Histamine receptors

G-protein-coupled receptors (GPCRs) transmit downstream signals predominantly via G-protein pathways. However, the conformational basis of selective coupling of primary G-protein remains elusive. Histamine receptors H2 R and H3 R couple with Gs - or Gi -proteins respectively. Here, three cryo-EM structures of H2 R-Gs and H3 R-Gi complexes are presented at a global resolution of 2.6-2.7 Å. These structures reveal the unique binding pose for endogenous histamine in H3 R, wherein the amino group interacts with E2065...

INTRODUCTION: Pharmacological stress ulcer prophylaxis (SUP) has been recommended for many years to reduce the risk of clinically significant upper gastrointestinal (GI) bleeding caused by stress ulcers (SUs). Stress-related ulcer bleeding in surgical patients significantly increases morbidity and mortality. Therefore, preventing stress-induced hemorrhage is the most appropriate measure for patients who are at increased risk. However, the inappropriate use of SUP has increased in recent years, and its use in Ethiopian surgical patients has not been well studied...

Histamine 4 receptor (H4R), the most recently identified subtype of histamine receptor, primarily induces inflammatory reactions upon activation. Several H4R antagonists have been developed for the treatment of inflammatory bowel disease (IBD) and atopic dermatitis (AD), but their use has been limited by adverse side effects, such as a short half-life and toxicity. Natural products, as an important source of anti-inflammatory agents, offer minimal side effects and reduced toxicity. This work aimed to identify novel H4R antagonists from natural products...

OBJECTIVES: Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. METHODS: TRAF5 expression was detected in mouse carotid arteries subjected to wire injury...

Mast cells have long been recognized for their involvement in allergic pathology through the immunoglobulin E (IgE)-mediated degranulation mechanism. However, there is growing evidence of other "non-canonical" degranulation mechanisms activated by certain pathogen recognition receptors. Mast cells release several mediators, including histamine, cytokines, chemokines, prostaglandins, and leukotrienes, to initiate and enhance inflammation. The chemical nature of activating stimuli influences receptors, triggering mechanisms for the secretion of formed and new synthesized mediators...

The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM)...

Background: Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive...

Intestinal barrier dysfunction, leaky gut, is implicated in various diseases, including irritable bowel syndrome (IBS) and neurodegenerative conditions like Alzheimer's disease. Our recent investigation revealed that basal forebrain cholinergic neurons (BFCNs), critical for cognitive function, receive signals from butyrate and orexin, playing a role in regulating intestinal barrier function through adenosine A2B signaling and the vagus. This study explores the involvement and function of brain histamine, linked to BFCNs, in the regulation of intestinal barrier function...

Mast cells are activated through a variety of different receptors to release preformed granules and mediators synthesized de novo . However, the physiology and function of mast cells are not fully understood. Traditional studies of mast cell activation in humans have utilized cultures of tissue-derived mast cells including CD34+ progenitor cells or well-characterized commercially available cell lines. One limitation of these methods is that mast cells are no longer in a natural state. Therefore, their applicability to human skin disorders may be limited...

INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors are cornerstones in the treatment of Hormone Receptor (HR) positive and Human Epidermal Growth factor (HER2) negative metastatic breast cancer. Given their widespread use in the metastatic setting and emerging use in the adjuvant setting, studying the drug-drug interactions (DDI) of these medications is of utmost importance. AREAS COVERED: This review provides key background information on the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib...

BACKGROUND: Atherosclerosis is a chronic inflammatory disease characterized by abnormal lipid deposition in the arteries. Programmed cell death is involved in the inflammatory response of atherosclerosis, but PANoptosis, as a new form of programmed cell death, is still unclear in atherosclerosis. This study explored the key PANoptosis-related genes involved in atherosclerosis and their potential mechanisms through bioinformatics analysis. METHODS: We evaluated differentially expressed genes (DEGs) and immune infiltration landscape in atherosclerosis using microarray datasets and bioinformatics analysis...

The aims of this work were to evaluate the expression of histamine H3 receptor (H3 R) in triple negative breast cancer (TNBC) samples and to investigate the antitumoral efficacy and safety of the LINS01 series of H3 R antagonists, through in silico, in vitro, and in vivo approaches. Antitumor activity of LINS01009, LINS01010, LINS01022, LINS01023 was assayed in vitro in 4T1 and MDA-MB-231 TNBC cells (0.01-100 μM), and in vivo in 4T1 tumors orthotopically established in BALB/c mice (1 or 20 mg/kg)...

