Effectiveness of natural biomaterials in the protection and healing of experimentally induced gastric mucosa Ulcer in rats.

BACKGROUND: A gastric ulcer is a painful lesion of the gastric mucosa that can be debilitating or even fatal. The effectiveness of several plant extracts in the therapy of this illness has been demonstrated in traditional pharmacopoeias. AIM: this study was aimed to see if propolis, ginseng in normal or nano form, and amygdalin might help in preventing the ulcerative effects of absolute ethanol. METHODS: Gastroprotective properties of pretreatments before ethanol gavage in rats were compared to omeprazole. The ulcer and stomach parameters (ulcerated regions) were measured (mm2), ulcer inhibition percentage, the stomachs were assessed macroscopically with gastric biopsy histological examinations. RESULTS: Amygdalin, normal and nano ginseng, nano propolis followed by propolis all showed great efficacy in protecting the cyto-architecture and function of the gastric mucosa. The number of ulcerated sites was greatly reduced, and the percentage of stomach protection was increased. Histopathological examination had confirmed great protective effects of the nanoformulations followed by amygdalin. The protection and healing rate was completed to about 100% in all tested materials while ulcer areas were still partially unhealed in normal propolis and omeprazole. Quantitative assay of the m-RNA levels Enothelin 1(ET-1), leukotriene4 (LT-4), and caspase 3(Cas-3) genes and Histamine were done and revealed significant up-regulations in ethanol group and the maximum protective effect was reported with ginseng nano, moreover the histamine content was significantly decreased with nano- formulated extracts. CONCLUSION: Amygdalin and the nanoformulated ginseng and propolis had exhibited a marked protective effect against the ulcerative toxic effects of ethanol.

Effects of the immunoglobulin/histamine complex on panic disorder concurrent with chronic spontaneous urticaria: a case report.

BACKGROUND: Panic disorder and panic attacks are two of the most common problems in psychiatry. A psychoimmunological correlation between allergic diseases and panic disorder has been strongly suggested. Histamine H1 receptor antagonists have been suggested as alternative drugs for the treatment of panic disorder. Chronic spontaneous urticaria (CSU) and panic disorder improved simultaneously with selective serotonin reuptake inhibitor antidepressants. Panic disorder has also been treated with the antihistamine chlorpheniramine. The immunoglobulin/histamine complex is a histamine-fixed immunoglobulin preparation that was reported to be effective in treating CSU. This case report describes the successful treatment of a patient with concomitant panic disorder and CSU for 23 years using immunoglobulin/histamine complex therapy. CASE PRESENTATION: This report describes a 52-year-old female Korean patient who suffered from CSU with panic disorder for 23 years. Basic allergy tests (blood tests and skin prick tests) were conducted before and after treatment for the evaluation of allergic conditions. A multiple allergosorbent test (MAST) for the detection of allergen-specific IgE levels was also performed. The clinical severity of CSU was evaluated using the urticaria severity score system. Diagnostic interviews systematically assessed the diagnostic criteria outlined by the DSM-V, and the patient was evaluated before, during and after treatment using the Beck Depression Inventory (BDI-2) for depression, the State-Trait Anxiety Inventory (STAI) for anxiety and the Beck Hopelessness Score (BHS) for hopelessness. The patient received 2 ml of Histobulin™ (12 mg human immunoglobulin/0.15 µg histamine complex) once a week by subcutaneous injection for the treatment of CSU. Initial improvement of CSU was achieved after the third injection. After the twenty-seventh injection of Histobulin™, she showed no symptoms or signs and ceased allergic medication use. With the remission of CSU, allergic rhinitis was also completely resolved. The frequency of the common cold was significantly decreased during and after treatment. The medication frequency and development of clinical manifestations of panic disorder changed in parallel with the clinical severity of CSU. Moreover, the patient exhibited no clinical manifestations and ceased medication for panic disorder and sleeping pills for insomnia simultaneously with the remission of CSU. In the psychological evaluation, the BDI, STAI and BHS scores improved accordingly. CONCLUSIONS: The immunoglobulin/histamine complex was effective in treating CSU and concomitant panic disorder in this patient and could be effective in treating some types of panic disorder. Considering the mechanisms of action of histamine and the immunoglobulin/histamine complex together with the patient's clinical progress, histamine seemed to be related to panic disorder in this case. The concept of histamine-mediated syndromes, including allergies and psychiatric disorders, shows that a wider disease identity may be needed. Further studies on the immunopathogenesis of panic disorder and the mechanisms of action of the immunoglobulin/histamine complex are necessary.

