RESUMO
Cancer morbimortality is still a great concern despite advances in research and therapies. Histamine and its receptors' ligands can modulate different biological responses according to the cell type and the receptor subtype involved. Besides the wide variety of histamine functions in normal tissues, diverse roles in the acquisition of hallmarks of cancer such as sustained proliferative signaling, resistance to cell death, angiogenesis, metastasis, altered immunity and modified microenvironment have been described. This review summarizes the present knowledge of the various roles of histamine H2 receptor (H2R) ligands in neoplasias. A bioinformatic analysis of human tumors showed dissimilar results in the expression of the H2R gene according to tumor type when comparing malignant versus normal tissues. As well, the relationship between patients' survival parameters and H2R gene expression levels also varied, signaling important divergences in the role of H2R in neoplastic progression in different cancer types. Revised experimental evidence showed multiple effects of H2R antihistamines on several of the cited hallmarks of cancer. Interventional and retrospective clinical studies evaluated different H2R antihistamines in cancer patients with two main adjuvant uses: improving antitumor efficacy (which includes regulation of immune response) and preventing toxic adverse effects produced by chemo or radiotherapy. While there is a long path to go, research on H2R antihistamines may provide new opportunities for developing more refined combination therapeutic strategies for certain cancer types to improve patients' survival and health-related quality of life.
Assuntos
Histamina , Neoplasias , Humanos , Histamina/metabolismo , Estudos Retrospectivos , Qualidade de Vida , Antagonistas dos Receptores H2 da Histamina , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/uso terapêutico , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/metabolismo , Neoplasias/tratamento farmacológico , Microambiente TumoralRESUMO
It has been demonstrated that the nucleus accumbens (NAc) plays an important role in modulation of nociception due to its extensive connections with different regions of the brain. In addition, this nucleus receives histaminergic projections from tuberomammillary nucleus. Considering the role of the central histaminergic system in nociception, the effect of histamine and its H 2 and H 3 receptors agonist and antagonist microinjections into the NAc on orofacial formalin nociception was investigated. In male Wistar rats, using stereotaxic surgery, two guide cannulas were bilaterally implanted into the right and left sides of the NAc. Diluted formalin solution (1.5%, 50 µl) injection into the vibrissa pad led to orofacial nociception. Immediately after injection, face rubbing was observed at 3-min blocks for 45 min. Orofacial formalin nociception was characterized by a biphasic nociceptive response (first phase: 0-3 min and second phase: 15-33 min). Microinjections of histamine (0.5 and 1 µg/site), dimaprit (1 µg/site, H 2 receptor agonist) and thioperamide (2 µg/site, H 3 receptor antagonist) attenuated both phases of formalin orofacial nociception. Prior microinjection of famotidine (2 µg/site) inhibited the antinociceptive effects of dimaprit (1 µg/site). Furthermore, comicroinjection of thioperamide (2 µg/site) and immepip (1 µg/site) prevented thioperamide (2 µg/site)-induced antinociception. Naloxone (2 µg/site) also prevented histamine, dimaprit- and thioperamide-induced antinociception. The results of this study demonstrate that at the level of the NAc, histamine and its H 2 and H 3 receptors are probably involved in the modulation of orofacial nociception with an opioid system-dependent mechanism.
Assuntos
Histamina , Receptores Opioides , Ratos , Animais , Masculino , Histamina/farmacologia , Ratos Wistar , Receptores Opioides/metabolismo , Núcleo Accumbens/metabolismo , Nociceptividade , Formaldeído/efeitos adversos , Dimaprit/efeitos adversos , Dor Facial/tratamento farmacológico , Receptores Histamínicos H2/metabolismoRESUMO
Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with numerous neurodegenerative diseases such as aging and Alzheimer's disease (AD). Overactivation of microglia induced neuroinflammation is well acknowledged to contribute to the impaired neurogenesis in pathologies of these diseases and then leading to cognitive dysfunction. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia to modulate inflammatory response. However, whether inhibition of H3R is responsible for the neurogenesis and cognition in chronic neuroinflammation induced injury and the mechanism remains unclear. In this study, we found that inhibition of H3R by thioperamide reduced the microglia activity and promoted a phenotypical switch from pro-inflammatory M1 to anti-inflammatory M2 in microglia, and ultimately attenuated lipopolysaccharide (LPS) induced neuroinflammation in mice. Additionally, thioperamide rescued the neuroinflammation induced impairments of neurogenesis and cognitive function. Mechanically, the neuroprotection of thioperamide was involved in histamine dependent H2 receptor (H2R) activation, because cimetidine, an H2R antagonist but not pyrilamine, an H1R antagonist reversed the above effects of thioperamide. Moreover, thioperamide activated the H2R downstream phosphorylated protein kinase A (PKA)/cyclic AMP response element-binding protein (CREB) pathway but inhibited nuclear factor kappa-B (NF-κB) signaling. Activation of CREB by thioperamide promoted interaction of CREB-CREB Binding Protein (CBP) to increase anti-inflammatory cytokines (Interleukin-4 and Interleukin-10) and brain-derived neurotrophic factor (BDNF) release but inhibited NF-κB-CBP interaction to decrease pro-inflammatory cytokines (Interleukin-1ß, Interleukin-6 and Tumor necrosis factor α) release. H89, an inhibitor of PKA/CREB signaling, abolished effects of thioperamide on neuroinflammation and neurogenesis. Taken together, these results suggested under LPS induced neuroinflammation, the H3R antagonist thioperamide inhibited microglia activity and inflammatory response, and ameliorated impairment of neurogenesis and cognitive dysfunction via enhancing histamine release. Histamine activated H2R and reinforced CREB-CBP interaction but weakened NF-κB-CBP interaction to exert anti-inflammatory effects. This study uncovered a novel histamine dependent mechanism behind the therapeutic effect of thioperamide on neuroinflammation.
