawieja
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas
| | - Cynthia J Meininger
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas
| | - Anatoliy A Gashev
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas
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Abstract
Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein-coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting β 2-agonists are widely used bronchodilators that signal through the activation of the β 2-adrenergic receptor. Short-acting and long-acting antagonists of muscarinic acetylcholine receptors are used to reduce bronchoconstriction by blocking the action of acetylcholine. Leukotriene antagonists that block the signaling of cysteinyl leukotriene receptor 1 are used as an add-on therapy to reduce bronchoconstriction and inflammation induced by cysteinyl leukotrienes. A number of GPCR-targeting asthma drug candidates are also in different stages of development. Among them, antagonists of prostaglandin D2 receptor 2 have advanced into phase III clinical trials. Others, including antagonists of the adenosine A2B receptor and the histamine H4 receptor, are in early stages of clinical investigation. In the past decade, significant research advancements in pharmacology, cell biology, structural biology, and molecular physiology have greatly deepened our understanding of the therapeutic roles of GPCRs in asthma and drug action on these GPCRs. This review summarizes our current understanding of GPCR signaling and pharmacology in the context of asthma treatment. SIGNIFICANCE STATEMENT: Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein-coupled receptors (GPCRs) in asthma therapy, and discusses controversies regarding the use of GPCR drugs and new opportunities in developing GPCR-targeting therapeutics for the treatment of asthma.
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Affiliation(s)
- Stacy Gelhaus Wendell
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)
| | - Hao Fan
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)
| | - Cheng Zhang
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (S.G.W., C.Z.); Bioinformatics Institute, Agency for Science, Technology, and Research, Singapore (H.F.); and Department of Biological Sciences, National University of Singapore, and Center for Computational Biology, DUKE-NUS Medical School, Singapore (H.F.)
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Sanna MD, Borgonetti V, Masini E, Galeotti N. Histamine H 4 receptor stimulation in the locus coeruleus attenuates neuropathic pain by promoting the coeruleospinal noradrenergic inhibitory pathway. Eur J Pharmacol 2019; 868:172859. [PMID: 31843515 DOI: 10.1016/j.ejphar.2019.172859] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/18/2019] [Accepted: 12/10/2019] [Indexed: 11/24/2022]
Abstract
The locus coeruleus (LC) adrenergic nuclei constitute a pain-control inhibitory system nucleus implicated in descending modulation of pain through the action on spinal α2-adrenoceptors. Histaminergic innervation from the tuberomammillary nucleus of the LC increases firing of noradrenergic neurons and might contribute to pain control. Here we evaluated the contribution of LC histaminergic innervation in descending modulation of neuropathic hypersensitivity, by investigating the role of the histamine H4 receptor subtype in a mouse model of neuropathic pain. Intra LC administration of the H4 agonist VUF 8430 attenuated mechanical and thermal allodynia of mice that underwent spared nerve injury (SNI). Similarly, histamine in the LC showed mechanical and thermal anti-hypersensitivity. Pretreatment of LC with JNJ 10191584 (H4 antagonist) prevented the beneficial effect of VUF 8430 and histamine on nociceptive behaviour. Comparable results were obtained after intrathecal administration of drugs. The intrathecal administration of the α2-adrenoceptor agonist clonidine ameliorated mechanical and thermal allodynia in SNI mice. The clonidine-induced anti-hypersensitivity effect was prevented by intra LC pretreatment with JNJ 10191584. In addition, clonidine failed to suppress neuropathic pain in H4 deficient mice. LC H4 receptors showed a ubiquitous distribution within LC, a neuronal localization and H4 immunostaining was detected on noradrenergic neurons expressing phosphorylated cAMP response element-binding protein (CREB), a marker of neuronal activation. Under pain pathological conditions H4 stimulation might promote the activation of the coeruleospinal noradrenergic neurons that exert an inhibitory control over spinal dorsal horn neuronal excitability. Thus, histamine H4 receptor stimulation may represent a perspective for neuropathic pain management.
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Affiliation(s)
- Maria Domenica Sanna
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, University of Florence, 50139, Florence, Italy
| | - Vittoria Borgonetti
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, University of Florence, 50139, Florence, Italy
| | - Emanuela Masini
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, University of Florence, 50139, Florence, Italy
| | - Nicoletta Galeotti
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, Viale G. Pieraccini 6, University of Florence, 50139, Florence, Italy.
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Zhao YX, Pan JB, Wang YN, Zou Y, Guo L, Tang QQ, Qian SW. Stimulation of histamine H4 receptor participates in cold-induced browning of subcutaneous white adipose tissue. Am J Physiol Endocrinol Metab 2019; 317:E1158-E1171. [PMID: 31550180 DOI: 10.1152/ajpendo.00131.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Although many studies have shown that histamine and its signaling regulate energy homeostasis through the central nervous system, their roles in adipose tissues remain poorly understood. Here, we identified that the histamine H4 receptor (HrH4) was highly expressed in adipocytes at a level higher than that of the other three receptors (i.e., HrH1, HrH2, and HrH3). The HrH4 expression in adipocytes responded to cold through thermogenesis and lipolysis, supported by results from both mouse and cell models. When HrH4 expression was knocked down in the subcutaneous white adipose tissue (scWAT), browning and lipolysis effects triggered by cold were ablated, and the oxygen consumption was also lowered both at the normal and cold conditions. Moreover, mice exhibited browned scWAT, accelerated metabolic rates, and tolerance to hypothermia when 4-methylhistamine (4MH), a selective HrH4 agonist, was adjacently injected to the scWAT. Consistent with these findings, 4MH also triggered the browning and lipolytic effects in cultured C3H10T1/2 adipocytes. Mechanically, we demonstrated that p38/MAPK and ERK/MAPK pathways were involved in these processes. In conclusion, our findings have uncovered an effective role of HrH4 in adipose tissue browning.
