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BACKGROUND: Clostridium difficile infection (CDI) is a debilitating nosocomial infection. C. difficile produces toxins A and B, which cause inflammation. Existing therapies have issues with recurrence, cost, and safety. We aim to discover a safe, effective, and economical nonmicrobiological therapeutic approach against CDI. METHODS: We included human primary peripheral blood mononuclear cells (PBMCs), fresh human colonic explants, and humanized HuCD34-NCG mice. Toxin A+B+ VPI 10463 and A-B+ ribotype 017 C. difficile strains were used. We used single-cell RNA profiling and high-throughput screening to find actionable toxin B-dependent pathways in PBMCs. RESULTS: Histamine 1 receptor-related drugs were found among the hit compounds that reversed toxin-mediated macrophage inflammatory protein (MIP) 1α expression in PBMCs. We identified loratadine as the safest representative antihistamine for therapeutic development. Loratadine inhibited toxin B-induced MIP-1α secretion in fresh human colonic tissues. Oral loratadine (10 mg/kg/d) maintained survival, inhibited intestinal CCl3 messenger RNA expression, and prevented vancomycin-associated recurrence in the VPI 10463-infected mice and ribotype 017-infected hamsters. Splenocytes from loratadine-treated mice conferred anti-inflammatory effects to the VPI 10463-infected T/B-cell--deficient Rag-/- mice. Oral loratadine suppressed human MIP-1α expression in monocytes/macrophages in toxin B-expressing ribotype 017-infected humanized HuCD34-NCG mice. CONCLUSIONS: Loratadine may be repurposed to optimize existing therapies against CDI.

Signaling interplay between the histamine 1 receptor (H1R) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in mediating histaminergic itch has been well-established in mammalian models, but whether this is conserved in humans remains to be confirmed due to the difficulties in obtaining human sensory neurons (SNs) for experimentation. Additionally, previously reported species-specific differences in TRPV1 function indicate that use of human SNs is vital for drug candidate screening to have a higher chance of identifying clinically effective TRPV1 antagonists. In this study, we built a histamine-dependent itch model using peripheral SNs derived from human induced pluripotent stem cells (hiPSC-SNs), which provides an accessible source of human SNs for pre-clinical drug screening. We validated channel functionality using immunostaining, calcium imaging, and multielectrode array (MEA) recordings, and confirmed the interdependence of H1R and TRPV1 signalling in human SNs. We further tested the amenability of our model for pre-clinical studies by screening multiple TRPV1 antagonists in parallel, identifying SB366791 as a potent inhibitor of H1R activation and potential candidate for alleviating histaminergic itch. Notably, some of the results using our model corroborated with efficacy and side effect findings from human clinical trials, underscoring the importance of this species-specific platform. Taken together, our results present a robust in vitro human model for histaminergic itch, which can be used to further interrogate the molecular basis of human SN function as well as screen for TRPV1 activity-modifying compounds for a number of clinical indications. [ABSTRACT FROM AUTHOR]

Dm9 neurons in Drosophila have been proposed as functional homologs of horizontal cells in the outer retina of vertebrates. Here we combine genetic dissection of neuronal circuit function, two-photon calciumimaging in Dm9 and inner photoreceptors, and immunohistochemical analysis to reveal novel insights into the functional role of Dm9 in early visual processing. Our experiments show that Dm9 receive input from all four types of inner photoreceptor R7p, R7y, R8p, and R8y. Histamine released from all types R7/R8 directly inhibits Dm9 via the histamine receptorOrt, and outweighs simultaneous histamine-independent excitation of Dm9 by UV-sensitive R7. Dm9 in turn provides inhibitory feedback to all R7/R8, which is sufficient for color-opponent processing in R7 but not R8. Color opponent processing in R8 requires additional synaptic inhibition by R7 of the same ommatidium via axo-axonal synapses and the second Drosophila histamine receptor HisCl1. Notably, optogenetic inhibition of Dm9 prohibits color opponent processing in all types of R7/R8 and decreases intracellular calciumin photoreceptor terminals. The latter likely results fromreduced release of excitatory glutamate from Dm9 and shifts overall photoreceptor sensitivity toward higher light intensities. In summary, our results underscore a key role of Dm9 in color opponent processing in Drosophila and suggest a second role of Dm9 in regulating light adaptation in inner photoreceptors. These novel findings on Dm9 are indeed reminiscent of the versatile functions of horizontal cells in the vertebrate retina. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We tested hypothesis that aerobic exercise with blood flow restriction (BFR) induced postexercise hypotension (PEH), and the reduction in blood pressure (BP) was due to peripheral vasodilation via the histamine receptors. Ten male subjects participated in this study. The subjects were randomly assigned to walk for 10 min at 6.4 km/h, 0% grade with or without BFR after taking histamine receptor blockade. Following exercise, BP was measured at 10 min interval for 60 min. Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), and total peripheral resistance (TPR) were evaluated. Our results indicated that MAP was significantly lowered immediately after exercise at 20 min, 30 min, and 40 min before the blockade as opposed to after the blockade. A significant reduction in diastolic BP (DBP) occurred. There were no significant differences in HR, SV, CO, and TPR between before the blockade and after the blockade. MAP was substantially decreased at 20 min, 30 min, and 40 min before the blockade compared to resting (−3.2 ± 2.2, −3.3 ± 2.8, and −2.9 ± 2.5, respectively) while increasing MAP after the blockade. The current study demonstrated that low-intensity aerobic exercise with BFR lowered MAP via histamine receptor-induced peripheral vasodilation. In conclusion, BFR exercise training using short periods and low intensity would be greatly beneficial as a potential treatment to lower BP.