Assuntos
Lipopolissacarídeos , NF-kappa B , Animais , Anti-Inflamatórios/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Citocinas/metabolismo , Hipocampo , Histamina/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia , NF-kappa B/metabolismo , Neurogênese , Doenças Neuroinflamatórias , Receptores Histamínicos H2/metabolismoRESUMO
In an integrative approach, we studied cardiac effects of recently published novel H2 receptor agonists in the heart of mice that overexpress the human H2 receptor (H2-TG mice) and littermate wild type (WT) control mice and in isolated electrically driven muscle preparations from patients undergoing cardiac surgery. Under our experimental conditions, the H2 receptor agonists UR-Po563, UR-MB-158, and UR-MB-159 increased force of contraction in left atrium from H2-TG mice with pEC50 values of 8.27, 9.38, and 8.28, respectively, but not in WT mice. Likewise, UR-Po563, UR-MB-158, and UR-MB-159 increased the beating rate in right atrium from H2-TG mice with pEC50 values of 9.01, 9.24, and 7.91, respectively, but not from WT mice. These effects could be antagonized by famotidine, a H2 receptor antagonist. UR-Po563 (1 µM) increased force of contraction in Langendorff-perfused hearts from H2-TG but not WT mice. Similarly, UR-Po563, UR-MB-158, or UR-MB-159 increased the left ventricular ejection fraction in echocardiography of H2-TG mice. Finally, UR-Po563 increased force of contraction in isolated human right atrial muscle strips. The contractile effects of UR-Po563 in H2-TG mice were accompanied by an increase in the phosphorylation state of phospholamban. In summary, we report here three recently developed agonists functionally stimulating human cardiac H2 receptors in vitro and in vivo. We speculate that these compounds might be of some merit to treat neurologic disorders if their cardiac effects are blocked by concomitantly applied receptor antagonists that cannot pass through the blood-brain barrier or might be useful to treat congestive heart failure in patients. SIGNIFICANCE STATEMENT: Recently, a new generation of histamine H2 receptor (H2R) agonists has been developed as possible treatment option for Alzheimer's disease. Here, possible cardiac (side) effects of these novel H2R agonists have been evaluated.
