RESUMEN

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

Asunto(s)

Calcio , Chamaecyparis , Contracción Muscular , Músculo Liso , Extractos Vegetales , Quercetina , Tráquea , Animales , Cobayas , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Contracción Muscular/efectos de los fármacos , Quercetina/farmacología , Quercetina/química , Tráquea/efectos de los fármacos , Tráquea/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Chamaecyparis/química , Calcio/metabolismo , Masculino , Bloqueadores de los Canales de Calcio/farmacología , Histamina/metabolismo , Canales de Calcio Tipo L/metabolismo , Hojas de la Planta/química

RESUMEN

The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.

Asunto(s)

Dihidroergotamina , Escopolamina , Animales , Ratas , Histamina , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Encéfalo , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Antagonistas de los Receptores H2 de la Histamina

RESUMEN

Psidium brownianum Mart is reported in the literature by antinociceptive and antioxidant activities, indicating that this species' secondary metabolites might be used to control inflammatory processes. The present study aimed to characterize the topical antiedematogenic activity of the essential oil of Psidium brownianum Mart. (OEPB) in ear edema models by different inflammatory agents. Female Swiss mice (25-35 g) and Wistar albino rats (200-300 g) were used throughout tests (n=6/group) on acute or chronic edema models induced by single and multiple topical applications. The OEPB is administered topically pure or at a concentration of 100 or 200 mg/mL. The antiedematogenic mechanism of OEPB was analyzed by administering capsaicin, arachidonic acid, histamine, and phenol at the best effective dose (200 mg/mL). The results showed a significant reduction of edema-induced single (28.87 %) and multiple (50.13 %) applications of croton oil compared to the negative control group. Regarding potential mechanisms of action, OEPB (200 mg/mL) inhibited the development of edema triggered by capsaicin (29.95 %), arachidonic acid (22.66 %), phenol (23.35 %), and histamine (75.46 %), suggesting an interference with the histaminergic pathway. These results indicate that OEPB presents a topical antiedematogenic effect in acute and chronic murine models, possibly interfering with inflammatory pathways triggered by mediators such as histamine.

Asunto(s)

Aceites Volátiles , Psidium , Ratones , Femenino , Animales , Aceites Volátiles/farmacología , Aceites Volátiles/uso terapéutico , Capsaicina , Histamina/efectos adversos , Ácido Araquidónico/efectos adversos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Extractos Vegetales/farmacología

RESUMEN

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.

Asunto(s)

Histamina , Neoplasias , Humanos , Histamina/metabolismo , Estudios Retrospectivos , Calidad de Vida , Antagonistas de los Receptores H2 de la Histamina , Antagonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/uso terapéutico , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/metabolismo , Neoplasias/tratamiento farmacológico , Microambiente Tumoral

RESUMEN

Exacerbated inflammatory responses to harmful stimuli can lead to significant pain, edema, and other complications that require pharmacological intervention. Abietic acid (AA) is a diterpene found as a significant constituent in pine species, and evidence has identified its biological potential. The present study aimed to evaluate abietic acid's antiedematogenic and anti-inflammatory activity in mice. Swiss mice (Mus musculus) weighing 20-30 g were treated with AA at 50, 100, and 200 mg/kg. The central nervous system (CNS) effects were evaluated using open-field and rotarod assays. The antinociceptive and anti-inflammatory screening was assessed by the acetic acid and formalin tests. The antiedematogenic activity was investigated by measuring paw edema induced by carrageenan, dextran, histamine, arachidonic acid, and prostaglandin, in addition to using a granuloma model. The oral administration of abietic acid (200 mg/Kg) showed no evidence of CNS effects. The compound also exhibited significant antiedematogenic and anti-inflammatory activities in the carrageenan and dextran models, mostly related to the inhibition of myeloperoxidase (MOP) activity and histamine action and, to a lesser extent, the inhibition of eicosanoid-dependent pathways. In the granuloma model, abietic acid's effect was less expressive than in the acute models investigated in this study. In conclusion, abietic acid has analgesic and antiedematogenic activities related to anti-inflammatory mechanisms.