Cluster-Analytic Identification of Clinically Meaningful Subtypes in MCAS: The Relevance of Heat and Cold.

BACKGROUND: Mast cell activation syndrome (MCAS) is a clinically heterogeneous disease with allergy-like symptoms and abdominal complaints. Its etiology is only partially understood and it is often overlooked. AIMS: The aim of this study was to identify subgroups of MCAS patients to facilitate diagnosis and allow a personalized therapy. METHODS: Based on data from 250 MCAS patients, hierarchical and two-step cluster analyses as well as association analyses were performed. The data used included data from a MCAS checklist asking about symptoms and triggers and a set of diagnostically relevant laboratory parameters. RESULTS: Using a two-step cluster analysis, MCAS patients could be divided into three clusters. Physical trigger factors were particularly decisive for the classification as they showed remarkable differences between the three clusters. Cluster 1, labeled high responders, showed high values for the triggers heat and cold, whereas cluster 2, labeled intermediate responders, presented with high values for the trigger heat and low values for cold. The third cluster, labeled low responders, did not react to thermal triggers. The first two clusters showed more divers clinical symptoms especially with regard to dermatological and cardiological complaints. Subsequent association analyses revealed relationships between triggers and clinical complaints: Abdominal discomfort is mainly triggered by histamine consumption, dermatological discomfort by exercise, and neurological symptoms are related to physical exertion and periods of starvation. The reasons for the occurrence of cardiological complaints are manifold and triggers for respiratory complaints still need better identification. CONCLUSION: Our study identified three distinct clusters on the basis of physical triggers, which also differ significantly in their clinical symptoms. A trigger-related classification can be helpful in clinical practice for diagnosis and therapy. Longitudinal studies should be conducted to further understand the relationship between triggers and symptoms.

Mast cell activation: beyond histamine and tryptase.

INTRODUCTION: Mast cells are found in all tissues and express numerous surface receptors allowing them to sense and respond to allergic, autoimmune, environmental, neurohormonal, pathogenic and stress triggers. Stimulated mast cells are typically called 'activated' but the mechanisms involved and the mediators released can vary considerably. Mast cell activation diseases (MCADs) include primary, secondary and idiopathic conditions, especially mast cell activation syndrome (MCAS), but mast cells are activated in many other disorders making the diagnosis and treatment challenging. AREAS COVERED: Mast cells can release numerous biologically active mediators, some of which are prestored in secretory granules while others are newly synthesized and released without degranulation. Most of the emphasis has so far been on secretion of histamine and tryptase, which do not explain all the multisystemic symptoms experienced by patients with MCADs. As a result, drug development has focused on antiproliferative therapy or blocking the action of individual mediators and not on inhibitors of mast cell activation. EXPERT OPINION: Activated mast cells are involved in the pathogenesis of MCADs, but also in other disorders making appropriate diagnosis and treatment challenging. The definition of mast cell activation should be expanded beyond histamine and tryptase, with an emphasis on better detection and treatments.

Structural alterations in cell organelles induced by photodynamic treatment with chlorin p6 -histamine conjugate in human oral carcinoma cells probed by 3D fluorescence microscopy.