Assuntos
Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Contração Miocárdica/efeitos dos fármacos , Receptores Histamínicos H2/metabolismo , Idoso , Animais , Relação Dose-Resposta a Droga , Feminino , Histamina/farmacologia , Humanos , Preparação de Coração Isolado/métodos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Contração Miocárdica/fisiologiaRESUMO
Intracellular cAMP (i-cAMP) levels play an important role in acute myeloid leukemia (AML) cell proliferation and differentiation. Its levels are the result of cAMP production, degradation, and exclusion. We have previously described histamine H2 receptors and MRP4/ABCC4 as two potential targets for AML therapy. Acting through histamine H2 receptors, histamine increases cAMP production/synthesis, while MRP4/ABCC4 is responsible for the exclusion of this cyclic nucleotide. In this study, we show that histamine treatment induces MRP4/ABCC4 expression, augmenting cAMP efflux, and that histamine, in combination with MRP inhibitors, is able to reduce AML cell proliferation. Histamine, through histamine H2 receptor, increases i-cAMP levels and induces MRP4 transcript and protein levels in U937, KG1a, and HL-60 cells. Moreover, histamine induces MRP4 promoter activity in HEK293T cells transfected with histamine H2 receptor (HEK293T-H2 R). Our results support that the cAMP/Epac-PKA pathway, and not MEK/ERK nor PI3K/AKT signaling cascades, is involved in histamine-mediated upregulation of MRP4 levels. Finally, the addition of histamine potentiates the inhibition of U937, KG1a, and HL-60 cell proliferation induced by MRP4 inhibitors. Our data highlight that the use of a poly-pharmacological approach aimed at different molecular targets would be beneficial in AML treatment.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/genética , AMP Cíclico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Histamina/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Receptores Histamínicos H2/genética , Benzotiazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação Leucêmica da Expressão Gênica , Genes Reporter , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células HEK293 , Células HL-60 , Histamina/metabolismo , Humanos , Luciferases/genética , Luciferases/metabolismo , Terapia de Alvo Molecular/métodos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Probenecid/farmacologia , Regiões Promotoras Genéticas , Propionatos/farmacologia , Quinolinas/farmacologia , Receptores Histamínicos H2/metabolismo , Transdução de Sinais , Triazóis/farmacologia , Células U937RESUMO
The majority of advanced prostate cancer therapies aim to inhibit androgen receptor (AR) signaling. However, AR reactivation inevitably drives disease progression to castration-resistant prostate cancer (CRPC). Here we demonstrate that protein arginine methyltransferase 5 (PRMT5) functions as an epigenetic activator of AR transcription in CRPC, requiring cooperation with a methylosome subunit pICln. In vitro and in xenograft tumors in mice, targeting PRMT5 or pICln suppressed growth of CRPC cells. Full-length AR and AR-V7 transcription activation required both PRMT5 and pICln but not MEP50. This activation of transcription was accompanied by PRMT5-mediated symmetric dimethylation of H4R3 at the proximal AR promoter. Further, knockdown of PRMT5 abolished the binding of pICln (but not vice versa) to the AR proximal promoter region, suggesting that PRMT5 recruits pICln to the AR promoter to activate AR transcription. Differential gene expression analysis in 22Rv1 cells confirmed that PRMT5 and pICln both regulate the androgen signaling pathway. In addition, PRMT5 and pICln protein expression positively correlated with AR and AR-V7 protein expression in CRPC tissues and their expression was highly correlated at the mRNA level across multiple publicly available CRPC datasets. Our results suggest that targeting PRMT5 or pICln may be explored as a novel therapy for CRPC treatment by suppressing expression of AR and AR splice variants to circumvent AR reactivation. SIGNIFICANCE: This study provides evidence that targeting PRMT5 can eliminate expression of AR and can be explored as a novel therapeutic approach to treat metastatic hormone-naïve and castration-resistant prostate cancer.
Assuntos
Canais Iônicos/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Proteína-Arginina N-Metiltransferases/fisiologia , Receptores Androgênicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Crescimento Celular , Progressão da Doença , Regulação para Baixo , Epigênese Genética/fisiologia , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Canais Iônicos/antagonistas & inibidores , Canais Iônicos/genética , Masculino , Metilação , Camundongos , Transplante de Neoplasias , Regiões Promotoras Genéticas , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos H3/metabolismoRESUMO
Gastric ulcer is a painful lesion of the gastric mucosa which can be disabling, or even more very serious in the case of a perforation of the stomach and internal hemorrhage. Traditional pharmacopeias have shown the efficacy of various plant extracts in the treatment of this pathology. Some extracts from Opuntia ficus indica (OFI) have been proven to have medicinal therapeutic benefits. The aim of this study was to investigate the preventive and curative effects of OFI seed oil extracted by cold pressing on an ethanol-induced gastric ulcer model in rats. Gastroprotective activities of the oil were assessed as pretreatments prior to ethanol gavage of Wistar rats compared to reference drugs. Two oil dose effects were tested. Ulcer and gastric parameters were measured (ulcerated areas (mm2), % of ulcer inhibition, gastric juice volume and pH, and mucus weight). Macroscopical and microscopical assessments of the stomachs as well as gastric biopsy histological studies were carried out. OFI oil exhibited a high efficiency in the protection of the cytoarchitecture and function of the gastric mucosa against the severe damages provoked by ethanol intake. Ulcerated areas were very significantly reduced and the % of ulcer inhibition was the highest under OFI oil pretreatment. Mucus production was stimulated, gastric juice volume was reduced, and its pH was increased. Histopathological examination of H&E-stained biopsies collected from gastric mucosae from the different experimental groups confirmed the gastroprotective efficacy of OFI oil against ethanol-induced symptoms such as inflammation and damages like bleeding, erosions, lesions, necrosis, and ulcers. Furthermore, OFI oil treatment speeded-up the reduction of the surface of ethanol-induced ulcerated areas in a dose-dependent manner, leading to a time gain in the healing process. The healing rate reached 91% on day 2 and 99% on day 3, and a complete heal was attained at the fourth day under OFI oil treatment, while ulcer areas were still partially unhealed in all the other groups. The therapeutic effects of OFI oil against gastric ulcer could be mediated by its varied bioactive compounds that we have demonstrated in the analytical study. They could act synergistically or in a delayed manner to optimize the healing process through protective antioxidant properties, as well as an antagonism against histamine H2-receptors, a stimulation of the signaling pathways necessary for mucus and bicarbonate production, and reduction of inflammatory processes in the gastric mucosa. Additionally, OFI oil fatty acids (especially unsaturated) and triacylglycerols contribute to the reconstruction and the repair of the cell membrane lipid bilayer during the gastric ulcer healing process.
