Mechanisms of unconventional CD8 Tc2 lymphocyte induction in allergic contact dermatitis: Role of H3/H4 histamine receptors.

Histamine (HA) is a potent mediator that plays a central role in inflammation and allergy, acting through four G-protein-coupled receptors (i.e. H1-H4). HA is an accepted promoter of type 2 immunity in CD4+ T cells during hypersensitivity. Previously, we demonstrated that HA can promote antigen cross-presentation, inducing the activation of antigen-specific CD8+ T cells in an asthmatic murine model. Non-classical CD8+ T-cell profiles, such as Tc2 or Tc17, are associated with allergic disease persistence and chronicity. In this paper, we focus on the role of the H3 receptor (H3R) and the H4 receptor (H4R) in the development of allergic contact dermatitis. We were able to show that induction of the type 2 profiles associated with interleukin 13 production, both by CD4 and CD8 lymphocytes, depend on the interaction of HA with H3R and H4R. Blocking both receptors using the selective H3/H4 receptor antagonist thioperamide or the selective H4R ligand JNJ777120 reduces the inflammatory response, inducing an immunosuppressive profile associated with the increased proportion of FOXp3+ regulatory T lymphocytes and CD11b+Gr-1+ myeloid suppressor cells. Interestingly, in dendritic cells, only H4R blockade, and not H3R blockade, is capable of modulating most of the inflammatory effects observed in our model.

Histamine in cancer immunology and immunotherapy. Current status and new perspectives.

Cancer is the second leading cause of death globally and its incidence and mortality are rapidly increasing worldwide. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer. Immunotherapy comes to the forefront of cancer treatments, resulting in impressive and durable responses but only in a fraction of patients. Thus, understanding the characteristics and profiles of immune cells in the tumor microenvironment (TME) is a necessary step to move forward in the design of new immunomodulatory strategies that can boost the immune system to fight cancer. Histamine produces a complex and fine-tuned regulation of the phenotype and functions of the different immune cells, participating in multiple regulatory responses of the innate and adaptive immunity. Considering the important actions of histamine-producing immune cells in the TME, in this review we first address the most important immunomodulatory roles of histamine and histamine receptors in the context of cancer development and progression. In addition, this review highlights the current progress and foundational developments in the field of cancer immunotherapy in combination with histamine and pharmacological compounds targeting histamine receptors.

Pharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines: Novel Antagonists for the Histamine H3 and H4 Receptors with Anti-inflammatory Potential.

The histamine receptors (HRs) are traditional G protein-coupled receptors of extensive therapeutic interest. Recently, H3R and H4R subtypes have been targeted in drug discovery projects for inflammation, asthma, pain, cancer, Parkinson's, and Alzheimer's diseases, which includes searches for dual acting H3R/H4R ligands. In the present work, nine 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01 series) molecules were synthesized and evaluated as H3R and H4R ligands. Our data show that the N-allyl-substituted compound LINS01004 bears the highest affinity for H3R (pKi 6.40), while the chlorinated compound LINS01007 has moderate affinity for H4R (pKi 6.06). In addition, BRET assays to assess the functional activity of Gi1 coupling indicate that all compounds have no intrinsic activity and act as antagonists of these receptors. Drug-likeness assessment indicated these molecules are promising leads for further improvements. In vivo evaluation of compounds LINS01005 and LINS01007 in a mouse model of asthma showed a better anti-inflammatory activity of LINS01007 (3 g/kg) than the previously tested compound LINS01005. This is the first report with functional data of these compounds in HRs, and our results also show the potential of their applications as anti-inflammatory.

Antihistamínicos Parte II - ¿Cuáles son las opciones y en qué basarse para elegir la mejor? / Antihistamines Part II - What are the options and how to choose the best?

Los antihistamínicos han sido usados durante los últimos 50 años y se han convertido en los medicamentos de mayor prescripción en el mundo. En este artículo se revisa el desarrollo de nuestro conocimiento referente a la histamina en el transcurso del siglo, como mediador biológico almacenado y liberado mayormente por los basófilos y mastocitos; mediador biológico situado en diferentes tejidos corporales, y otras células, con un papel fisiológico fundamental en el control de la secreción de ácido gástrico y un papel fisiopatológico en una gama de trastornos alérgicos. La síntesis y estudios farmacológicos de agonistas y antagonistas selectivos han establecido la existencia de cuatro tipos de receptores de histamina y antagonistas de ellos, que han encontrado muy importantes aplicaciones terapéuticas. Debido al aumento de la prevalencia de las enfermedades alérgicas según el Libro Blanco de Alergia (WAO), se deben crear normas que promuevan el uso de los antihistamínicos de manera adecuada y racional. De esta manera, la correcta elección debe ser realizada de acuerdo a su eficacia, tolerabilidad, seguridad, grupo etario, situaciones y precauciones particulares en pacientes con algún riesgo incrementado. El crear normas que promuevan una práctica terapéutica óptima o uso racional de dichos medicamentos. Elegirlos de acuerdo a su eficacia, tolerabilidad, seguridad, grupo etario, situaciones y precauciones especiales en pacientes portadores de ciertas enfermedades de riesgo a utilizarlos.(AU)

Antihistamines have been used for the past 50 years and have become the most prescribed drugs in the world. This article reviews the development of our knowledge concerning the histamine in the course of the century, as a biological mediator mostly stored and released by basophils and mast cells biological mediator located in different body tissues, and other cells, having a fundamental physiological role in the control of gastric acid secretion and pathophysiological role in a variety of allergic disorders. The synthesis and pharmacological studies of selective agonists and antagonists has established the existence of four types of histamine receptor antagonists and histamine receptor found important therapeutic applications. Power demonstrations relate most allergic diseases whose symptoms are chronic and persistent emphasis by (WAO) White Paper on Alergia1 a steady increase in allergic diseases with a prevalence of 30-40% of the world population affected at least one allergic condition, considering the most common allergic rhinitis and chronic diseases common in our modern society. Creating standards that promote optimal therapeutic practice or rational use of such drugs. Choose them according to their efficacy, tolerability, safety, age group, situations and special precautions in patients with certain diseases risk to use. (AU)