We have explored the intracellular cell organelle's structural alterations after photodynamic treatment with chlorin p6 -histamine conjugate (Cp6 -his) in human oral cancer cells. Herein, the cells were treated with Cp6 -his (10 µm) and counterstained with organelle-specific fluorescence probes to find the site of intracellular localization using confocal microscopy. For photodynamic therapy (PDT), the cells were exposed to ~30 kJ/m2 red light (660 ± 20 nm) to induce ~90% cytotoxicity. We used the three-dimensional (3D) image reconstruction approach to analyze the photodynamic damage to cell organelles. The result showed that Cp6 -his localized mainly in the endoplasmic reticulum (ER) and lysosomes but not in mitochondria and Golgi apparatus (GA). The 3D model revealed that in necrotic cells, PDT led to extensive fragmentation of ER and fragmentation and swelling of GA as well. Results suggest that the indirect damage to GA occurred due to loss of connection between ER and GA. Moreover, in damaged cells with no sign of necrosis, the perinuclear ER appeared condensed and surrounded by several small clumps at the peripheral region of the cell, and the GA was observed to form a single condensed structure. Since these structural changes were associated with apoptotic cell death, it is suggested that the necrotic and apoptotic death induced by PDT with Cp6 -his is determined by the severity of damage to ER and indirect damage to GA. The results suggest that the indirect damage to cell organelle apart from the sites of photosensitizer localization and the severity of damage at the organelle level contribute significantly to the mode of cell death in PDT.

Orally administered solasodine, a steroidal glycoalkaloid, suppresses ovalbumin-induced exaggerated Th2-immune response in rat model of bronchial asthma.

Bronchial asthma is a chronic lung disorder, that affects an estimated 262 million people worldwide, thereby, causing a large socio-economic burden. Drug molecules from natural sources have exhibited a good promise in providing an alternative therapy in many chronic ailments. Solasodine, a glycoalkaloid has received an immense interest due to its large pharmacological and industrial value, however, its usefulness in asthma control has not been investigated till date. In this work, solasodine was tested for its ability to reverse several characteristics of bronchial asthma induced by intraperitoneal injection of ovalbumin (OVA) and aluminium hydroxide in experimental rats. Treating asthmatic animals with solasodine (1 mg/kg b.w. or 10 mg/kg b.w.) or dexamethasone (2.5 mg/kg b.w.) reversed OVA-induced airway hyperresponsiveness, infiltration of inflammatory cells and histamine levels in the airways. Furthermore, as compared to OVA-control rats, allergen-induced elevated levels of IgE, nitrites, nitric oxide, and pro-inflammatory mediators, including TNF-α, IL-1ß, LTD-4, and Th2-cytokines, particularly, IL-4, IL-5 were remarkably reduced in both bronchoalveolar lavage fluid and blood. These findings are supported by significant protection offered by various treatments against OVA-induced airway inflammation and mast cell degranulation in mesenteric tissues. Further, In-silico molecular docking studies performed to determine inhibitory potential of solasodine at IL-4 and IL-5, demonstrated strong affinity of phytocompound for these receptors than observed with antagonists previously reported. Results of current study imply that solasodine has therapeutic promise in allergic asthma, presumably due to its ability to prevent mast cell degranulation and consequent generation of histamine and Th2-associated cytokines in airways.

Identification of Preoperative Serum Metabolites Associated With Postoperative Opioid Consumption in Gastric Cancer Patients by Extreme Phenotype Sampling.

BACKGROUND: Postoperative pain increases patients' risk and opioids remain the main analgesics to relieve it. However, improper use of opioids causes many side effects and identification of suitable preoperative biomarkers that predict postoperative opioid consumption may aid clinicians in improving analgesic strategies for patients. The activity of metabolites modulates multiple phenotypes and can function as biomarkers for disease prediction and diagnosis. OBJECTIVES: In this study, we explore whether preoperative serum metabolites are associated with postoperative opioid consumption in gastric cancer patients by extreme phenotype sampling. STUDY DESIGN: This was a case-control, observational study. SETTING: This study was conducted at Beijing Cancer Hospital. METHODS: One hundred and sixty-nine gastric cancer patients participated in this study. After exclusion of 51 patients, postoperative pain intensity and opioid consumption data of 118 patients were collected. Patients were sorted by gender and classified into 2 groups based on opioid consumption during the 24h postoperative period. Patients in the sufentanil high consumption (SHC) group and patients in the sufentanil low consumption (SLC) group were ranked in the top or bottom 30% of sufentanil consumption, respectively. Untargeted metabolomic analysis of preoperative serum samples from both groups was performed by ultra-performance liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and orthogonal partial least square discriminant analysis. Allele frequencies of DAO rs10156191 and MAOB rs1799836 SNPs in both groups were detected by Sanger sequencing. RESULTS: Thirty-five metabolites in preoperative serum were significantly different between the SLC and SHC groups. Hydrogen phosphate had the highest area under the curve in a ROC analysis (0.98), suggesting that it may serve as a predictive biomarker for postoperative opioid consumption. Differential metabolites unique to the male and female subgroups were also identified. Histidine metabolism was the most altered pathway between the SLC and SHC groups. There were no significant differences in the allele frequencies of 2 SNPs associated with histamine degradation; however, 2 metabolites of histamine degradation, imidazole-4-acetaldehyde, and methylimidazole acetaldehyde, showed different trends in the 2 groups. LIMITATIONS: Our study was restricted to gastric cancer patients with strict exclusion criteria, which may limit the generalizability to other groups. CONCLUSION: Preoperative serum metabolites were associated with postoperative opioid consumption. Different efficiencies of histamine degradation may be one cause of the variable sensitivity of patients to acute pain and warrants further study.