Assuntos
Opuntia/metabolismo , Óleos de Plantas/química , Substâncias Protetoras/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Antioxidantes/química , Cromatografia Gasosa , Etanol/toxicidade , Ácidos Graxos Insaturados/farmacologia , Flavonoides/análise , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Antagonistas dos Receptores H2 da Histamina/química , Antagonistas dos Receptores H2 da Histamina/farmacologia , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Masculino , Extratos Vegetais/química , Óleos de Plantas/farmacologia , Óleos de Plantas/uso terapêutico , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Wistar , Receptores Histamínicos H2/química , Receptores Histamínicos H2/metabolismo , Sementes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Úlcera Gástrica/prevenção & controleRESUMO
The histamine H2 receptor (H2R) is a G protein-coupled receptor that mediates cyclic AMP production, protein kinase A activation, and MAP kinase signaling. In order to explore the multifaceted effects of histamine signaling on immune cells, phagocytosis was evaluated using primary mouse-derived macrophages. Phagocytosis is initiated by signaling via surface-bound scavenger receptors and can be regulated by autophagy. Absence of H2R signaling resulted in diminished phagocytosis of live bacteria and synthetic microspheres by primary macrophages from histamine H2 receptor gene (Hrh2)-deficient mice. Flow cytometry and immunofluorescence microscopy were used to quantify phagocytosis of phylogenetically diverse bacteria as well as microspheres of defined chemical composition. Autophagy and scavenger receptor gene expression were quantified in macrophages after exposure to Escherichia coli. Expression of the autophagy genes, Becn1 and Atg12, was increased in Hrh2-/- macrophages, indicating upregulation of autophagy pathways. Expression of the Macrophage Scavenger Receptor 1 gene (Msr1) was diminished in Hrh2-deficient macrophages, supporting the possible importance of histamine signaling in scavenger receptor abundance and macrophage function. Flow cytometry confirmed diminished MSR1 surface abundance in Hrh2-/- macrophages. These data suggest that H2R signaling is required for effective phagocytosis by regulating the process of autophagy and scavenger receptor MSR1 abundance in macrophages.
Assuntos
Macrófagos/imunologia , Fagocitose , Receptores Histamínicos H2/metabolismo , Receptores Depuradores Classe A/metabolismo , Transdução de Sinais , Animais , Autofagia , Células Cultivadas , Escherichia coli/imunologia , Citometria de Fluxo , Camundongos , Microscopia de Fluorescência , Microesferas , Receptores Histamínicos H2/deficiênciaRESUMO
Histamine exerts potent modulatory impacts on the cells of innate- [including neutrophils, monocytes, macrophages, dendritic cells (DCs), natural killer (NK) cells and NKT cells] and adaptive immunity (such as Th1-, Th2-, Th17-, regulatory T-, CD8+ cytotoxic T cells, and B cells) through binding to histamine receptor 2 (H2R). Cimetidine, as an H2R antagonist, reverses the histamine-mediated immunosuppression, as it has powerful stimulatory effects on the effector functions of neutrophils, monocytes, macrophages, DCs, NK cells, NKT cells, Th1-, Th2-, Th17-, and CD8+ cytotoxic T cells. However, cimetidine reduces the regulatory/suppressor T cell-mediated immunosuppression. Experimentally, cimetidine potentiate some immunologic activities in vitro and in vivo. The therapeutic potentials of cimetidine as an immunomodulatory agent were also investigated in a number of human diseases (such as cancers, viral warts, allergic disorders, burn, and bone resorption) and vaccination. This review aimed to provide a concise summary regarding the impacts of cimetidine on the immune system and highlight the cellular mechanisms of action and the immunomodulatory effects of this drug in various diseases to give novel insights regarding the therapeutic potentials of this drug for treatment of immune-related disorders. The review encourages more investigations to consider the immunomodulatory characteristic of cimetidine for managing of immune-related disorders.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Queimaduras/tratamento farmacológico , Cimetidina/farmacologia , Células Dendríticas/imunologia , Hipersensibilidade/tratamento farmacológico , Linfócitos/imunologia , Neoplasias/tratamento farmacológico , Neutrófilos/imunologia , Animais , Cimetidina/uso terapêutico , Histamina/metabolismo , Humanos , Imunidade Celular , Imunidade Inata , Imunização , Receptores Histamínicos H2/metabolismoRESUMO