Revisão sobre a efícacia e segurança dos anti-histamínicos de primeira e segunda geração / Revision on efficacy and safety of antihistamines of first and second generation

Objetivo: Revisar a eficácia e segurança dos principais anti-histamínicos de primeira e segunda geração. Os anti-histamínicos correspondem a um grupo extenso de medicamentos que vêm apresentando grandes avanços no conhecimento de suas ações e estão entre os agentes mais utilizados na prática clínica em diversas doenças alérgicas. Método: Levantamento bibliográfico nos bancos de dados PubMed, Medline, LILACS, SCIELO e capítulos de livros nos últimos 10 anos, sendo incluídos artigos históricos. Resultados: Nessa revisão são destacadas as principais características da histamina, as diferenças entre os receptores de histamina, o desenvolvimento dos anti-histamínicos de primeira e segunda geração, sua classificação e os principais efeitos colaterais de cada grupo de anti-histamínicos. Conclusão: A presente revisão não pretende esgotar o assunto sobre eficácia e segurança dos anti-histamínicos, mas destaca a falta de estudos bem conduzidos sobre eficácia dos anti-histamínicos de primeira geração e o número crescente de metanálises sobre farmacodinâmica, potência, eficácia e segurança dos anti-histamínicos de segunda geração.

Objective: To review the efficacy and safety of the main antihistamines of first and second generation. The antihistamines represent an extensive group of drugs that are showing great advances in knowledge of their actions and are among the most common agents used in clinical practice in various allergic diseases. Method: Searches in PubMed, Medline, LILACS, SCIELO database and book chapters in the last 10 years, including historic articles. Results: This review highlights the main features of histamine, the differences between histamine receptors, development of first and second generation antihistamines, their classification, and the main side effects of each group of antihistamines. Conclusion: The present review is not intended to exhaust the subject on efficacy and safety of antihistamine, but it highlights the lack of well conducted studies of the efficacy of first-generation antihistamine and the rising number of meta-analysis of pharmacodynamics, potency, efficacy and safety of second-generation antihistamines.

El ácido gástrico / Gastric acid

El ácido gástrico, producto de la secreción de las células gástricas parietales u oxínticas, cumple roles biológicos imprescindibles para la homeostasis corporal. La producción del ácido gástrico depende de un proceso celular efector constituido por histamina, acetilcolina y gastrina en el primer nivel, constituyendo primeros mensajeros de dicho proceso. Estos interaccionan con receptores específicos, lo que a su vez activa segundos mensajeros representados por AMPc y el sistema calciocalmodulín. Estos luego activan en cascada sucesiva a una proteinokinasa que fosforila una proteína específica, activándola, lo que inicia la síntesis de ácido. Una bomba de protones situada en el polo luminal de la célula parietal, extruye finalmente el ácido sintetizado hacia el lumen gástrico. El proceso secretor descrito es puesto en movimiento, secuencialmente en tres fases, dos de ellas estimuladoras -fase cefálica y fase gástrica- y una inhibidora o fase intestinal. Estas etapas son iniciadas por fenómenos sico-neurales -pensamiento, visión, olfación o recuerdo-; por alimentos y otras sustancias ingeridas; y por productos de la digestión de nutrientes. Alteraciones en la regulación de la secreción ácida; en la constitución de la barrera mucosa gastroduodenal, protectora frente a la acción potencialmente lesiva de alimentos y fármacos o drogas; y potenciación de su acción por la presencia de H. pylori, constituyen la base etiopatogénica de la enfermedad ácido-péptica, entidad nosográfica donde juega un rol fundamental. Desde el punto de vista terapéutico, tanto dentro del marco teórico como del práctico, se puede interferir con la secreción ácida neutralizando alguno de los pasos de su proceso celular efector. Un adecuado conocimiento de los aspectos básicos relacionados con la problemática del ácido gástrico, permite plantear estrategias para el manejo de la patología asociada con él, en forma particular en lo concerniente a la enfermedad ácido-péptica en todas...

Gastric acid, a product of parietal cells secretion, fullfills multiple biological roles which are absolutely necessary to keep corporal homeostasis. The production of the acid depends upon an effector cellular process represented in the first step by histamine, acetilcholine and gastrin, first messengers of the process. These interact with specific receptors than in sequence activate second messengers -cAMP and the calcium-calmodulin system- which afterwards activate a kinase. An specific protein is then phosphorilated by this enzyme, being the crucial factor that starts the production of acid. Finally, a proton bomb, extrudes the acid towards the gastric lumen. The secretion process mentioned above, is progressively activated in three steps, two of which are stimulators -cephalic and gastric phases- and the other one inhibitor or intestinal phase. These stages are started by mental and neurological phenomena -thought, sight, smell or memory-; by food, drugs or other ingested substances; and by products of digestion. Changes in regulation of acid secretion, in the structure of gastro-duodenal mucosal barrier by a wide spectrum of factors and agents including food, drugs and H. pylori, are the basis of acid-peptic disease, entity in which gastric acid plays a fundamental role. From the therapeutic point of view, so at the theoretical as at the practical levels, ¡t is possible to interfere with the secretion of acid by neutralization of some of the steps of the effector cellular process. An adequate knowledge of the basics related to gastric acid, allows to create strategies for the clinical handling of associated pathology, specifically in relation to peptic acid disease in all of the known clinical forms.