Dm9 neurons in Drosophila have been proposed as functional homologs of horizontal cells in the outer retina of vertebrates. Here we combine genetic dissection of neuronal circuit function, two-photon calcium imaging in Dm9 and inner photoreceptors, and immunohistochemical analysis to reveal novel insights into the functional role of Dm9 in early visual processing. Our experiments show that Dm9 receive input from all four types of inner photoreceptor R7p, R7y, R8p, and R8y. Histamine released from all types R7/R8 directly inhibits Dm9 via the histamine receptor Ort, and outweighs simultaneous histamine-independent excitation of Dm9 by UV-sensitive R7. Dm9 in turn provides inhibitory feedback to all R7/R8, which is sufficient for color-opponent processing in R7 but not R8. Color opponent processing in R8 requires additional synaptic inhibition by R7 of the same ommatidium via axo-axonal synapses and the second Drosophila histamine receptor HisCl1. Notably, optogenetic inhibition of Dm9 prohibits color opponent processing in all types of R7/R8 and decreases intracellular calcium in photoreceptor terminals. The latter likely results from reduced release of excitatory glutamate from Dm9 and shifts overall photoreceptor sensitivity toward higher light intensities. In summary, our results underscore a key role of Dm9 in color opponent processing in Drosophila and suggest a second role of Dm9 in regulating light adaptation in inner photoreceptors. These novel findings on Dm9 are indeed reminiscent of the versatile functions of horizontal cells in the vertebrate retina.

Background: Allergy is an ever-increasing immune disorder and is often fatal under certain circumstances. Lack of total curative medication prompts the search for various compounds as the lead molecules. Ginger, Zingiber officinale Roscoe, is a well-established medicinal plant in different traditional practices. Its use as antiallergic or anti-inflammatory agent has been vindicated but the underlying mechanism of action is yet unknown. Method: In this study, we analyzed the phytocompounds characterized from ginger for their binding affinities on cysteinyl leukotriene receptor 1 (CysLTR1) and histamine H1 receptor (H1R) by molecular docking. The molecular interactions were compared against known agonists and antagonists of the two receptors. Results: The data indicate that ginger compounds have high binding affinity for both LTR1 and H1R comparable to those of antiallergic medications. The highest binding affinities were recorded for gingerenone-A (-7.3 kcal/mol) and zingiberol (-7.2 kcal/mol) on LTR1; and gingerenone-A (-8.7 kcal/mol) and a-curcumene (-8.0 kcal/mol) on H1R. Conclusion: In addition to antiallergic activity, molecular predications on the probable biological activities of the ginger compounds show that they can have a variety of medicinal applications including immunomodulatory and anticancer activities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] In diabetic patients, repeated episodes of hypoglycemia can increase glucose variability (GV), which may lead to glutamate neurotoxicity in the brain and consequently affect cognitive functions. Astrocytes play a crucial role in regulating the balance of glutamate within the brain, and their function is influenced by the histamine receptor (HR) signaling pathway. However, the specific role of this mechanism under conditions of high GV is not yet clear. The results showed that increased GV resulted in decreased expression of HRs in mice hippocampus and astrocytes cultured in vitro. Additionally, a decrease in the expression of proteins related to glutamate metabolic clearance was observed, accompanied by a reduction in glutamate reuptake capacity. Notably, the intervention with histidine/histamine was able to reverse the above changes. Further mechanistic studies showed that inhibition of HRs that increased GV led to significant disturbances in astrocytic mitochondrial function. These abnormalities encompassed increased fragmentation morphology and the accumulation of reactive oxygen species, accompanied by decreased mitochondrial respiratory capacity and dysregulation of dynamics. Distinct HR subtypes exhibited variations in the modulation of mitochondrial function, with H 3 R demonstrating the most pronounced impact. The overexpression of H 3 R could enhance glutamate metabolic by reversing disturbances in mitochondrial dynamics. Therefore, this study suggests that H 3 R is able to maintain glutamate metabolic clearance capacity and exert neuroprotective effects in astrocytes that increased GV by regulating mitochondrial dynamic balance. This provides an important basis for potential therapeutic targets for diabetes-related cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is widely used in the treatment of various cancers, increasing the great risk of adverse cardiovascular events, while the clinical intervention effect is not ideal. Histamine has been documented to participate in pathophysiological processes of cardiovascular diseases and inflammation-associated carcinogenesis. However, the potential roles of histamine in antitumor-related cardiotoxicity have not been fully elucidated. In this study, cardiomyocytes (hiPSC-CMs, HL-1 cells) and mice were treated with DOX to establish DOX-induced cardiotoxicity (DIC) models. Histidine decarboxylase knockout mice (HDC−/−) mice and histamine 1 receptor (H 1 R) antagonist were used to explore the effect of histamine/H 1 R signaling on DIC. Our results demonstrated that histamine deficiency or pharmaceutical inhibition of H 1 R accelerated myocardial ferroptosis, which is responsible for the aggravated DIC both in vivo and in vitro , while the supplementation of exogenous histamine reversed these changes. Our data revealed that the dysfunction of histamine/H 1 R signaling repressed the activation of transducer and activator of transcription 3 (STAT3), accompanying with decreased expression of solute carrier family7member11 (SLC7A11), a major modulator of ferroptosis. Conclusively, the disruption of histamine/H 1 R axis triggered ferroptosis and exacerbated DIC possibly by modulating STAT3-SLC7A11 pathway. Our findings point to a potential therapeutic target for DIC and provide more consideration on the usage of antihistamine drugs. [Display omitted] • Disruption of histamine/H 1 R signaling aggravated inflammation and Doxorubicin-induced cardiotoxicity (DIC). • Solute carrier family 7 member 11 mediated cardiac ferroptosis might be the underlying mechanisms of histamine/H1R signaling in regulating DIC. • Histamine/H1R pathway is a novel therapeutic target for DIC and sheds lights on the safety of antihistamine drugs. [ABSTRACT FROM AUTHOR]