Efficacy and safety of proton pump inhibitors versus histamine-2 receptor blockers in the cardiac surgical population: insights from the PEPTIC trial.

OBJECTIVES: The comparative effectiveness and safety of proton pump inhibitors (PPIs) versus histamine-2 receptor blockers for stress ulcer prophylaxis in the cardiac surgical intensive care unit population is uncertain. Although the Proton Pump Inhibitors versus Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) trial reported a higher risk of mortality in the PPI arm with no difference in gastrointestinal bleeding, detailed information on surgical variables and clinically relevant surgical subgroups was not available. METHODS: The analysis included all Canadian cardiac surgery patients enrolled in the PEPTIC trial. Data were electronically linked using unique patient identifiers to a clinical information system. Outcomes of interest included in-hospital mortality, gastrointestinal bleeding, Clostridium difficile infections, ventilator-associated conditions and length of stay. RESULTS: We studied 823 (50.6%) randomized to PPIs and 805 (49.4%) to histamine-2-receptor blockers. In the intention-to-treat analysis, there were no differences in hospital mortality [PPI: 4.3% vs histamine-2 receptor blockers: 4.8%, adjusted odds ratio (aOR) 0.97, 95% confidence interval (CI) 0.55-1.70], gastrointestinal bleeding (3.9% vs 4.8%, aOR 1.09, 95% CI 0.66-1.81), C. difficile infections (0.9% vs 0.1%, aOR 0.18, 95% CI 0.02-1.59), ventilator-associated conditions (1.6% vs 1.7%, aOR 0.92, 95% CI 0.85-1.00) or median length of stay (9.2 vs 9.8 days, adjusted risk ratio 1.06, 85% CI 0.99-1.13). No significant treatment differences were observed among subgroups of interest or per-protocol populations. CONCLUSIONS: In a secondary analysis of cardiac surgery patients enrolled in the PEPTIC trial in Canada, no differences in effectiveness or safety were observed between use of PPIs and histamine-2 receptor blockers for stress ulcer prophylaxis. CLINICAL TRIAL REGISTRATION NUMBER: anzctr.org.au identifier: ACTRN12616000481471.

Immunotherapy with HDC/IL-2 may be clinically efficacious in acute myeloid leukemia of normal karyotype.

Immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) reduces the risk of relapse in the post-chemotherapy phase of acute myeloid leukemia (AML). Here we report the results of exploratory analyses of the clinical efficacy of HDC/IL-2 in AML with focus on the impact of karyotype aberrations in leukemic cells. Post-hoc analyses of phase III trial data suggested that HDC/IL-2 is primarily beneficial for patients with AML of normal karyotype. These results may be helpful in the selection of patients who are suitable for therapy and in the design of future immunotherapy protocols aiming at further defining the mechanism of relapse prevention by HDC/IL-2.

Histaminergic transmission slows progression of amyotrophic lateral sclerosis.