Asunto(s)

Dextranos , Histamina , Ratones , Animales , Carragenina/efectos adversos , Dextranos/efectos adversos , Histamina/efectos adversos , Analgésicos/farmacología , Analgésicos/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Extractos Vegetales/farmacología , Edema/inducido químicamente , Edema/tratamiento farmacológico , Granuloma/tratamiento farmacológico

RESUMEN

Inflammation is a protective response of the body potentially caused by microbial, viral, or fungal infections, tissue damage, or even autoimmune reactions. The cardinal signs of inflammation are consequences of immunological, biochemical, and physiological changes that trigger the release of pro-inflammatory chemical mediators at the local of the injured site thus, increasing blood flow, vascular permeability, and leukocyte recruitment. The aim of this study is to give an overview of the inflammatory process, focusing on chemical mediators. The literature review was based on a search of journals published between the years 2009 and 2023, regarding the role of major chemical mediators in the inflammatory process and current studies in pathogenesis, diagnosis, and therapy. Some of the recent contributions in the study of inflammatory pathologies and their mediators, including cytokines and chemokines, the kinin system, free radicals, nitric oxide, histamine, cell adhesion molecules, leukotrienes, prostaglandins and the complement system and their role in human health and chronic diseases.

Asunto(s)

Inflamación , Leucocitos , Humanos , Inflamación/patología , Citocinas , Prostaglandinas , Histamina , Mediadores de Inflamación/metabolismo

RESUMEN

Edema is one of the obvious indicators of inflammation and a crucial factor to take into account when assessing a substance's capacity to reduce inflammation. We aimed to evaluate the antiedematogenic and anti-inflammatory profile of the hydroethanolic barks extract of Ximenia americana (HEXA). The possible antiedematogenic and anti-inflammatory effect of EHXA (50, 100 mg/kg and 250 mg/kg v.o) was evaluated using the paw edema induced by carrageenan, zymosan, dextran, CFA and by different agents inflammatory (serotonin, histamine, arachidonic acid and PGE2), and pleurisy model induced by carrageenan and its action on IL-1ß and TNF-α levels was also evaluated. HEXA demonstrated a significant antiedematogenic effect at concentrations of 50, 100 and 250 mg/kg on paw edema induced by carrageenan, zymosan and dextran. However, the concentration of 50 mg/kg as standard, demonstrating the effect in the subchronic model, induced CFA with inhibition of 59.06 %. In models of histamine-induced paw edema, HEXA showed inhibition of - 30 min: 40.49 %, 60 min: 44.70 % and 90 min: 48.98 %; serotonin inhibition - 30 min: 57.09 %, 60 min: 66.04 % and 90 min: 61.79 %; arachidonic acid inhibition - 15 min: 36.54 %, 30 min: 51.10 %, 45 min: 50.32 % and 60 min: 76.17 %; and PGE2 inhibition - 15 min: 67.78 %, 30 min: 62.30 %, 45 min: 54.25 % and 60 min: 47.92 %. HEXA significantly reduced (p < 0.01) leukocyte migration in the pleurisy model and reduced TNF-α and IL-1ß levels in pleural lavage (p < 0.0001). The results showed that HEXA has the potential to have an antiedematogenic impact in both acute and chronic inflammation processes, with a putative mode of action including the suppression or regulation of inflammatory mediators.

Asunto(s)

Olacaceae , Pleuresia , Ácido Araquidónico , Carragenina , Dextranos , Histamina , Corteza de la Planta , Serotonina , Factor de Necrosis Tumoral alfa , Zimosan , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Pleuresia/inducido químicamente , Pleuresia/tratamiento farmacológico , Dinoprostona , Modelos Teóricos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico

RESUMEN

OBJECTIVE: Mast cell population and histamine affect on blastocyst implantation. This study aimed to evaluate the effects of progesterone administration after induction of ovulation on the uterine tissue mast cell population and histamine content in mice. METHODS: We ran an experimental study on three groups of mice; control group, ovulation induction (induction group), and ovulation induction along with progesterone administration (progesterone group). Mast cells were counted using toluidine blue staining, and the histamine level was measured through spectrophotometry. RESULTS: According to the analysis of variance (ANOVA), there was no difference in mast cell population in endometrium (p=0.138) nor in myometrium (p=0.611). The ratio of mast cells in the myometrium per endometrium increased in the progesterone group in comparison to the control group based on a generalized linear model (p=0.041). The uterine histamine level was different between the groups, based on the ANOVA (p=0.039), in which the progesterone group had lower amounts of histamine. CONCLUSIONS: Progesterone administration after ovulation induction did not decrease the number of endometrial mast cells and could have increased the ratio of myometrium mast cells per endometrium mast cell. The histamine level in uterus decreased by the administration of progesterone in the ovulation-induced mice.

