-
Frontiers in Bioscience (Scholar... Jun 2015Breast cancer is the second most common cancer worldwide, and the leading cause of cancer death in women. Several studies underlined the critical role of histamine in... (Review)
Review
Breast cancer is the second most common cancer worldwide, and the leading cause of cancer death in women. Several studies underlined the critical role of histamine in breast cancer development and progression. This review addresses the latest evidence regarding the involvement of histamine and histamine receptors in breast cancer, focusing particularly in the histamine H4 receptor (H4R). Histamine concentration in breast cancer tissues was found to be higher than that in normal tissues of healthy controls by means of an increase in the activity of histidine decarboxylase (HDC), the enzyme involved in histamine production. The expression of H4R in different experimental models and human biopsies, the associated biological responses, as well as the in vivo treatment of experimental tumors with H4R ligands is reviewed. Evidence demonstrates that the H4R exhibits a key role in histamine-mediated biological processes such as cell proliferation, senescence and apoptosis in breast cancer. The polymorphisms of the H4R and HDC genes and their association with breast cancer risk and malignancy reinforce the critical (patho)physiological role of H4R in breast cancer. In addition, H4R agonists display anti-tumor effects in vivo in a triple negative breast cancer model. The findings support the exploitation of the H4R as a molecular target for breast cancer drug development.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Female; Heterografts; Histamine; Histamine Antagonists; Humans; Ligands; Molecular Targeted Therapy; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4
PubMed: 25961682
DOI: 10.2741/S420 -
American Journal of Alzheimer's Disease... Jun 2013Alzheimer's disease (AD) is a neurodegenerative disorder characterized by beta-amyloid plaques accumulation and cognitive impairment. Both environmental factors and... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by beta-amyloid plaques accumulation and cognitive impairment. Both environmental factors and heritable predisposition have a role in AD. Histamine is a biogenic monoamine that plays a role in several physiological functions, including induction of inflammatory reactions, wound healing, and regeneration. The Histamine mediates its functions via its 4 G-protein-coupled Histamine H1 receptor (H1R) to histamine H1 receptor (H4R). The histaminergic system has a role in the treatment of brain disorders by the development of histamine receptor agonists, antagonists. The H1R and H4R are responsible for allergic inflammation. But recent studies show that histamine antagonists against H3R and regulation of H2R can be more efficient in AD therapy. In this review, we focus on the role of histamine and its receptors in the treatment of AD, and we hope that histamine could be an effective therapeutic factor in the treatment of AD.
Topics: Alzheimer Disease; Histamine; Histamine Antagonists; Humans; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Receptors, Histamine H4
PubMed: 23677734
DOI: 10.1177/1533317513488925 -
British Journal of Pharmacology Feb 2020Histamine has been one of the most studied substances in medicine, playing a major role in diverse (patho)physiological processes. It elicits its multifaceted modulatory... (Review)
Review
Histamine has been one of the most studied substances in medicine, playing a major role in diverse (patho)physiological processes. It elicits its multifaceted modulatory functions by activating four types of GPCRs, designated as H . Despite the heterogeneity and the complexity of histamine receptor pharmacology, many discoveries over the past 100 years resulted in the development of H antihistamines and H -targeting 'blockbuster' therapeutics for the management of allergies and gastrointestinal disorders respectively. Recently, a first-in-class H inverse agonist was approved for the treatment of narcolepsy, whereas H antagonists are under clinical evaluation for their potential therapeutic exploitation in immune-related diseases. This review critically presents the past successes and drawbacks in histamine research, complemented by the modern conceptual innovations in molecular and receptor pharmacology. It targets both young and experienced researchers in an ongoing effort to stimulate novel insights for the dissection of the translational potential of histamine pharmacology. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.
Topics: Histamine; Histamine Antagonists; Receptors, Histamine
PubMed: 30341770
DOI: 10.1111/bph.14524 -
Frontiers in Bioscience (Landmark... Jun 2012The histamine H4 receptor (H4R) is the youngest member of the histamine receptor family. Based on its predominant expression pattern in hematopoietic cells, the H4R is... (Review)
Review
The histamine H4 receptor (H4R) is the youngest member of the histamine receptor family. Based on its predominant expression pattern in hematopoietic cells, the H4R is considered to be an interesting drug target for inflammatory disorders such as allergy and asthma. Since the identification and cloning of the H4R in 2000, drug discovery programs boosted the development of various H4R (specific) ligands. Differences between H4R orthologs in combination with available three-dimensional G protein-coupled receptor (GPCR) models have guided site-directed mutagenesis studies to gain insight in ligand binding and receptor activation. In addition, ongoing characterization of H4R-mediated signaling in transfected and native cells contributes to further unravel the (patho-) physiological functions of H4Rs.
Topics: Amino Acid Sequence; Animals; Binding Sites; Gene Expression Profiling; Histamine Agonists; Histamine Antagonists; Humans; Ligands; Molecular Sequence Data; Phylogeny; Protein Processing, Post-Translational; Protein Structure, Secondary; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Signal Transduction
PubMed: 22652766
DOI: 10.2741/4039 -
Current Allergy and Asthma Reports Apr 2011Histamine and the histamine receptors are important regulators of a plethora of biological processes, including immediate hypersensitivity reactions and acid secretion... (Review)
Review
Histamine and the histamine receptors are important regulators of a plethora of biological processes, including immediate hypersensitivity reactions and acid secretion in the stomach. In these roles, antihistamines have found widespread therapeutic applications, while the last receptor to be discovered, the H4 histamine receptor, has become a major target of novel therapeutics. Recent studies involving human genetic variance and the development of mice lacking specific receptors or the ability to generate histamine have shown roles for the histamine pathway that extend well beyond the established roles. These include identification of previously unappreciated mechanisms through which histamine regulates inflammation in allergy, as well as roles in autoimmunity, infection, and pain. As a result, antihistamines may have wider applications in the future than previously predicted.