BACKGROUND: Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti-inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine-mediated therapeutic strategy in ALS mice. METHODS: We adopted an integrative multi-omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)-G93A mice that recapitulate key ALS features, with the brain-permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1-G93A motor neuron-like cells. RESULTS: We identified 13 histamine-related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine-related genes overlapped with genomic regions disrupted by DNA copy number and with ALS-linked pathogenic variants. Histidine treatment in SOD1-G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro. CONCLUSIONS: Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine-related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi-gene network responsible for ALS and, furthermore, in the drug development process.

Histamine targets myeloid-derived suppressor cells and improves the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade.

Myeloid-derived suppressor cells (MDSCs) are immature monocytes and granulocytes that impede immune-mediated clearance of malignant cells by multiple mechanisms, including the formation of immunosuppressive reactive oxygen species (ROS) via the myeloid cell NADPH oxidase (NOX2). Histamine dihydrochloride (HDC), a NOX2 inhibitor, exerts anti-cancer efficacy in experimental tumor models but the detailed mechanisms are insufficiently understood. To determine effects of HDC on the MDSC compartment we utilized three murine cancer models known to entail accumulation of MDSC, i.e. EL-4 lymphoma, MC-38 colorectal carcinoma, and 4T1 mammary carcinoma. In vivo treatment with HDC delayed EL-4 and 4T1 tumor growth and reduced the ROS formation by intratumoral MDSCs. HDC treatment of EL-4 bearing mice also reduced the accumulation of intratumoral MDSCs and reduced MDSC-induced suppression of T cells ex vivo. Experiments using GR1-depleted and Nox2 knock out mice supported that the anti-tumor efficacy of HDC required presence of NOX2+ GR1+ cells in vivo. In addition, treatment with HDC enhanced the anti-tumor efficacy of programmed cell death receptor 1 (PD-1) and PD-1 ligand checkpoint blockade in EL-4- and MC-38-bearing mice. Immunomodulatory effects of a HDC-containing regimen on MDSCs were further analyzed in a phase IV trial (Re:Mission Trial, ClinicalTrials.gov; NCT01347996) where patients with acute myeloid leukemia received HDC in conjunction with low-dose IL-2 (HDC/IL-2) for relapse prevention. Peripheral CD14+HLA-DR-/low MDSCs (M-MDSCs) were reduced during cycles of HDC/IL-2 therapy and a pronounced reduction of M-MDSCs during HDC/IL-2 treatment heralded favorable clinical outcome. We propose that anti-tumor properties of HDC may comprise the targeting of MDSCs.

Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia.

Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML. Cancer Immunol Res; 6(9); 1110-9. ©2018 AACR.

Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy.

Regulatory T cells (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3+CD25highCD4+ Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival. We observed a pronounced increase in Treg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating Tregs resembled thymic-derived natural Tregs (nTregs), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by Treg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of Treg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of Tregs in later treatment cycles and a short Treg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive Tregs that may be targeted for improved anti-leukemic efficiency.

Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H4 receptor agonists and opportunity for combination with radiation.

The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells.Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma.

Dynamics of myeloid cell populations during relapse-preventive immunotherapy in acute myeloid leukemia.

Relapse of leukemia in the postchemotherapy phase contributes to the poor prognosis and survival in patients with acute myeloid leukemia (AML). In an international phase IV trial (ClinicalTrials.gov; NCT01347996), 84 patients with AML in first complete remission who had not undergone transplantation received immunotherapy with histamine dihydrochloride (HDC) and low-dose IL-2 with the aim of preventing relapse. The dynamics of myeloid cell counts and expression of activation markers was assessed before and after cycles of immunotherapy and correlated with clinical outcome in terms of relapse risk and survival. During cycles, a pronounced increase in blood eosinophil counts was observed along with a reduction in monocyte and neutrophil counts. A strong reduction of blood monocyte counts during the first HDC/IL-2 treatment cycle predicted leukemia-free survival. The HDC component of the immunotherapy exerts agonist activity at histamine type 2 receptors (H2Rs) that are expressed by myeloid cells. It was observed that the density of H2 R expression in blood monocytes increased during cycles of immunotherapy and that high monocyte H2R expression implied reduced relapse risk and improved overall survival. Several other activation markers, including HLA-DR, CD86, and CD40, were induced in monocytes and dendritic cells during immunotherapy but did not predict clinical outcome. In addition, expression of HLA-ABC increased in all myeloid populations during therapy. A low expression of HLA-ABC was associated with reduced relapse risk. These results suggest that aspects of myeloid cell biology may impact clinical benefit of relapse-preventive immunotherapy in AML.