Histamine widely involves in local immune responses, physiological function in the gut, and acting as a neurotransmitter in the brain. Scientist also found the importance of histamine in the reproductive systems. The present study aimed to determine the existence of histamine receptor subtypes; H1R, H2R, H3R, and H4R on mouse oocytes through immunofluorescence (IF) staining and reverse transcription-polymerase chain reaction (RT-PCR). These further confirmed by the involvement of histamine receptor antagonists in in vitro fertilization (IVF). In IF staining, mouse oocytes were incubated with primary antibody against histamine receptor, followed by incubation with fluorescence conjugated secondary antibody. Then RT-PCR analysis was carried out for the undetected receptors during IF for confirmation. The RT-PCR used RNA extracted from mice COCs and cumulus free oocytes. In IVF, sperm was cultured in a group of treated histamine receptor antagonists oocytes. This investigation revealed the existance of H1R, H2R, and H3R on mouse oocytes in IF and RT-PCR analyses. The treatment of IVF with histamine receptor antagonists (H1R: pyrilamine; H2R: cimetidine; H3R: thioperamide) led to a significant reduction quantity of 2-cell embryos (4.61 ± 2.44%; 5.83 ± 4.65%; 3.83 ± 1.82%, respectively) as compared with the control group (22.50 ± 6.44%). Therefore, according to the results of this study, the presence of H1R, H2R, and H3R on mouse oocytes possibly will suggest the involvement of histamine in fertilization. [ABSTRACT FROM AUTHOR]

Votucalis is a biologically active protein in tick (R. appendiculatus) saliva, which specifically binds histamine with high affinity and, therefore, has the potential to inhibit the host's immunological responses at the feeding site. We hypothesized that scavenging of peripherally released endogenous histamine by Votucalis results in both anti-itch and anti-nociceptive effects. To test this hypothesis, adult male mice were subjected to histaminergic itch, as well as peripheral nerve injury that resulted in neuropathic pain. Thus, we selected models where peripherally released histamine was shown to be a key regulator. In these models, the animals received systemic (intraperitoneal, i.p.) or peripheral transdermal (subcutaneous, s.c. or intraplantar, i.pl.) administrations of Votucalis and itch behavior, as well as mechanical and thermal hypersensitivity, were evaluated. Selective histamine receptor antagonists were used to determine the involvement of histamine receptors in the effects produced by Votucalis. We also used the spontaneous object recognition test to confirm the centrally sparing properties of Votucalis. Our main finding shows that in histamine-dependent itch and neuropathic pain models peripheral (s.c. or i.pl.) administration of Votucalis displayed a longer duration of action for a lower dose range, when compared with Votucalis systemic (i.p.) effects. Stronger anti-itch effect was observed after co-administration of Votucalis (s.c.) and antagonists that inhibited peripheral histamine H1 and H2 receptors as well as central histamine H4 receptors indicating the importance of these histamine receptors in itch. In neuropathic mice, Votucalis produced a potent and complete anti-nociceptive effect on mechanical hypersensitivity, while thermal (heat) hypersensitivity was largely unaffected. Overall, our findings further emphasize the key role for histamine in the regulation of histaminergic itch and chronic neuropathic pain. Given the effectiveness of Votucalis after peripheral transdermal administration, with a lack of central effects, we provide here the first evidence that scavenging of peripherally released histamine by Votucalis may represent a novel therapeutically effective and safe long-term strategy for the management of these refractory health conditions. [ABSTRACT FROM AUTHOR]

