The role of histamine and its receptors in breast cancer: from pathology to therapeutic targets.

Breast cancer is the most common malignancy in women, and despite the development of new treatment methods and the decreasing mortality rate in recent years, one of the clinical problems in breast cancer treatment is chronic inflammation in the tumor microenvironment. Histamine, an inflammatory mediator, is produced by tumor cells and can induce chronic inflammation and the growth of some tumors by recruiting inflammatory cells. It can also affect tumor physiopathology, antitumor treatment efficiency, and patient survival. Antihistamines, as histamine receptor antagonists, play a role in modulating the effects of these receptors in tumor cells and can affect some treatment methods for breast cancer therapy; in this review, we investigate the role of histamine, its receptors, and antihistamines in breast cancer pathology and treatment methods.

Histamine-related genes participate in the establishment of an immunosuppressive microenvironment and impact the immunotherapy response in hepatocellular carcinoma.

Chronic inflammation is pivotal in the pathogenesis of hepatocellular carcinoma (HCC). Histamine is a biologically active substance that amplifies the inflammatory and immune response and serves as a neurotransmitter. However, knowledge of histamine's role in HCC and its effects on immunotherapy remains lacking. We focused on histamine-related genes to investigate their potential role in HCC. The RNA-seq data and clinical information regarding HCC were obtained from The Cancer Genome Atlas (TCGA). After identifying the differentially expressed genes, we constructed a signature using the univariate Cox proportional hazard regression and least absolute shrinkage and selection operator (LASSO) analyses. The signature's predictive performance was evaluated using a receiver operating characteristic curve (ROC) analysis. Furthermore, drug sensitivity, immunotherapy effects, and enrichment analyses were conducted. Histamine-related gene expression in HCC was confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). A histamine-related gene prognostic signature (HRGPS) was developed in TCGA. Time-dependent ROC and Kaplan-Meier survival analyses demonstrated the signature's strong predictive power. Importantly, patients in high-risk groups exhibited a higher frequency of TP53 mutations, elevated immune checkpoint-related gene expression, and increased infiltration of immunosuppressive cells-indicating a potentially favorable response to immunotherapy. In addition, drug sensitivity analysis revealed that the signature could effectively predict chemotherapy efficacy and sensitivity. qRT-PCR results validated histamine-related gene overexpression in HCC. Our findings demonstrate that inhibiting histamine-related genes and signaling pathways can impact the therapeutic effect of anti-PD-1/PD-L1. The precise predictive ability of our signature in determining the response to different therapeutic options highlights its potential clinical significance.

Therapeutic Potentials of Medicinal Leech in Chinese Medicine.

The use of medicinal leeches in clinical therapy has been employed for a long time, as it was originally recognized for exerting antithrombin effects. These effects were due to the ability of the leech to continuously suck blood while attached to human skin. According to Chinese Pharmacopoei, leeches used in traditional Chinese medicine mainly consist of Whitmania pigra Whitman, Hirudo nipponia Whitman, and Whitmania acranulata, but the latter two species are relatively scarce. The main constituents of leeches are protein and peptide macromolecules. They can be categorized into two categories based on their pharmacological effects. One group consists of active ingredients that directly target the coagulation system, such as hirudin, heparin, and histamine, which are widely known. The other group comprises protease inhibitor components like Decorsin and Hementin. Among these, hirudin secreted by the salivary glands of the leech is the most potent thrombin inhibitor and served as the sole remedy for preventing blood clotting until the discovery of heparin. Additionally, leeches play a significant role in various traditional Chinese medicine formulations. In recent decades, medicinal leeches have been applied in fields including anti-inflammatory treatment, cardiovascular disease management, antitumor treatment, and many other medical conditions. In this review, we present a comprehensive overview of the historical journey and medicinal applications of leeches in various medical conditions, emphasizing their pharmaceutical significance within traditional Chinese medicine. This review offers valuable insights for exploring additional therapeutic opportunities involving the use of leeches in various diseases and elucidating their underlying mechanisms for future research.