Histamine [2-(4-Imidazolyl)-ethylamine] modulates different biological processes, through histamine H1 and H2 receptors, and their respective blockers are widely used in treating allergic and gastric acid-related disorders. Histamine H1 and H2 receptor crossdesensitization and cointernalization induced by its agonists have been previously described. In this study, we show how this crosstalk determines the response to histamine H1 and H2 receptor inverse agonists and how histamine H1 and H2 receptor inverse agonists interfere with the other receptor's response to agonists. By desensitization assays we demonstrate that histamine H1 and H2 receptor inverse agonists induce a crossregulation between both receptors. In this sense, the histamine H1 receptor inverse agonists desensitize the cAMP response to amthamine, a histamine H2 receptor agonist. In turn, histamine H2 receptor inverse agonists interfere with histamine H1 receptor signaling. We also determine that the crossdesensitization induced by histamine H1 or H2 receptor agonists alters the histamine inverse agonists receptor response: activation of histamine H1 receptor affects cAMP response induced by histamine H2 receptor inverse agonists, whereas histamine H2 receptor agonist induces a negative regulation on the anti-inflammatory response of histamine H1 receptor inverse agonists. Binding studies revealed that histamine H1 and H2 receptors cointernalize after stimulus with histamine receptor inverse agonists. In addition, the inhibition of the internalization process prevents receptor crossregulation. Our study provides new insights in the mechanisms of action of histamine H1 and H2 receptors that explain the effect of histamine H1 and H2 receptor inverse agonists and opens up new venues for novel therapeutic applications.
Assuntos
Agonistas dos Receptores Histamínicos/metabolismo , Antagonistas dos Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Histamina/metabolismo , Humanos , Transdução de Sinais/fisiologia , Células U937RESUMO
Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apcmin/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1-receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2-receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. NEW & NOTEWORTHY Histamine-producing Lactobacillus reuteri can suppress development of inflammation-associated colon cancer in an established mouse model. The net effects of histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal inflammation and colorectal neoplasia could be developed.
Assuntos
Carcinogênese/metabolismo , Inflamação/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/metabolismo , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos Transgênicos , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H2/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Accumulating evidence suggests that histamine synthesis induced in several types of tumor tissues modulates tumor immunity. We found that a transient histamine synthesis was induced in CD11bâºGr-1⺠splenocytes derived from BALB/c mice transplanted with a syngeneic colon carcinoma, CT-26, when they were co-cultured with CT-26 cells. Significant levels of IFN-γ were produced under this co-culture condition. We explored the modulatory roles of histamine on IFN-γ production and found that several histamine receptor antagonists, such as pyrilamine, diphenhydramine, JNJ7777120, and thioperamide, could significantly suppress IFN-γ production. However, suppression of IFN-γ production by these antagonists was also found when splenocytes were derived from the Hdc-/- BALB/c mice. Suppressive effects of these antagonists were found on IFN-γ production induced by concanavalin A or the combination of an anti-CD3 antibody and an anti-CD28 antibody in a histamine-independent manner. Murine splenocytes were found to express H1 and H2 receptors, but not H3 and H4 receptors. IFN-γ production in the Hh1r-/- splenocytes induced by the combination of an anti-CD3 antibody and an anti-CD28 antibody was significantly suppressed by these antagonists. These findings suggest that pyrilamine, diphenhydramine, JNJ7777120, and thioperamide can suppress IFN-γ production in activated splenocytes in a histamine-independent manner.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Interferon gama/biossíntese , Baço/metabolismo , Animais , Linhagem Celular Tumoral , Histamina/genética , Histamina/metabolismo , Interferon gama/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/metabolismo , Baço/patologiaRESUMO
Probiotics have been used to ameliorate gastrointestinal symptoms since ancient times. Over the past 40 years, probiotics have been shown to impact the immune system, both in vivo and in vitro. This interaction is linked to gut microbes, their polysaccharide antigens, and key metabolites produced by these bacteria. At least four metabolic pathways have been implicated in mechanistic studies of probiotics, based on mechanistic studies in animal models. Microbialâ»immune system crosstalk has been linked to: short-chain fatty acid production and signaling, tryptophan metabolism and the activation of aryl hydrocarbon receptors, nucleoside signaling in the gut, and activation of the intestinal histamine-2 receptor. Several randomized controlled trials have now shown that microbial modification by probiotics may improve gastrointestinal symptoms and multiorgan inflammation in rheumatoid arthritis, ulcerative colitis, and multiple sclerosis. Future work will need to carefully assess safety issues, selection of optimal strains and combinations, and attempts to prolong the duration of colonization of beneficial microbes.