Histamine has been implicated in urinary bladder dysfunction as an inflammatory mediator driving sensory nerve hypersensitivity. However, the direct influence of histamine on smooth muscle has not been thoroughly investigated. We hypothesized that histamine directly contracts urinary bladder smooth muscle (UBSM) independent of effects on nerves. Single cell quantitative RT-PCR determined that only histamine H1 and H2 receptors were expressed on UBSM cells. In isolated tissue bath experiments, histamine (200 mM) caused a highly variable and rapidly desensitizing contraction that was completely abolished by the H1 receptor antagonist fexofenadine (5 mM) and the Gq/11 inhibitor YM254890 (1 mM). Neither the muscarinic receptor antagonist atropine (1 mM), the Naþ channel blocker tetrodotoxin (1 mM), nor the transient receptor potential vanilloid type 1 antagonist capsazepine (10 mM) altered responses to histamine, suggesting that nerve activation was not involved. UBSM desensitization to histamine was not due to receptor internalization, as neither the cholesterol-depleting agent methyl-b-cyclodextrin (10 mM), the dynamin-mediated endocytosis inhibitor dynasore (100 mM), nor the clathrin-mediated endocytosis inhibitor pitstop2 (15 mM) augmented or prolonged histamine contractions. Buffer from desensitized tissues still contracted histamine-naïve tissues, revealing that histamine was not metabolized. Prolonged exposure to histamine also had no effect on contractions due to electrical field stimulation, suggesting that both efferent nerve and UBSM excitability were unchanged. Together, these data suggest that histamine, although able to transiently contract UBSM, does not have a lasting effect on UBSM excitability or responses to efferent nerve input. Thus, any acute effects of histamine directly on UBSM contractility are unlikely to alter urinary bladder function. NEW & NOTEWORTHY Histamine is commonly associated with inflammatory bladder pathologies. We sought to investigate the role of histamine on urinary bladder contractility. Histamine contracts the bladder, but this response is highly variable and desensitizes completely in minutes. This desensitization is not due to internalization of the receptor or metabolism of histamine. Because nerve-evoked contractions are also not increased in the presence of histamine, our findings suggest that histamine is not directly acting to change contractility. [ABSTRACT FROM AUTHOR]

Abstract Background Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation, and mast cells residing in the gut are a primary source of histamine. Methods Stroke was induced in male C57BL/6 J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice; mice underwent MCAO surgery and were euthanized at 6 h, 24 h, and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice were associated with age-related changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma. Results We found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of gut mast cells and gut histamine receptor expression levels. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucin-producing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24-h post-stroke. Conclusion An important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome.

Abstract Background The efficiency and quality of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are crucial for regenerative medicine, disease modeling, drug screening, and the study of the development events during cardiac specification. However, their applications have been hampered by the differentiation efficiency, poor maturation, and high interline variability. Recent studies have reported that histamine plays important roles in hematopoietic stem cell proliferation and neutrophil maturation. However, its roles in cardiovascular tissue regeneration have not been thoroughly investigated. In the current study, we identified a novel physiological function of the histamine/histamine 1 receptor (H1R) signal in regulating the differentiation of hiPSC-CMs and heart development. Methods Transgenic zebrafish model (cmlc2: mCherry) was treated with histamine and histamine receptor (HR) antagonists. Histological morphology and ultrastructure of zebrafish heart were measured. Histamine-deficient pregnant mice (HDC−/−) were treated with H1R antagonist (pyrilamine) by intragastric administration from E8.5 to E18.5. Cardiac histological morphology and ultrastructure were analyzed in neonatal mice, and cardiac function in adult mice was measured. In vitro, histamine and HR antagonists were administrated in the culture medium during hiPSC-CM differentiation at different stages. The efficiency and maturation of cardiac differentiation were evaluated. Finally, histamine-treated hiPSC-CMs were transplanted into ischemic myocardium to detect the possible therapeutic effect. Results Administration of H1R antagonist during heart development induced cardiac dysplasia in zebrafish. Furthermore, using histidine decarboxylase (HDC) knockout mice, we examined abnormal swelling of myocardial mitochondria and autophagy formation under the condition of endogenous histamine deficiency. Histamine significantly promoted myocardial differentiation from human induced pluripotent stem cells (hiPSCs) with better structure and function via a H1R-dependent signal. The activation of histamine/H1R signaling pathway augmented hiPSC-derived cardiomyocyte (hiPSC-CM) differentiation through the ERK1/2-STAT3 signaling pathway. In addition, histamine-pre-treated hiPSC-CMs were transplanted into the ischemic hearts of myocardial injured mice and exhibited better survival and myocardial protection. Conclusions Thus, these findings indicated that histamine/H1R and its downstream signals were not only involved in cardiac differentiation but also provided a better survival environment for stem cell transplanted into ischemic myocardium.

Votucalis is a biologically active protein in tick (R. appendiculatus) saliva, which specifically binds histamine with high affinity and, therefore, has the potential to inhibit the host’s immunological responses at the feeding site. We hypothesized that scavenging of peripherally released endogenous histamine by Votucalis results in both anti-itch and anti-nociceptive effects. To test this hypothesis, adult male mice were subjected to histaminergic itch, as well as peripheral nerve injury that resulted in neuropathic pain. Thus, we selected models where peripherally released histamine was shown to be a key regulator. In these models, the animals received systemic (intraperitoneal, i.p.) or peripheral transdermal (subcutaneous, s.c. or intraplantar, i.pl.) administrations of Votucalis and itch behavior, as well as mechanical and thermal hypersensitivity, were evaluated. Selective histamine receptor antagonists were used to determine the involvement of histamine receptors in the effects produced by Votucalis. We also used the spontaneous object recognition test to confirm the centrally sparing properties of Votucalis. Our main finding shows that in histamine-dependent itch and neuropathic pain models peripheral (s.c. or i.pl.) administration of Votucalis displayed a longer duration of action for a lower dose range, when compared with Votucalis systemic (i.p.) effects. Stronger anti-itch effect was observed after co-administration of Votucalis (s.c.) and antagonists that inhibited peripheral histamine H1 and H2 receptors as well as central histamine H4 receptors indicating the importance of these histamine receptors in itch. In neuropathic mice, Votucalis produced a potent and complete anti-nociceptive effect on mechanical hypersensitivity, while thermal (heat) hypersensitivity was largely unaffected. Overall, our findings further emphasize the key role for histamine in the regulation of histaminergic itch and chronic neuropathic pain. Given the effectiveness of Votucalis after peripheral transdermal administration, with a lack of central effects, we provide here the first evidence that scavenging of peripherally released histamine by Votucalis may represent a novel therapeutically effective and safe long-term strategy for the management of these refractory health conditions.