Exploring factors influencing the levels of biogenic amines in wine and microbiological strategies for controlling their occurrence in winemaking.

Fermented beverages, including wine, can accumulate high concentrations of biogenic amines (BAs), which can pose potential health risks. BAs are produced by various yeasts and lactic acid bacteria (LAB) during winemaking. LAB are the main contributors to the formation of histamine and tyramine, the most toxic and food safety relevant biogenic amines. Numerous factors, ranging from agricultural and oenological practices to sanitation conditions, can contribute to the formation of BAs in wines. Moreover, organic and biodynamic wines impose limitations on the use of common food additives employed to control the proliferation of native and spoilage microorganisms during vinification and storage. To mitigate histamine production, commercial starter cultures incapable of synthesising histamine have been effectively utilised to reduce wine histamine content. Alternative fermentative microorganisms are currently under investigation to enhance the safety, quality, and typicity of wines, including indigenous LAB, non-Saccharomyces yeasts, and BAs degrading strains. Furthermore, exploration of extracts from BAs-degrading microorganisms and their purified enzymes has been undertaken to reduce BAs levels in wines. This review highlights microbial contributors to BAs in wines, factors affecting their growth and BA production, and alternative microorganisms that can degrade or avoid BAs. The aim is to lessen reliance on additives, providing consumers with safer wine choices.

The macrophage polarization in allergic responses induced by tropomyosin of Macrobrachium nipponense in cell and murine models.

Macrophages are one of the important immune cells, which play important roles in innate and adaptive immune. However, the roles of macrophages in food allergy are not thoroughly understood. To investigate the roles of macrophages during food allergy, we focused on the relationship between macrophage polarization and allergic responses induced by tropomyosin (TM) in the present study. Arg 1 and CD206 expressions in the TM group were significantly higher than those of the PBS group, while iNOS and TNF-α expressions were no obvious difference, moreover, the morphology of macrophages stimulated by TM was similar to that of M2 macrophages. These results indicated macrophages were mainly polarized toward M2 phenotypes in vitro. The antibodies, mMCP-1, histamine and cytokines, revealed that macrophages could participate in food allergy, and macrophage polarization was associated with changes in allergic-related factors. The cytokine levels of M2 phenotypes were significantly higher than those of M1 phenotypes in peripheral blood. The mRNA expressions and protein levels of Arg1 and iNOS in the jejunum and peritoneal cells indicated that M2 phenotypes were the major macrophage in these tissues compared with M1 phenotypes. Hence, macrophage polarization plays an important role in food allergy.

Lactic acid bacteria and yeast co-fermented milk alleviate cow milk allergy.

Cow milk allergy is one of the common food allergies. Our previous study showed that the allergenicity of fermented milk is lower than that of unfermented skimmed milk in vitro, and the antigenicity of ß-lactoglobulin and α-lactalbumin in fermented milk was decreased by 67.54% and 80.49%, respectively. To confirm its effects in vivo, allergic BALB/C mice model was used to further study the allergenicity of fermented milk. It was found that compared with the skim milk (SM) group, the intragastrically sensitization with fermented milk had no obvious allergic symptoms and the fingers were more stable: lower levels of IgE, IgG, and IgA in serum, lower levels of plasma histamine and mast cell protein-1, and immune balance of Th1/Th2 and Treg/Th17. At the same time, intragastrically sensitization with fermented milk increased the α diversity of intestinal microbiota and changed the microbiota abundance: the relative abundance of norank-f-Muribaculaceae and Staphylococcus significantly decreased, and the abundance of Lachnospiraceae NK4A136 group, Bacteroides, and Turicibacter increased. In addition, fermented milk can also increase the level of short-chain fatty acids in the intestines of mice. It turns out that fermented milk is much less allergenicity than SM. PRACTICAL APPLICATION: Fermentation provides a theoretical foundation for reducing the allergenicity of milk and dairy products, thereby facilitating the production of low-allergenic dairy products suitable for individuals with milk allergies.