Assuntos
Doenças Autoimunes/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Probióticos/farmacologia , Doenças Reumáticas/microbiologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/imunologia , Humanos , Inflamação/microbiologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/terapia , Intestinos/imunologia , Intestinos/microbiologia , Nucleosídeos/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Histamínicos H2/metabolismo , Doenças Reumáticas/imunologia , Doenças Reumáticas/terapia , Triptofano/metabolismoRESUMO
It seems that histamine release in the site of neuronal injury could contribute to the neuropathic pain mechanism. In the present study, we investigated the anti-allodynic effects of chronic administration of different classes of histamine H1 and H2 receptor antagonists on neuropathic nociceptive behavior following tibial nerve transection (TNT) in rats. Peripheral neuropathy was induced by TNT surgery. We performed acetone tests (AT) to record cold allodynia, Von Frey tests (VFT) to measure mechanical allodynia, double plate test (DPT) to evaluate thermal place preference/avoidance and open field test (OFT) for evaluation of animal activity. TNT rats showed a significant mechanical and cold allodynia compared to the sham group. Chlorpheniramine (5 and 15â¯mg/kg, i.p) significantly attenuated cold allodynia and prevented cold plate avoidance behavior and at the dose of 15â¯mg/kg remarkably decreased mechanical allodynia. Fexofenadine (10 and 30â¯mg/kg, p.o) significantly attenuated the mechanical allodynia and prevented cold plate avoidance. Ranitidine (5 and 15â¯mg/kg, i.p) significantly prevented cold plate avoidance behavior and at the dose of 15â¯mg/kg notably improved mechanical and cold allodynia. Famotidine (1 and 3â¯mg/kg, p.o) was ineffective on all nociceptive tests. Gabapantin (100â¯mg/kg, p.o) significantly improved all types of nociceptive behaviors. These results indicate that both blood brain barrier penetrating (chlorpheniramine) and poorly penetrating (fexofenadine) histamine H1 receptor antagonists could improve the neuropathic pain sign, but only the blood brain barrier penetrating histamine H2 receptor antagonist (ranitidine) could produce anti-allodynic effects in the TNT model of neuropathic pain in rats.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/complicações , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Nervo Tibial/lesões , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Reação de Fuga/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Hiperalgesia/complicações , Masculino , Neuralgia/complicações , Neuralgia/etiologia , Neuralgia/metabolismo , Ratos , Ratos WistarRESUMO
Astrocytes play key roles in regulating brain homeostasis and neuronal activity. This is, in part, accomplished by the ability of neurotransmitters in the synaptic cleft to bind astrocyte membrane receptors, activating signalling cascades that regulate concentration of intracellular Ca2+ ([Ca2+]i) and gliotransmitter release, including ATP and glutamate. Gliotransmitters contribute to dendrite formation and synaptic plasticity, and in some cases, exacerbate neurodegeneration. The neurotransmitter histamine participates in several physiological processes, such as the sleep-wake cycle and learning and memory. Previous studies have demonstrated the expression of histamine receptors on astrocytes, but until now, only a few studies have examined the effects of histamine on astrocyte intracellular signalling and gliotransmitter release. Here, we used the human astrocytoma cell line 1321N1 to study the role of histamine in astrocyte intracellular signalling and gliotransmitter release. We found that histamine activated astrocyte signalling through histamine H1 and H2 receptors, leading to distinct cellular responses. Activation of histamine H1 receptors caused concentration-dependent release of [Ca2+]i from internal stores and concentration-dependent increase in glutamate release. Histamine H2 receptor activation increased cyclic adenosine monophosphate (cAMP) levels and phosphorylation of transcription factor cAMP response-element binding protein. Taken together, these data emphasize a role for histamine in neuron-glia communication.