Epilepsy is a common neurological disorder characterized by repeated and spontaneous epileptic seizures and is not well controlled by current medication. Traditional theory suggests that epilepsy results from an imbalance of excitatory glutamate neurons and inhibitory GABAergic neurons. However, new evidence from clinical and preclinical research suggests that histamine in the CNS plays an important role in the modulation of neural excitability and in the pathogenesis of epilepsy. Many histamine receptor ligands have achieved curative effects in animal epilepsy models, among which the histamine H3 receptor antagonist pitolisant has shown anti‐epileptic effects in clinical trials. Recent studies, therefore, have focused on the potential action of histamine receptors to control and treat epilepsy. In this review, we summarize the findings from animal and clinical epilepsy research on the role of brain histamine and its receptors. We also identify current gaps in the research and suggest where further studies are most needed. [ABSTRACT FROM AUTHOR]

• Mast cells are important mediators in cardiovascular diseases. • The mast cell mediator, histamine is involved in cardiovascular pathophysiology. • Histamine receptors are better target for treating cardiovascular therapies. • Antihistamines have been used widely in preclinical and clinical studies for CVDs. • Repurposing of H2 receptor antagonists will aid in better adjuvant therapies for CVDs. Undermining new mediators involved in the development and progression of cardiovascular diseases (CVDs) is vital for better disease management. Existing studies implicate a crucial role for inflammation and inflammatory cells, particularly mast cells, in cardiac diseases. Interestingly, the mast cell mediator, histamine, and its receptors profoundly impact the pathophysiology of the heart, resulting in hypertension-induced cardiac hypertrophy and other cardiac anomalies. In this review, we provide a detailed description of mast cell activation, mediators, and histamine receptors, with a particular focus on histamine 2 receptors (H2Rs). Preclinical and clinical studies using histamine receptor antagonists report improvement in cardiac function. Insights into the precise function of histamine receptors will aid in developing novel therapies and pave the way for repurposing antihistamines for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Garnered literature points toward the role of the dorsal hippocampus (CA1) in ethanol withdrawal-induced responses, wherein a strong presence of the histaminergic system is also reported. Therefore, the present study investigated the effect of an enhanced CA1 histaminergic transmission on the expression of chronic ethanol withdrawal-induced despair in mice on the tail suspension test (TST). The results revealed that mice who were on an ethanol-fed diet (5.96%, v/v) for 8 days exhibited maximum immobility time on the TST, and decreased locomotion at 24 h post-ethanol withdrawal (10th day), indicating ethanol withdrawal-induced despair. Enhancement of CA1 histaminergic activity achieved by the treatment of intra-CA1 microinjection of histaminergic agents such as histamine (0.1, 10 μg/mouse, bilateral), the histamine precursor l-histidine (1, 10 μg/mouse, bilateral), the histamine neuronal releaser/H3 receptor antagonist thioperamide (2, 10 μg/mouse, bilateral), the histamine H1 receptor agonist FMPH (2, 6.5 μg/mouse, bilateral), or the H2 receptor agonist amthamine (0.1, 0.5 μg/mouse, bilateral) to ethanol-withdrawn mice, 10 min before the 24-h post-ethanol withdrawal time point, significantly alleviated the expression of ethanol withdrawal-induced despair in mice on the TST. On the other hand, only the pre-treatment of the histamine H1 receptor agonist FMPH (2, 6.5 μg/mouse, intra-CA1 bilateral) reversed the reduction in locomotor activity induced in ethanol-withdrawn mice, whereas other employed histaminergic agents were devoid of any effect on this behavior. Therefore, our findings indicate that an enhanced CA1 histaminergic transmission, probably via stimulation of CA1 postsynaptic histamine H1 or H2 receptor, could preclude the behavioral despair, while H1 stimulation affects motor deficit expressed after ethanol withdrawal. [ABSTRACT FROM AUTHOR]

Histamine is known to lead to arrhythmias in the human heart. A mouse model to mimic these effects has hitherto not been available but might be useful to study the mechanism(s) of H2-histamine receptor-induced arrhythmias and may support the search for new antiarrhythmic drugs. In order to establish such a model in mice, we studied here the incidence of cardiac arrhythmias under basal and under stimulated conditions in atrial and ventricular preparations from mice that overexpressed the human H2-histamine receptors in a cardiac-specific way (H2-TG) in comparison with their wild-type (WT) littermate controls. We had shown before that histamine exerted concentration and time-dependent positive inotropic and positive chronotropic effects only in cardiac preparations from H2-TG and not from WT. We noted under basal conditions (no drug addition) that right atrial preparations from H2-TG exhibited more spontaneous arrhythmias than right atrial preparations from WT. These arrhythmias in H2-TG could be blocked by the H2-histamine receptor antagonist cimetidine. In a similar fashion, histamine and dimaprit (an agonist at H2 and not H1-histamine receptors) more often induced arrhythmias in right atrial preparations from H2-TG than from WT. To understand better the signal transduction mechanism(s) involved in these arrhythmias, we studied partially depolarized left atrial preparations. In these preparations, a positive inotropic effect of histamine was still present in the additional presence of 44 mM potassium ions (used to block sodium channels) in H2-TG but not WT and this positive inotropic effect could be blocked by cimetidine and this is consistent with the involvement of calcium ion channels in the contractile and thus might mediate also the arrhythmogenic effects of histamine in H2-TG. However, compounds reported to release histamine from cells and thereby leading to arrhythmias in humans, namely morphine, ketamine, and fentanyl, failed to induce a more pronounced positive inotropic effect in atrial preparations from H2-TG compared to WT, arguing against an involvement of histamine release in their proarrhythmic side effects in patients. Measuring left ventricular contractility in isolated retrogradely perfused hearts (Langendorff mode), we detected under basal conditions (no drug application) more spontaneous arrhythmias in hearts from H2-TG than from WT. In summary, we noted that overexpression of human H2-histamine receptors in a novel transgenic animal model can lead to arrhythmias. We suggest that this model might be useful to understand the mechanism(s) of histamine-induced cardiac arrhythmias in humans better in a molecular way and may be of value to screen novel antiarrhythmic drugs. [ABSTRACT FROM AUTHOR]