Three cases of scombroid syndrome in Italy: clinical and preventive considerations.

Background: Foodborne diseases are common sources of morbidity and mortality worldwide. Scombroid syndrome represents a particular condition since it is not directly related to the ingestion of spoiled food but is determined by high levels of histamine, a chemical mediator naturally produced within the human body under particular conditions. In these cases, histamine is formed as a result of the bacterial activity from histidine, an amino acid present at high levels in some fish species. The resulting symptomatology can range from mild symptoms such as headache and skin rash to more severe manifestations such as hypotension and coronary spasms. Reference regulations in Italy set maximum levels of histamine in food at 200 mg/kg. Cases description: The cases described involve a family of three who, following the ingestion of a tuna dish, started to exhibit symptoms typical of an allergic reaction. In one case, hypotension, tachycardia, and electrocardiographic changes in the ST-tract suggestive of myocardial ischemia also appeared with negative myocardionecrosis enzyme dosage. All three cases experienced complete remission of symptoms in the absence of sequelae. Histamine concentrations in fish sampled three days later were 169 mg/kg. Conclusion: The cases described emphasize the importance of proper differential diagnosis as well as the importance of implementing specific controls in food hygiene.

Chemogenetic activation or inhibition of histaminergic neurons bidirectionally modulates recognition memory formation and retrieval in male and female mice.

Several lines of evidence demonstrate that the brain histaminergic system is fundamental for cognitive processes and the expression of memories. Here, we investigated the effect of acute silencing or activation of histaminergic neurons in the hypothalamic tuberomamillary nucleus (TMNHA neurons) in vivo in both sexes in an attempt to provide direct and causal evidence of the necessary role of these neurons in recognition memory formation and retrieval. To this end, we compared the performance of mice in two non-aversive and non-rewarded memory tests, the social and object recognition memory tasks, which are known to recruit different brain circuitries. To directly establish the impact of inactivation or activation of TMNHA neurons, we examined the effect of specific chemogenetic manipulations during the formation (acquisition/consolidation) or retrieval of recognition memories. We consistently found that acute chemogenetic silencing of TMNHA neurons disrupts the formation or retrieval of both social and object recognition memory in males and females. Conversely, acute chemogenetic activation of TMNHA neurons during training or retrieval extended social memory in both sexes and object memory in a sex-specific fashion. These results suggest that the formation or retrieval of recognition memory requires the tonic activity of histaminergic neurons and strengthen the concept that boosting the brain histaminergic system can promote the retrieval of apparently lost memories.

Effects of systemic inflammation on the network oscillation in the anterior cingulate cortex and cognitive behavior.

Network oscillation in the anterior cingulate cortex (ACC) plays a key role in attention, novelty detection and anxiety; however, its involvement in cognitive impairment caused by acute systemic inflammation is unclear. To investigate the acute effects of systemic inflammation on ACC network oscillation and cognitive function, we analyzed cytokine level and cognitive performance as well as network oscillation in the mouse ACC Cg1 region, within 4 hours after lipopolysaccharide (LPS, 30 µg/kg) administration. While the interleukin-6 concentration in the serum was evidently higher in LPS-treated mice, the increases in the cerebral cortex interleukin-6 did not reach statistical significance. The power of kainic acid (KA)-induced network oscillation in the ACC Cg1 region slice preparation increased in LPS-treated mice. Notably, histamine, which was added in vitro, increased the oscillation power in the brain slices from LPS-untreated mice; for the LPS-treated mice, however, the effect of histamine was suppressive. In the open field test, frequency of entries into the center area showed a negative correlation with the power of network oscillation (0.3 µM of KA, theta band (3-8 Hz); 3.0 µM of KA, high-gamma band (50-80 Hz)). These results suggest that LPS-induced systemic inflammation results in increased network oscillation and a drastic change in histamine sensitivity in the ACC, accompanied by the robust production of systemic pro-inflammatory cytokines in the periphery, and that these alterations in the network oscillation and animal behavior as an acute phase reaction relate with each other. We suggest that our experimental setting has a distinct advantage in obtaining mechanistic insights into inflammatory cognitive impairment through comprehensive analyses of hormonal molecules and neuronal functions.