Assuntos
Astrócitos/metabolismo , Glutamatos/metabolismo , Histamina/farmacologia , Histamina/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Astrócitos/fisiologia , Cálcio/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Humanos , Neurotransmissores/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
AIM: CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines and is involved in monocyte migration and recruitment. We have previously investigated CCL22 and histamine in atherosclerosis. Here, we investigated the hypothesis that CCL22 is involved in atherosclerosis, which is influenced by the differentiation of macrophage phenotypes via histamine. METHODS: CCL22 expression was investigated in human carotid arteries and coronary arteries with bare metal stents. Ligated carotid arteries of wild-type (C57BL/6J) and apolipoprotein E-deficient mice were also used as atherosclerotic models. The localization and expression of CCL22 and classical (M1)-like and M2-like macrophages in various human and mouse atherosclerotic lesions were investigated by immunohistochemical examination and quantitative real-time polymerase chain reaction. Histamine is expressed in atherosclerosis, and it induces inflammation and immunity. Human- and mice-derived monocytes and macrophages were used to examine the role of histamine in macrophage differentiation and CCL22-expression. Macrophages derived from histamine receptor 1 (H1R)- and 2 (H2R)-knockout (KO) mice were also examined. RESULTS: Atherosclerotic lesions showed a distribution of heterogeneous macrophage phenotypes with M1-like and M2-like macrophage dominant sites. CCL22 was distributed in sparse areas of vascular smooth muscle cells (VSMCs) and associated with M2-like macrophages. Moreover, H2R stimulation was associated with CCL22 expression via M2-like macrophage dominant differentiation. CONCLUSION: The expression of M1- or M2-like macrophages in atherosclerosis were observed to be dependent on the distribution of VSMCs owing to differences in causal stimuli and the switching of histamine receptors via Th1 or Th2 cytokines. These results suggest that CCL22 may control atherosclerosis.
Assuntos
Aterosclerose/patologia , Quimiocina CCL22/metabolismo , Macrófagos/patologia , Músculo Liso Vascular/patologia , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Animais , Apolipoproteínas E/fisiologia , Aterosclerose/genética , Aterosclerose/metabolismo , Biomarcadores/metabolismo , Células Cultivadas , Quimiocina CCL22/genética , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Receptores Histamínicos H1/genética , Receptores Histamínicos H2/genéticaRESUMO
The anaphylactoid reaction described follows cessation of ranitidine in a 19-year-old female with the disease cluster: mast cell activation syndrome, hypermobile Ehlers-Danlos syndrome and postural tachycardia syndrome. Anaphylaxis can give wide-ranging symptoms from rhinorrhoea and urticaria to tachycardia and system-wide, life-threatening, anaphylactic shock. Individuals with a disorder of mast cell activation can experience many such symptoms. H2 receptor antagonists, such as ranitidine, are commonly prescribed in this population. A mechanism for the reaction is proposed in the context of ranitidine, as an inverse agonist, causing upregulation of H2 histamine receptors and raised histamine levels due to enzyme induction. This effect, following extended and/or high antihistamine dosing, may have implications for other individuals with a disorder of mast cell activation, such as mastocytosis or mast cell activation syndrome. There are potential policy and patient guidance implications for primary and secondary care with respect to cessation of H2 antagonists.
Assuntos
Anafilaxia/imunologia , Histamina/sangue , Receptores Histamínicos H2/metabolismo , Suspensão de Tratamento , Adulto , Anafilaxia/sangue , Anafilaxia/diagnóstico , Anafilaxia/tratamento farmacológico , Clorfeniramina/uso terapêutico , Epinefrina/administração & dosagem , Feminino , Histamina/imunologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Ranitidina/administração & dosagem , Receptores Histamínicos H2/imunologia , Resultado do Tratamento , Regulação para Cima , Adulto JovemRESUMO
Doxorubicin (DOX), an anthracycline-based antibiotic, is regularly used in the management of carcinomas, and haematological malignancies have been downplayed in chemotherapy because of its ability to induce dilated cardiomyopathy (DCM). Dexrazoxane is approved to combat the cardiotoxicity, but limited by its adverse effects. Redox imbalance and reactive oxygen species generation plays major role in DOX-induced cardiotoxicity. Histamine, known to mediate various cardiovascular effects, but nevertheless the role of histamine or its receptors in DOX-induced DCM is remained obscure. Hence, this study is aimed to examine the effect of Famotidine (FAM), a H2 receptor antagonist on DOX-induced DCM in Wistar rats. Myocardial antioxidant status, stress and apoptosis markers, myocardial morphology and function were evaluated as the end points. Treatment with FAM has alleviated DOX doxorubicin-induced cardiotoxicity by reducing oxidative and nitrosative stress evident from lipid peroxidation and total nitrate-to-nitrite ratio, and enhanced the activity of super oxide dismutase. Cardiac stress markers like LDH and Na+-K+ATPase activities as well as CK-MB and Cardiac troponin levels were reduced by FAM treatment. It also normalised the myocardial function as assessed by 2D echocardiography and myocardial index. Treatment imparted anti-apoptotic effect as evident from decrease in myocardial caspase 3 and 9 activity and cleaved PARP expression. Effect of FAM is found to be comparable to the standard ACE inhibitor Captopril (CAP). The results from this study collectively suggest H2 receptor antagonism as a novel therapeutic strategy to impart biochemical, structural and functional improvement indicating its cardio-protective activity.