Abstract Background Mounting evidences observed that subacute ruminal acidosis (SARA) induced by high concentration (HC) diet increases the translocation of histamine from digestive tract into circulation causing a diverse of diseases in dairy cows. However, it is largely unknown how it does affect the function of mammary gland and milk quality. Hence, this study aims to observe the effects of histamine derived from the digestive tract on the inflammatory response and casein synthesis in the mammary glands during SARA. Twelve cows fitted rumen fistula were randomly divided into either control group administrated low concentration (LC) diet (60% forage, n = 6) or treatment group administrated HC diet (40% forage, n = 6) for 18 weeks. Results Our data showed that HC diet resulted in significant declines in rumen pH value, milk yield and milk quality, as well as longer duration of averaged pH value below 5.6 per day (more than 180 min) compared to LC diet, these findings confirmed SARA occurence. Our study also observed that SARA increased the content of histamine in rumen fluid, plasma, liver and mammary gland, and enhanced the mRNA expression of histamine specific receptor in the mammary gland. Additionally, we found that the mRNA expression of inflammatory response genes in mammary glands was increased, which was consistent with the protein expression results, showing that the protein kinase C(PKC) / nuclear factor kappa B (NF-κB) or protein kinase A (PKA) / NF-κB signalling pathways of the inflammatory response were activated. The mRNA expression of mTOR, P70S6K and αS1 in mammary glands were significantly decreased with the protein expression of mTOR, P70S6K and αS1-casein, and the phosphorylation levels of the mTOR and P70S6K proteins were also decreased. Conclusions Our study showed that the milk protein of lactating cows is depressed after long-term feeding of HC at the individual level, which was paralleled at the gene and protein levels. The inflammatory response in mammary gland caused by histamine derived from the digestive tract is related to the decline of casein synthesis. Our findings point to a new link between the inflammatory response and casein synthesis, but the understanding of the molecular mechanisms involved in this process will require further research.

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Objective: Reports that the over-the-counter histamine H2 receptor antagonist famotidine could help treat the novel coronavirus disease (COVID-19) appeared from April 2020. We, therefore, examined reports on interactions between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and histamine receptor antagonists. Methods: A systematic literature search was performed by 19 September 2020, and updated on 28 October 2020, in PubMed, Scopus, Cochrane Library and Google Scholar using (COVID-19 OR coronavirus OR SARS-CoV-2) AND (histamine antagonist OR famotidine OR cimetidine). ClinicalTrials.gov was searched for COVID-19 and (famotidine or histamine). Results: Famotidine may be a useful addition in COVID-19 treatment, but the results from prospective randomized trials are as yet awaited. Bioinformatics/drug repurposing studies indicated that, among several medicines, H1 and H2 receptor antagonists may interact with key viral enzymes. However, in vitro studies have to date failed to show a direct inhibition of famotidine on SARS-CoV-2 replication. Conclusions: Clinical research into the potential benefits of H2 receptor antagonists in managing COVID-19 inflammation began from a simple observation and now is being tested in multi-centre clinical trials. The positive effects of famotidine may be due to H2 receptor-mediated immunomodulatory actions on mast cell histamine–cytokine cross-talk, rather than a direct action on SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Background: Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation, and mast cells residing in the gut are a primary source of histamine.Methods: Stroke was induced in male C57BL/6 J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice; mice underwent MCAO surgery and were euthanized at 6 h, 24 h, and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice were associated with age-related changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma.Results: We found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of gut mast cells and gut histamine receptor expression levels. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucin-producing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24-h post-stroke.Conclusion: An important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome. [ABSTRACT FROM AUTHOR]