Chamaecyparis lawsoniana and Its Active Compound Quercetin as Ca2+ Inhibitors in the Contraction of Airway Smooth Muscle.

The Cupressaceae family includes species considered to be medicinal. Their essential oil is used for headaches, colds, cough, and bronchitis. Cedar trees like Chamaecyparis lawsoniana (C. lawsoniana) are commonly found in urban areas. We investigated whether C. lawsoniana exerts some of its effects by modifying airway smooth muscle (ASM) contractility. The leaves of C. lawsoniana (363 g) were pulverized mechanically, and extracts were obtained by successive maceration 1:10 (w:w) with methanol/CHCl3. Guinea pig tracheal rings were contracted with KCl, tetraethylammonium (TEA), histamine (HIS), or carbachol (Cch) in organ baths. In the Cch experiments, tissues were pre-incubated with D-600, an antagonist of L-type voltage-dependent Ca2+ channels (L-VDCC) before the addition of C. lawsoniana. Interestingly, at different concentrations, C. lawsoniana diminished the tracheal contractions induced by KCl, TEA, HIS, and Cch. In ASM cells, C. lawsoniana significantly diminished L-type Ca2+ currents. ASM cells stimulated with Cch produced a transient Ca2+ peak followed by a sustained plateau maintained by L-VDCC and store-operated Ca2+ channels (SOCC). C. lawsoniana almost abolished this last response. These results show that C. lawsoniana, and its active metabolite quercetin, relax the ASM by inhibiting the L-VDCC and SOCC; further studies must be performed to obtain the complete set of metabolites of the extract and study at length their pharmacological properties.

Peptide-Based Recognition Agents of Histamine: A Biopanning Approach with Enhanced Specificity.

Histamine is a biogenic amine that poses a potential threat to public health due to its toxicological effects. In this study, we identified histamine-binding peptides by screening a random 12-mer peptide library, employing a novel biopanning approach that excluded histidine-binding sequences in the final round. This additional step enhanced the selectivity of the peptides and prevented interference from histidine during detection. The binding affinities of synthesized peptides to histamine were assessed using isothermal titration calorimetry (ITC). Among the identified peptides, HBF10 (SGFRDGIEDFLW) and HBF26 (IPLENQHKIYST) showed significant affinity to histamine, with Ka values of 2.56×104 (M-1) and 8.94×104 (M-1), respectively. Notably, the identified peptides did not demonstrate binding affinity towards histidine, despite its structural similarity to histamine. Subsequently, the surface plasmon resonance (SPR) sensor surface was prepared by immobilizing the peptide HBF26 to investigate the potential of the peptide as a recognition agent for histamine detection. The findings suggest that the identified peptides have an affinity to histamine specifically, showcasing their potential applications as diagnostic agents with specific targeting capabilities.

A phytosphingosine derivative mYG-II-6 inhibits histamine-mediated TRPV1 activation and MRGPRX2-dependent mast cell degranulation.