Gastroprotective and ulcer healing effects of hydroethanolic extract of leaves of Caryocar coriaceum: Mechanisms involved in the gastroprotective activity.

This work aimed to determine the chemical fingerprint of hydroethanolic extract of leaves of Caryocar coriaceum (HELCC) and the gastroprotective activity. The chemical fingerprint of HELCC was analyzed by HPLC-DAD, to quantify total phenols and flavonoids were carried out by Folin-Ciocalteu reagent and aluminum chloride assay, while in vitro antioxidant activity was evaluated by the DPPH method. The methods used to determine pharmacological activity were: gastroprotective screening test in classical models of induced acute and chronic gastric lesions and physical barrier test. Further assays were performed to demonstrate the involvement of NO, prostaglandins, ATP-dependent potassium channels, TRPV, noradrenergic α2 receptors, histamines, and opioids. The DPPH method demonstrated the antioxidant activity of the extract, in vitro, explained by the presence of polyphenols and flavonoids. Oral administration of the extract, previously dissolved in deionized water, at a dose of 100 mg/kg decreased the lesions induced by indomethacin, acidified ethanol, ethanol and acetic acid by 75.0, 72.8, 69.4 and 86.2% respectively. It was demonstrated that opioid receptors, α2-adrenergic receptors and primary afferent neurons sensitive to capsaicin were involved in the mechanism of gastric protection, in addition to the contribution of NO and prostaglandins. The results show that extract is a promising candidate for the treatment of gastric ulcers.

Survey of immuno-allergological ultra high dilution research.

BACKGROUND: Experiments about basic research in Immuno-allergology reported by M. Bastide and B. Poitevin in Ultra High Dilution (1994) have been appraised from a 20 year perspective. The numerous experiments published mainly focus on immunological regulation, inflammatory process and basophil activation. They are analyzed according to one essential criterion: repeatability. METHODS: The commentary reflects the research details made available in a recently published literature review, also published in French. RESULTS: The regulatory effect of high dilution of bursin on immune response has been observed in multiple experiments but not reproduced by independent teams. The immunomodulating effect of Thymulin has been confirmed in mice. Rhus toxicodendron has an anti-inflammatory activity on different models, from mother tincture (TM) to very high dilutions. The homeopathic complex Canova activates macrophages in vitro and in vivo, induces lymphocyte proliferation, and reduces the size of tumors and mortality of sarcoma-bearing mice. Some homeopathic medicines used in clinical inflammation modulate in vitro the neutrophil activation, with variability in the protocols used and in the medicines tested. In allergology, high dilution histamine has an inhibitory effect on basophil activation in multicenter trials and with independent teams, either with methods implying a change in basophil staining or with flow cytometry. However, high dilution histamine had no effect in some well-conducted experiments. The inhibitory effect of Apis mellifica has not been studied with the flow cytometry method, as well as the activation of basophil by anti-IgE high dilution, published in Nature. CONCLUSIONS: Despite considerable research activity in immuno-allergology and a great increase in the number of publications, there is still not in this domain a "gold standard" trial in basic research in homeopathy. The most studied system, the inhibitory effect of histamine high dilutions on basophil activation, requires clarifications of various factors, including individual sensitivity. For scientific and epistemological reasons, the same work should be carried out for independent reproduction of the experiments conducted with anti-IgE and Apis mel high dilution, in complement of the new axes of research in immunoallergology developed since 20 years.

Histamine reduces boron neutron capture therapy-induced mucositis in an oral precancer model.