Background: The efficiency and quality of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are crucial for regenerative medicine, disease modeling, drug screening, and the study of the development events during cardiac specification. However, their applications have been hampered by the differentiation efficiency, poor maturation, and high interline variability. Recent studies have reported that histamine plays important roles in hematopoietic stem cell proliferation and neutrophil maturation. However, its roles in cardiovascular tissue regeneration have not been thoroughly investigated. In the current study, we identified a novel physiological function of the histamine/histamine 1 receptor (H1R) signal in regulating the differentiation of hiPSC-CMs and heart development. Methods: Transgenic zebrafish model (cmlc2: mCherry) was treated with histamine and histamine receptor (HR) antagonists. Histological morphology and ultrastructure of zebrafish heart were measured. Histamine-deficient pregnant mice (HDC−/−) were treated with H1R antagonist (pyrilamine) by intragastric administration from E8.5 to E18.5. Cardiac histological morphology and ultrastructure were analyzed in neonatal mice, and cardiac function in adult mice was measured. In vitro, histamine and HR antagonists were administrated in the culture medium during hiPSC-CM differentiation at different stages. The efficiency and maturation of cardiac differentiation were evaluated. Finally, histamine-treated hiPSC-CMs were transplanted into ischemic myocardium to detect the possible therapeutic effect. Results: Administration of H1R antagonist during heart development induced cardiac dysplasia in zebrafish. Furthermore, using histidine decarboxylase (HDC) knockout mice, we examined abnormal swelling of myocardial mitochondria and autophagy formation under the condition of endogenous histamine deficiency. Histamine significantly promoted myocardial differentiation from human induced pluripotent stem cells (hiPSCs) with better structure and function via a H1R-dependent signal. The activation of histamine/H1R signaling pathway augmented hiPSC-derived cardiomyocyte (hiPSC-CM) differentiation through the ERK1/2-STAT3 signaling pathway. In addition, histamine-pre-treated hiPSC-CMs were transplanted into the ischemic hearts of myocardial injured mice and exhibited better survival and myocardial protection. Conclusions: Thus, these findings indicated that histamine/H1R and its downstream signals were not only involved in cardiac differentiation but also provided a better survival environment for stem cell transplanted into ischemic myocardium. [ABSTRACT FROM AUTHOR]

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-B-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 MChistamine 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-B-mediated maintenance of body homeostasis. [ABSTRACT FROM AUTHOR]

Histamine, an auto-reactive substance and mediator of inflammation, is synthesized from histidine through the action of histidine decarboxylase (HDC). It primarily acts on histamine receptors in the central nervous system (CNS). Increasing evidence suggests that histamine and its receptors play a crucial role in neuroinflammation, thereby modulating the pathology of neurodegenerative diseases. Recent studies have demonstrated that histamine regulates the phenotypic switching of microglia and astrocytes, inhibits the production of pro-inflammatory cytokines, and alleviates inflammatory responses. In the CNS, our research group has also found that histamine and its receptors are involved in regulating inflammatory responses and play a central role in ameliorating chronic neuroinflammation in neurodegenerative diseases. In this review, we will discuss the role of histamine and its receptors in neuroinflammation associated with neurodegenerative diseases, potentially providing a novel therapeutic target for the treatment of chronic neuroinflammation-related neurodegenerative diseases in clinical settings. [Display omitted] [ABSTRACT FROM AUTHOR]

Histamine does not only modulate the immune response and inflammation, but also acts as a neurotransmitter in the mammalian brain. The histaminergic system plays a significant role in the maintenance of wakefulness, appetite regulation, cognition and arousal, which are severely affected in neuropsychiatric disorders. In this review, we first briefly describe the distribution of histaminergic neurons, histamine receptors and their intracellular pathways. Next, we comprehensively summarize recent experimental and clinical findings on the precise role of histaminergic system in neuropsychiatric disorders, including cell-type role and its circuit bases in narcolepsy, schizophrenia, Alzheimer’s disease, Tourette’s syndrome and Parkinson’s disease. Finally, we provide some perspectives on future research to illustrate the curative role of the histaminergic system in neuropsychiatric disorders.

Background: This study investigated the histamine H1 and H4 receptors mRNA (H1R and H4R, respectively) expression on the ocular surface of patients with chronic forms of allergic conjunctival diseases to determine whether they can serve as biomarkers for allergic inflammation in the conjunctiva. Methods: We examined 19 patients with vernal or atopic keratoconjunctivitis (AKC/VKC group) and 15 healthy volunteers (control group). The AKC/VKC group was divided into active and stable stage subgroups. Specimens were obtained from the upper tarsal conjunctiva of each participant using a modified impression cytology method. H1R, H4R, and eotaxin-1, -2, and -3 mRNA (eotaxin-1, eotaxin-2, eotaxin-3, respectively) expression was determined by real-time RT-PCR. Immunohistochemical analysis for eosinophil cationic protein (ECP), eosinophil major basic protein (MBP), eotaxin-2, and histamine H4 receptor (H4R) were performed using conjunctival smears. Results: The number of H4R-positive patients was higher in the active than the stable stage subgroup and control group, whereas no difference was observed for H1R. H1R levels were higher in the active than in the stable stage subgroup, while those of H4R were higher in the active stage subgroup than in the control group. H1R and H4R levels were correlated with eotaxin-2 level. In immunohistochemical analysis, H4R revealed their expression on eosinophils in conjunctival smears of patients with AKC/VKC. Conclusions: H4R is useful as biomarkers of allergic inflammation on ocular surfaces. Most notably, H4R expressed on eosinophils is useful as a biomarker of eosinophilic inflammation of the ocular surface.