BACKGROUND: Phytosphingosine and its derivative are known for their skin-protective properties. While mYG-II-6, a phytosphingosine derivative, has shown anti-inflammatory and antipsoriatic effects, its potential antipruritic qualities have yet to be explored. This study aimed to investigate mYG-II-6's antipruritic properties. METHODS: The calcium imaging technique was employed to investigate the activity of ion channels and receptors. Mast cell degranulation was confirmed through the ß-hexosaminidase assay. Additionally, in silico molecular docking and an in vivo mouse scratching behavior test were utilized. RESULTS: Using HEK293T cells transfected with H1R and TRPV1, we examined the impact of mYG-II-6 on histamine-induced intracellular calcium rise, a key signal in itch-mediating sensory neurons. Pretreatment with mYG-II-6 significantly reduced histamine-induced calcium levels and inhibited TRPV1 activity, suggesting its role in blocking the calcium influx channel. Additionally, mYG-II-6 suppressed histamine-induced calcium increase in primary cultures of mouse dorsal root ganglia, indicating its potential antipruritic effect mediated by histamine. Interestingly, mYG-II-6 exhibited inhibitory effects on human MRGPRX2, a G protein-coupled receptor involved in IgE-independent mast cell degranulation. However, it did not inhibit mouse MrgprB2, the ortholog of human MRGPRX2. Molecular docking analysis revealed that mYG-II-6 selectively interacts with the binding pocket of MRGPRX2. Importantly, mYG-II-6 suppressed histamine-induced scratching behaviors in mice. CONCLUSIONS: Our findings show that mYG-II-6 can alleviate histamine-induced itch sensation through dual mechanisms. This underscores its potential as a versatile treatment for various pruritic conditions.

Role of histaminergic regulation of astrocytes in alcohol use disorder.

Alcohol use disorder (AUD) is a severe, yet not fully understood, mental health problem. It is associated with liver, pancreatic, and gastrointestinal diseases, thereby highly increasing the morbidity and mortality of these individuals. Currently, there is no effective and safe pharmacological therapy for AUD. Therefore, there is an urgent need to increase our knowledge about its neurophysiological etiology to develop new treatments specifically targeted at this health condition. Recent findings have shown an upregulation in the histaminergic system both in alcohol dependent individuals and in animals with high alcohol preference. The use of H3 histaminergic receptor antagonists has given promising therapeutic results in animal models of AUD. Interestingly, astrocytes, which are ubiquitously present in the brain, express the three main histamine receptors (H1, H2 and H3), and in the last few years, several studies have shown that astrocytes could play an important role in the development and maintenance of AUD. Accordingly, alterations in the density of astrocytes in brain areas such as the prefrontal cortex, ventral striatum, and hippocampus that are critical for AUD-related characteristics have been observed. These characteristics include addiction, impulsivity, motor function, and aggression. In this work, we review the current state of knowledge on the relationship between the histaminergic system and astrocytes in AUD and propose that histamine could increase alcohol tolerance by protecting astrocytes from ethanol-induced oxidative stress. This increased tolerance could lead to high levels of alcohol intake and therefore could be a key factor in the development of alcohol dependence.

Histamine Intolerance: Symptoms, Diagnosis, and Beyond.

Histamine intolerance is a condition characterized by the accumulation of histamine to a point that exceeds the body's capacity to eliminate it. Researchers have attributed several reasons to this condition, such as genetic factors, alcohol, and dietary deficiencies, among other elements. Symptoms of histamine intolerance have been found to extend beyond the gastrointestinal tract and to the whole body, with these symptoms being sporadic and non-specific. This review will explore various aspects related to histamine intolerance, such as its causes, symptoms, diagnosis, and information related to management.

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

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

A Closer Look at Histamine in Drosophila.

The present work intends to provide a closer look at histamine in Drosophila. This choice is motivated firstly because Drosophila has proven over the years to be a very simple, but powerful, model organism abundantly assisting scientists in explaining not only normal functions, but also derangements that occur in higher organisms, not excluding humans. Secondly, because histamine has been demonstrated to be a pleiotropic master molecule in pharmacology and immunology, with increasingly recognized roles also in the nervous system. Indeed, it interacts with various neurotransmitters and controls functions such as learning, memory, circadian rhythm, satiety, energy balance, nociception, and motor circuits, not excluding several pathological conditions. In view of this, our review is focused on the knowledge that the use of Drosophila has added to the already vast histaminergic field. In particular, we have described histamine's actions on photoreceptors sustaining the visual system and synchronizing circadian rhythms, but also on temperature preference, courtship behavior, and mechanosensory transmission. In addition, we have highlighted the pathophysiological consequences of mutations on genes involved in histamine metabolism and signaling. By promoting critical discussion and further research, our aim is to emphasize and renew the importance of histaminergic research in biomedicine through the exploitation of Drosophila, hopefully extending the scientific debate to the academic, industry, and general public audiences.