Topics: Animals; Genetic Variation; Histamine; Histamine Antagonists; Humans; Hypersensitivity; Inflammation; Mice; Receptors, Histamine
PubMed: 21104347
DOI: 10.1007/s11882-010-0163-6 -
British Journal of Pharmacology May 2009The elucidation of the human genome has had a major impact on histamine receptor research. The identification of the human H4 receptor by several groups has been... (Review)
Review
The elucidation of the human genome has had a major impact on histamine receptor research. The identification of the human H4 receptor by several groups has been instrumental for a new appreciation of the role of histamine in the modulation of immune function. In this review, we summarize the historical developments and the molecular and biochemical pharmacology of the H4 receptor.
Topics: Animals; Binding Sites; Humans; Ligands; Models, Molecular; Phylogeny; Protein Conformation; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Species Specificity
PubMed: 19413568
DOI: 10.1111/j.1476-5381.2009.00250.x -
Biomolecules Aug 2021High 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,... (Review)
Review
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.
Topics: Animals; Disease Progression; Histamine; Humans; Immune System; Ligands; Mast Cells; Neoplasms; Prognosis; Receptors, Histamine; Receptors, Histamine H3; Receptors, Histamine H4; Signal Transduction; T-Lymphocytes; Tumor Microenvironment
PubMed: 34439898
DOI: 10.3390/biom11081232 -
Journal of Cellular and Molecular... Nov 2020Despite the success of immunotherapy in several haematological neoplasms, the effectiveness in acute myeloid leukaemia (AML) is still controversial, partially due to the...
Despite the success of immunotherapy in several haematological neoplasms, the effectiveness in acute myeloid leukaemia (AML) is still controversial, partially due to the lack of knowledge regarding immune-related processes in this disease and similar neoplasias. In this study, we analysed the role and expression of histamine receptor 1 (HRH1) in haematological malignancies. Although the histamine receptor type 1 was widely expressed in healthy and malignant haematopoiesis, especially along the myeloid lineage, HRH1 lacked a relevant role in survival/proliferation and chemoresistance of AML cells, as analysed by HRH1 knockdown (KD) and pharmacological modulation. However, HRH1-mediated signalling was critical for the activation of the differentiation process induced by several agents including all-trans retinoic acid, establishing a role for HRH1 in myeloid differentiation. Pharmacological activation of Erk was able to partially restore differentiation capacity in HRH1 KD AML cells, suggesting that HRH1 signalling acts upstream MAPK-Erk pathway. As an indirect consequence of our results, treatment-related histamine release is not expected to confer a proliferative advantage in leukaemic cells.
Topics: Biomarkers; Cell Differentiation; Cell Line, Tumor; Gene Expression Regulation, Leukemic; Hematopoiesis; Humans; Immunohistochemistry; Immunophenotyping; Leukemia, Myeloid, Acute; Receptors, Histamine H1
PubMed: 33080103
DOI: 10.1111/jcmm.15930 -
American Journal of Physiology.... Jan 2019Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can...
Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apc mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1-receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2-receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. NEW & NOTEWORTHY Histamine-producing Lactobacillus reuteri can suppress development of inflammation-associated colon cancer in an established mouse model. The net effects of histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal inflammation and colorectal neoplasia could be developed.
Topics: Animals; Carcinogenesis; Colon; Disease Models, Animal; Gastrointestinal Microbiome; Histamine; Histamine H1 Antagonists; Inflammation; Intestinal Mucosa; Lipopolysaccharides; Mice, Transgenic; Receptors, Histamine H1; Receptors, Histamine H2; Signal Transduction
PubMed: 30462522
DOI: 10.1152/ajpgi.00212.2018 -
Viruses Apr 2023Although Kaposi's sarcoma-associated herpesvirus (KSHV) has been reported to cause several human cancers including Kaposi's sarcoma (KS) and primary effusion lymphoma...
Although Kaposi's sarcoma-associated herpesvirus (KSHV) has been reported to cause several human cancers including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), the mechanisms of KSHV-induced tumorigenesis, especially virus-host interaction network, are still not completely understood, which therefore hinders the development of effective therapies. Histamine, together with its receptors, plays an important role in various allergic diseases by regulating different inflammation and immune responses. Our previous data showed that antagonists targeting histamine receptors effectively repressed KSHV lytic replication. In the current study, we determined that histamine treatment increased cell proliferation and anchorage-independent growth abilities of KSHV-infected cells. Furthermore, histamine treatment affected the expression of some inflammatory factors from KSHV-infected cells. For clinical relevance, several histamine receptors were highly expressed in AIDS-KS tissues when compared to normal skin tissues. We determined that histamine treatment promoted KSHV-infected lymphoma progression in immunocompromised mice models. Therefore, besides viral replication, our data indicate that the histamine and related signaling are also involved in other functions of KSHV pathogenesis and oncogenesis.
Topics: Humans; Animals; Mice; Herpesvirus 8, Human; Histamine; Sarcoma, Kaposi; Receptors, Histamine; Carcinogenesis; Cell Transformation, Neoplastic
PubMed: 37112991
DOI: 10.3390/v15041011