Spectrally opponent responses, that is, wavelength‐dependent inversions of response polarity, have been observed at the level of photoreceptors in butterflies. As inter‐photoreceptor connections have been found in the butterfly Papilio xuthus, and histamine is the only neurotransmitter so far identified in insect photoreceptors, we hypothesize that histaminergic sign‐inverting synapses exist in the lamina between different spectral receptors as a mechanism for spectral opponency as in the medulla of Drosophila. Here, we localized two histamine‐gated chloride channels, PxHCLA (Drosophila Ort homolog) and PxHCLB (Drosophila HisCl1 homolog), in the visual system of Papilio xuthus by using specific antisera. The antiPxHCLA labeling was associated with the membrane of nonphotoreceptor cells that are postsynaptic to photoreceptors, while the antiPxHCLB labeling overlapped with photoreceptor axons, indicating that PxHCLB is expressed at inter‐photoreceptor synapses: PxHCLB is likely involved in producing spectral opponency at the first visual synapses. Color processing in Papilio may appear earlier than previously hypothesized in insect visual systems. Two histamine‐gated chloride channels, PxHCLA (Drosophila Ort homolog) and PxHCLB (HisCl1 homolog), were localized in the spectrally‐rich visual system of a butterfly Papilio. PxHCLA was detected in nonphotoreceptor cells postsynaptic to photoreceptors. PxHCLB was detected at inter‐photoreceptor synapses, likely producing spectral opponency in photoreceptors even in the lamina. [ABSTRACT FROM AUTHOR]

We used a range of computational techniques to reveal an increased histamine affinity for its H2 receptor upon deuteration, which was interpreted through altered hydrogen bonding interactions within the receptor and the aqueous environment preceding the binding. Molecular docking identified the area between third and fifth transmembrane α-helices as the likely binding pocket for several histamine poses, with the most favorable binding energy of −7.4 kcal mol−1 closely matching the experimental value of −5.9 kcal mol−1. The subsequent molecular dynamics simulation and MM-GBSA analysis recognized Asp98 as the most dominant residue, accounting for 40% of the total binding energy, established through a persistent hydrogen bonding with the histamine −NH3+ group, the latter further held in place through the N–H∙∙∙O hydrogen bonding with Tyr250. Unlike earlier literature proposals, the important role of Thr190 is not evident in hydrogen bonds through its −OH group, but rather in the C–H∙∙∙π contacts with the imidazole ring, while its former moiety is constantly engaged in the hydrogen bonding with Asp186. Lastly, quantum-chemical calculations within the receptor cluster model and utilizing the empirical quantization of the ionizable X–H bonds (X = N, O, S), supported the deuteration-induced affinity increase, with the calculated difference in the binding free energy of −0.85 kcal mol−1, being in excellent agreement with an experimental value of −0.75 kcal mol−1, thus confirming the relevance of hydrogen bonding for the H2 receptor activation.

BackgroundThe histamine receptor 2 antagonist ranitidine is a commonly used, non-prescription, medication. It limits the development, growth, and metastasis of breast cancers in mouse models of disease. In this study, we examined the role of B cells in this response, the impact of ranitidine on the development of antitumor antibodies and subpopulations of natural killer cells using murine breast cancer models.MethodsPeripheral blood granulocyte populations were assessed in both E0771-GFP and 4T1 orthotopic tumor-bearing mice by evaluation of stained blood smears. Antibody responses were assessed both in terms of the levels of anti-GFP antibodies detected by enzyme-linked immunosorbent assay and also by antibody binding to the surface of tumor cells evaluated by flow cytometry. B cell and NK cell populations were examined in the draining lymph nodes and spleens of tumor-bearing animals, by flow cytometry with and without ranitidine treatment.ResultsOral ranitidine treatment was not associated with changes in peripheral blood granulocyte populations in tumor-bearing mice. However, ranitidine treatment was associated with the development of enhanced antitumor antibody responses. This was not limited to the tumor setting since ranitidine-treated mice immunized with ovalbumin also demonstrated increased IgG antibody responses. Analysis of B cell populations indicated that while B1 cell populations remained unchanged there was a significant decrease in B2 cells in the tumor-draining inguinal lymph nodes. Notably, ranitidine did not significantly inhibit primary tumor growth in B cell-deficient animals. Examination of NK cell populations revealed a significant decrease in the proportion of intermediately functionally mature NK cells populations (CD27+CD11b−) in ranitidine-treated tumor-bearing mice compared with untreated tumor-bearing controls.ConclusionThese data demonstrate an important role for B cells in the enhanced antitumor immune response that occurs in response to ranitidine treatment. Our findings are consistent with a model, whereby ranitidine reduces tumor-associated immune suppression allowing for the development of more effective antitumor responses mediated by B cells which may include the participation of NK cells. These data underline the importance of considering widely used histamine receptor antagonists as modulators of antitumor immunity to breast cancer.

Histamine has long been accepted as a pro-cognitive agent. However, lines of evidence have suggested that the roles of histamine in learning and memory processes are much more complex than previously thought. When explained by the spatial perspectives, there are many contradictory results. However, using emotional memory perspectives, we suspect that the histaminergic system may interplay with stress, reward inhibition, and attention to modulate emotional memory formation. The functional diversity of histamine makes it a viable target for clinical management of neuropsychiatric disorders. Here, we update the current knowledge about the functions of histamine in emotional memory and summarize the underlying molecular and neural circuit mechanisms. Finally, we review the main clinical studies about the impacts of histamine-related compounds on memory and discuss insights into future research on the roles of histamine in emotional memory. Despite the recent progress in histamine research, the histaminergic emotional memory circuits are poorly understood, and it is also worth verifying the functions of histamine receptors in a more spatiotemporally specific manner., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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