Assuntos
Cardiomiopatias , Doxorrubicina/efeitos adversos , Famotidina/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Miocárdio/metabolismo , Receptores Histamínicos H2/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiomiopatias/prevenção & controle , Doxorrubicina/farmacologia , Masculino , Proteínas Musculares/metabolismo , Miocárdio/patologia , Ratos , Ratos WistarRESUMO
Microbiome-mediated suppression of carcinogenesis may open new avenues for identification of therapeutic targets and prevention strategies in oncology. Histidine decarboxylase (HDC) deficiency has been shown to promote inflammation-associated colorectal cancer by accumulation of CD11b+Gr-1+ immature myeloid cells, indicating a potential antitumorigenic effect of histamine. Here, we demonstrate that administration of hdc+Lactobacillus reuteri in the gut resulted in luminal hdc gene expression and histamine production in the intestines of Hdc-/- mice. This histamine-producing probiotic decreased the number and size of colon tumors and colonic uptake of [18F]-fluorodeoxyglucose by positron emission tomography in Hdc-/- mice. Administration of L. reuteri suppressed keratinocyte chemoattractant (KC), Il22, Il6, Tnf, and IL1α gene expression in the colonic mucosa and reduced the amounts of proinflammatory, cancer-associated cytokines, keratinocyte chemoattractant, IL-22, and IL-6, in plasma. Histamine-generating L. reuteri also decreased the relative numbers of splenic CD11b+Gr-1+ immature myeloid cells. Furthermore, an isogenic HDC-deficient L. reuteri mutant that was unable to generate histamine did not suppress carcinogenesis, indicating a significant role of the cometabolite, histamine, in suppression of chronic intestinal inflammation and colorectal tumorigenesis. These findings link luminal conversion of amino acids to biogenic amines by gut microbes and probiotic-mediated suppression of colorectal neoplasia.
Assuntos
Carcinogênese/patologia , Neoplasias Colorretais/patologia , Microbioma Gastrointestinal , Histamina/biossíntese , Inflamação/patologia , Animais , Carcinogênese/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/genética , Citocinas/sangue , Regulação Neoplásica da Expressão Gênica , Histidina Descarboxilase/genética , Histidina Descarboxilase/metabolismo , Humanos , Inflamação/sangue , Inflamação/genética , Mucosa Intestinal/patologia , Limosilactobacillus reuteri/metabolismo , Camundongos Endogâmicos BALB C , Modelos Biológicos , Células Mieloides/metabolismo , Tomografia por Emissão de Pósitrons , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/metabolismo , Baço/patologia , Análise de SobrevidaRESUMO
Mesenchymal stem cells (MSCs) in ossification of the posterior longitudinal ligament (OPLL) patients have a high propensity toward osteogenesis. Histamine receptor H2 (H2R) antagonists (H2 blockers) like famotidine decrease ossification in patients, by an unclear mechanism. To confirm that MSCs express H2R and to clarify how H2 blockers suppress osteogenic differentiation, we used spinal-ligament MSCs from patients with OPLL or with cervical spondylotic myelopathy (CSM) (control). The MSCs were treated with 10, 30, or 100nM famotidine for 7 or 21 days. Flow cytometry revealed that cells from both groups expressed MSC surface markers CD44, CD90, and CD105 (> 97.5%) but not CD34 or CD45 (< 2.5%). Immunoblotting showed that the MSCs from both groups expressed H2R, but those from OPLL patients expressed it at higher levels. Real-time qPCR indicated the H2R expression was significantly suppressed by 30nM famotidine for 7 days or by 30 or 100nM for 21 days. However, histidine decarboxylase, a key enzyme in histamine production, did not change significantly after famotidine addition. Famotidine treatment at 100nM for 21 days significantly suppressed mRNA expression of the osteogenic markers osteocalcin (OCN), bone morphogenetic protein 2 (BMP2), and runt-related transcription factor 2 (RUNX2) only in OPLL-derived MSCs. Immunoblots showed that famotidine suppressed BMP2 and OCN in the OPLL group and H2R and RUNX2 in both groups. These results suggest famotidine inhibits osteogenic differentiation in OPLL-derived MSCs by acting as an H2R antagonist, but also by decreasing H2R expression, and support the clinical use of famotidine to treat OPLL.