Interactions between Age-Related Type 2 Diabetes and the Small Intestine.

The number of patients with type 2 diabetes is increasing worldwide. The mechanisms leading to type 2 diabetes and its complications is being researched; however, the pathological mechanisms of diabetes in the small intestine remain unclear. Therefore, we examined these pathological mechanisms in the small intestine using a mouse model of type 2 diabetes (KK-Ay/TaJcl) aged 10 and 50 weeks. The results showed that diabetes worsened with age in the mice with type 2 diabetes. In these mice, advanced glycation end products (AGEs) in the small intestine and mast cell expression increased, whereas diamine oxidase (DAO) decreased; increased tumor necrosis factor (TNF)-α and histamine levels in the plasma and small intestine were also detected. Additionally, the expression of zonula occludens (ZO)-1 and Claudin1 and cell adhesion molecules in the small intestine reduced. These results exacerbated with age. These findings indicate that type 2 diabetes causes AGE/mast cell/histamine and TNF-α signal transmission in the small intestine and decreases small intestinal wall cell adhesion molecules cause TNF-α and histamine to flow into the body, worsening the diabetic condition. In addition, this sequence of events is suggested to be strengthened in aged mice with type 2 diabetes, thus exacerbating the disease. These findings of this study may facilitate the elucidation of the pathological mechanisms of type 2 diabetes and its associated complications.

Brain histamine improves colonic hyperpermeability through the basal forebrain cholinergic neurons, adenosine A2B receptors and vagus nerve in rats.

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. Colonic permeability, assessed by quantifying absorbed Evans blue in rat colonic tissue, showed that histamine did not affect increased colonic permeability induced by LPS when administered subcutaneously. However, intracisternal histamine administration improved colonic hyperpermeability. Elevating endogenous histamine levels in the brain with SKF91488, a histamine N-methyltransferase inhibitor, also improved colonic hyperpermeability. This effect was abolished by intracisternal chlorpheniramine, an histamine H1 receptor antagonist, not ranitidine, an H2 receptor antagonist. The SKF91488-induced improvement in colonic hyperpermeability was blocked by vagotomy, intracisternal pirenzepine (suppressing BFCNs activity), or alloxazine (an adenosine A2B receptor antagonist). Additionally, intracisternal chlorpheniramine injection eliminated butyrate-induced improvement in colonic hyperpermeability. These findings suggest that brain histamine, acting via the histamine H1 receptor, regulates intestinal barrier function involving BFCNs, adenosine A2B signaling, and the vagus. Brain histamine appears to centrally regulate intestinal barrier function influenced by butyrate, differentiating its actions from peripheral histamine in conditions like IBS, where mast cell-derived histamine induces leaky gut. Brain histamine emerges as a potential pharmacological target for diseases associated with leaky gut, such as dementia and IBS.

An insular cortical circuit required for itch sensation and aversion.

Itch encompasses both sensory and emotional dimensions, with the two dimensions reciprocally exacerbating each other. However, whether a shared neural circuit mechanism governs both dimensions remains elusive. Here, we report that the anterior insular cortex (AIC) is activated by both histamine-dependent and -independent itch stimuli. The activation of AIC elicits aversive emotion and exacerbates pruritogen-induced itch sensation and aversion. Mechanistically, AIC excitatory neurons project to the GABAergic neurons in the dorsal bed nucleus of the stria terminalis (dBNST). Manipulating the activity of the AIC → dBNST pathway affects both itch sensation and itch-induced aversion. Our study discovers the shared neural circuit (AIC â†’ dBNST pathway) underlying the itch sensation and aversion, highlights the critical role of the AIC as a central hub for the itch processing, and provides a framework to understand the neural mechanisms underlying the sensation and emotion interaction.