OBJECTIVES: Searching for more effective and selective therapies for head and neck cancer, we demonstrated the therapeutic effect of boron neutron capture therapy (BNCT) to treat oral cancer and inhibit long-term tumor development from field-cancerized tissue in the hamster cheek pouch model. However, BNCT-induced mucositis in field-cancerized tissue was dose limiting. In a clinical scenario, oral mucositis affects patients' treatment and quality of life. Our aim was to evaluate different radioprotectors, seeking to reduce the incidence of BNCT-induced severe mucositis in field-cancerized tissue. MATERIALS AND METHODS: Cancerized pouches treated with BNCT mediated by boronophenylalanine at 5 Gy were treated as follows: control: saline solution; Hishigh : histamine 5 mg kg(-1) ; Hislow : histamine 1 mg kg(-1) ; and JNJ7777120: 10 mg kg(-1). RESULTS: Hislow reduced the incidence of severe mucositis in field-cancerized tissue to 17% vs CONTROL: 55%; Hishigh : 67%; JNJ7777120: 57%. Hislow was non-toxic and did not compromise the long-term therapeutic effect of BNCT or alter gross boron concentration. CONCLUSION: Histamine reduces BNCT-induced mucositis in experimental oral precancer without jeopardizing therapeutic efficacy. The fact that both histamine and boronophenylalanine are approved for use in humans bridges the gap between experimental work and potential clinical application to reduce BNCT-induced radiotoxicity in patients with head and neck cancer.

Histamine upregulates Nav1.8 expression in primary afferent neurons via H2 receptors: involvement in neuropathic pain.

INTRODUCTION: The upregulation of Nav1.8 in primary afferents plays a critical role in the development and persistence of neuropathic pain. The mechanisms underlying the upregulation are not fully understood. AIMS: The present study aims to investigate the regulatory effect of histamine on the expression of Nav1.8 in primary afferent neurons and its involvement in neuropathic pain. RESULTS: Histamine at 10(-8) M increased the expression of Nav1.8 in cultured DRG neurons. This effect could be blocked by H2 receptor antagonist cimetidine or famotidine, but not by H1 receptor antagonist pyrilamine or dual H3 /H4 antagonist thioperamide. Peri-sciatic administration of histamine increased Nav1.8 expression in the sciatic nerve and L4/L5 DRG neurons in a dose-dependent manner, accompanied with remarkable mechanical allodynia and heat hyperalgesia in the ipsilateral hindpaw. Famotidine but not pyrilamine or thioperamide inhibited Nav1.8 upregulation and pain hypersensitivity. In addition, famotidine (40 mg/kg, i.p.) not only suppressed autotomy behavior in the rat neuroma model of neuropathic pain but also attenuated mechanical allodynia and thermal hyperalgesia following partial sciatic nerve ligation. Moreover, famotidine inhibited Nav1.8 upregulation in the neuroma and ligated sciatic nerve. CONCLUSIONS: Our findings indicate that histamine increases Nav1.8 expression in primary afferent neurons via H2 receptor-mediated pathway and thereby contributes to neuropathic pain. H2 receptor antagonists may potentially be used as analgesics for patients with neuropathic pain.

Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma.

BACKGROUND: Functional presence of histamine H4 receptor (H4R) was demonstrated in human melanoma cell lines and biopsies. OBJECTIVE: The purposes of this work were to investigate signal transduction pathways and biological responses triggered by the activation of H4R in human primary (WM35) and metastatic (M1/15) melanoma cell lines and to evaluate the in vivo antitumor activity of histamine (HA) and clozapine (CLZ) on human M1/15 melanoma xenografts. METHODS: Clonogenic assay, incorporation of BrdU, cell cycle distribution, phosphorylation levels of ERK1/2 and cAMP production were evaluated in vitro. An experimental human melanoma model was developed into athymic nude mice. Tumor growth, survival and histochemical studies were performed in order to investigate the expression levels of H4R, HA, PCNA, mitotic index (MI), and angiogenesis. RESULTS: The results indicate that H4R agonists inhibited forskolin-induced cAMP levels only in M1/15 cells while increased phosphorylation levels of ERK1/2 and decreased proliferation in both cell types. In vivo studies show that HA and CLZ (1mgkg(-1), sc) significantly increased median survival and decreased tumor volume. These effects were associated to a reduction in MI, in the expression of proliferation marker and in intratumoral neovascularization. CONCLUSIONS: We conclude that HA and CLZ exhibit an antitumoral effect in vitro and in vivo on human melanoma, suggesting the therapeutic potential of these compounds for the treatment of malignant melanoma.