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Affiliation(s)
- Ya-Xin Zhao
- Institute of Stem Cell Research and Regenerative Medicine of Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jia-Bao Pan
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi-Na Wang
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Zou
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liang Guo
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qi-Qun Tang
- Institute of Stem Cell Research and Regenerative Medicine of Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shu-Wen Qian
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
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Mast Cell Degranulation Decreases Lipopolysaccharide-Induced Aortic Gene Expression and Systemic Levels of Interleukin-6 In Vivo. Mediators Inflamm 2019; 2019:3856360. [PMID: 31780858 PMCID: PMC6855011 DOI: 10.1155/2019/3856360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 07/30/2019] [Accepted: 08/31/2019] [Indexed: 11/18/2022] Open
Abstract
Mast cells play an important role in immunomodulation and in the maintenance of vascular integrity. Interleukin-6 (IL-6) is one of the key biomarkers and therapeutic target in systemic vasculitis. The objective of the current study is to describe the role of mast cells in arterial IL-6 homeostasis. Eight- to ten-week-old male C57BL/6 (wild-type) mice were injected with either (a) saline, (b) compound 48/80 (a systemic mast cell degranulating agent), (c) lipopolysaccharide (LPS), or (d) a combination of C48/80 and LPS. Twenty-four hours after the injections, mice were sacrificed and serum samples and aortic tissues were analyzed for determining inflammatory response and cytokine expression profile. The results revealed that induction of mast cell degranulation significantly lowers serum IL-6 levels and aortic expression of IL-6 in LPS-treated mice. Significantly higher aortic expression of toll-like receptor-2 (TLR-2) and TNF-α was seen in the LPS and LPS+C48/80 groups of mice compared to controls. Aortic expression of TLR-4 was significantly decreased in LPS+C48/80 compared to C48/80 alone. LPS+C48/80-treated mice presented with a 3-fold higher aortic expression of suppressor of cytokine signaling (SOCS-1) compared to saline-injected groups. The inhibition of LPS-induced increase in serum IL-6 levels by mast cell degranulation was not seen in H1R knockout mice which suggests that mast cell-derived histamine acting through H1R may participate in the regulatory process. To examine whether the mast cell-mediated downregulation of LPS-induced IL-6 production is transient or cumulative in nature, wild-type mice were injected serially over a period of 10 days (5 injections) and serum cytokine levels were quantified. We found no significant differences in serum IL-6 levels between any of the groups. While mice injected with C48/80 or LPS had higher IL-10 compared to vehicle-injected mice, there was no difference between C48/80- and LPS+C48/80-injected mice. In conclusion, in an in vivo setting, mast cells appear to partially and transiently regulate systemic IL-6 homeostasis. This effect may be regulated through increased systemic IL-10 and/or aortic overexpression of SOCS-1.
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Nicoud MB, Sterle HA, Massari NA, Táquez Delgado MA, Formoso K, Herrero Ducloux MV, Martinel Lamas D, Cremaschi GA, Medina VA. Study of the antitumour effects and the modulation of immune response by histamine in breast cancer. Br J Cancer 2019; 122:348-360. [PMID: 31748740 PMCID: PMC7000401 DOI: 10.1038/s41416-019-0636-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/24/2019] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The aim of this work was to improve the knowledge of the role of histamine in breast cancer by assessing the therapeutic efficacy of histamine and histamine H4 receptor (H4R) ligands in a triple-negative breast cancer (TNBC) model developed in immunocompetent hosts. By using publicly available genomic data, we further investigated whether histidine decarboxylase (HDC) could be a potential biomarker. METHODS Tumours of 4T1 TNBC cells were orthotopically established in BALB/c mice. Treatments employed (mg kg-1): histamine (1 and 5), JNJ28610244 (H4R agonist, 1 and 5) and JNJ7777120 (H4R antagonist, 10). RESULTS Increased HDC gene expression is associated with better relapse-free and overall survival in breast cancer patients. Histamine treatment (5 mg kg-1) of 4T1 tumour-bearing mice reduced tumour growth and increased apoptosis. Although no immunomodulatory effects were observed in wild-type mice, significant correlations between tumour weight and cytotoxic lymphocyte infiltration were detected in H4R knockout mice. H4R agonist or antagonist differentially modulated tumour growth and immunity in 4T1 tumour-bearing mice. CONCLUSIONS Histamine plays a complex role and stands out as a promising drug for TNBC treatment, which deserves to be tested in clinical settings. HDC expression level is associated with clinicopathological characteristics, suggesting a prognostic value in breast cancer.
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Affiliation(s)
- Melisa B Nicoud
- Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.,Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
| | - Helena A Sterle
- Neuroimmunomodulation and Molecular Oncology Division, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Noelia A Massari
- Immunology Department, School of Natural Sciences, National University of Patagonia San Juan Bosco, Chubut, Argentina
| | - Mónica A Táquez Delgado
- Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Karina Formoso
- Pharmacology and Function of Ionic Channels Laboratory, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - María V Herrero Ducloux
- Pathology Department, School of Natural Sciences, National University of Patagonia San Juan Bosco, Chubut, Argentina
| | - Diego Martinel Lamas
- Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Graciela A Cremaschi
- Neuroimmunomodulation and Molecular Oncology Division, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Vanina A Medina
- Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina. .,Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
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