BACKGROUND: Mild chemical inhibition of mitochondrial respiration can confer resilience against a subsequent stroke or myocardial infarction, also known as preconditioning. However, the lack of chemicals that can safely inhibit mitochondrial respiration has impeded the clinical translation of the preconditioning concept. We previously showed that meclizine, an over-the-counter antivertigo drug, can toggle metabolism from mitochondrial respiration toward glycolysis and protect against ischemia-reperfusion injury in the brain, heart, and kidney...

Histamine is responsible for many processes mediated by different receptors expressed on a variety of cells. The discovery of the first H1 antihistamines in the 1940s led to the development of numerous H1 and H2 antagonists with a broad application in many indications. The recent identification of two new histamine receptors (H3, H4) in the 1980s and 2000s led to the market authorization in Switzerland of new drugs since 2018. The purpose of this review is to provide a brief overview of the physiology of histamine, the recent development of new compounds in this field, antihistamine drug indications and relevant side effects...

BACKGROUND: The pathogen responsible for tuberculosis is called Mycobacterium tuberculosis. Its interaction with macrophages has a significant impact on the onset and progression of the disease. METHODS: The respiratory pathway allows Mycobacterium tuberculosis to enter the body's lungs where it battles immune cells before being infected latently or actively. In the progress of tuberculosis, Mycobacterium tuberculosis activates the body's immune system and creates inflammatory factors, which cause tissue inflammation to infiltrate and the creation of granulomas, which seriously harms the body...

Mas-related G-protein-coupled receptor X2 (MRGPRX2), expressed on mast cells, is associated with drug-induced pseudo-allergic reactions. Although it is well known that there are differences of sensitivity between species in the pseudo-allergic reactions, no platform for evaluating a human risk of the pseudo-allergic reactions observed in nonclinical studies has been established. Valemetostat tosylate, developed as an anti-cancer drug, induced histamine release in a nonclinical study with dogs. The purpose of the current study was to identify the mechanism and assess the human risk of valemetostat-tosylate-induced histamine release using dog and human MRGPRX2-expressing cells...

Airway smooth muscle (ASM) contraction is determined by the increase in intracellular Ca2+ concentration ([Ca2+ ]i ) caused by its release from the sarcoplasmic reticulum (SR) or by extracellular Ca2+ influx. Major channels involved in Ca2+ influx in ASM cells are L-type voltage-dependent Ca2+ channels (L-VDCCs) and nonselective cation channels (NSCCs). Transient receptor potential vanilloid 4 (TRPV4) is an NSCC recently studied in ASM. Mechanical stimuli, such as contraction, can activate TRPV4. We investigated the possible activation of TRPV4 by histamine (His)- or carbachol (CCh)-induced contraction in guinea pig ASM...

Arrestins are known to be involved not only in the desensitization and internalization of G protein-coupled receptors but also in the G protein-independent activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), to regulate cell proliferation and inflammation. Our previous study revealed that the histamine H1 receptor-mediated activation of ERK is dually regulated by Gq proteins and arrestins. In this study, we investigated the roles of Gq proteins and arrestins in the H1 receptor-mediated activation of JNK in Chinese hamster ovary (CHO) cells expressing wild-type (WT) human H1 receptors, the Gq protein-biased mutant S487TR, and the arrestin-biased mutant S487A...

BACKGROUND: Vasculitis diseases include Kawasaki disease (KD), Kawasaki disease shock syndrome (KDSS), Multisystem Inflammatory Syndrome (MIS), Henoch-Schönlein purpura (HS), or IgA vasculitis, and additional vasculitis diseases. These diseases are often preceded by infections or immunizations. Disease incidence rates are higher in children than in adults. These diseases have been extensively studied, but understanding of the disease etiology remains to be established. OBJECTIVE: Many studies have failed to demonstrate an association between vasculitis diseases and vaccination; this study examines possible associations...

Histamine modulates immunity by binding to histamine receptor 2 (H2R). Cimetidine, an H2R antagonist that inhibits gastric acid secretion and treats gastrointestinal ulcers, interferes with histamine-mediated immunomodulation and may have anticancer activity. This study examined cimetidine's effect on the anticancer effect of anti-PD-L1 in colon cancer. The MTT assay, colony formation assay, and DNA histograms assessed cell viability, clonogenicity, and cell cycle distribution, respectively. Flow cytometry measured H2R and PD-L1 expression and estimated specific immune cell lineages...