Asunto(s)

Histamina , Progesterona , Femenino , Ratones , Animales , Histamina/farmacología , Progesterona/farmacología , Mastocitos , Útero , Inducción de la Ovulación

RESUMEN

Besides its function as a local mediator of the immune response, histamine can play a role as a neurotransmitter and neuromodulator. Histamine actions are classically mediated through four different G protein-coupled receptor subtypes but non-classical actions were also described, including effects on many ligand-gated ion channels. Previous evidence indicated that histamine acts as a positive modulator on diverse GABAA receptor subtypes, such as GABAAα1ß2γ2, GABAAα2ß3γ2, GABAAα3ß3γ2, GABAAα4ß3γ2 and GABAAα5ß3γ2. Meanwhile, its effects on GABAAρ1 receptors, known to stand for tonic currents in retinal neurons, had not been examined before. The effects of histamine on the function of human homomeric GABAAρ1 receptors were studied here, using heterologous expression in Xenopus laevis oocytes followed by the electrophysiological recording of GABA-evoked Cl- currents. Histamine inhibited GABAAρ1 receptor-mediated responses. Effects were reversible, independent of the membrane potential, and strongly dependent on both histamine and GABA concentration. A rightward parallel shift in the concentration-response curve for GABA was observed in the presence of histamine, without substantial change in the maximal response or the Hill coefficient. Results were compatible with a competitive antagonism of histamine on the GABAAρ1 receptors. This is the first report of inhibitory actions exerted by histamine on an ionotropic GABA receptor.

Asunto(s)

Histamina , Receptores de GABA-A , Humanos , Animales , Receptores de GABA-A/metabolismo , Histamina/farmacología , Histamina/metabolismo , Receptores de GABA , Fenómenos Electrofisiológicos , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/metabolismo , Xenopus laevis/metabolismo , Oocitos/metabolismo

RESUMEN

Scombrotoxin (histamine) fish poisoning is a common seafood-borne illness attributed to toxin production by histamine-producing bacteria (HPB) in fish tissues during decomposition. In laboratory studies, growth of HPB and other bacterial species is affected by physical and chemical attributes, but natural communities of HPB are not well understood. To determine how in situ environmental and water quality variables may affect density of HPB in the natural aquatic environment, we compared presence and abundance of HPB to ambient temperature, salinity, dissolved oxygen, fecal coliforms, male-specific coliphage, nutrient concentrations, carbon and nitrogen stable isotope ratios, and C:N in water samples collected from July 2017 to February 2018 along a natural salinity gradient in a tidal river on the coast of northern Gulf of Mexico. HPB in water samples were quantified using a real-time PCR, most probable number method. HPB species were identified via 16S rRNA gene sequences. Temperature and salinity were determined to be the main factors driving HPB presence and concentration. Canonical correspondence analysis revealed that different HPB were associated with different environmental conditions. Photobacterium damselae was found under warmer, higher-salinity conditions; Raoultella planticola was found at colder, lower-salinity conditions; Enterobacter aerogenes was found at warmer, lower-salinity conditions; and Morganella morganii was found at most sites, independent of environmental conditions. These results showed that naturally occurring HPB abundance and species composition can be affected by environmental conditions, which could manifest in various potentials for histamine formation and scombrotoxin fish poisoning risk based on environmental factors. IMPORTANCE This study determined the effects of environmental conditions on presence and abundance of naturally occurring histamine-producing bacteria in the northern Gulf of Mexico. Here, we show that HPB abundance and species composition are related to in situ ambient temperature and salinity, with the magnitude of this effect dependent on the particular HPB species. This finding suggests that environmental conditions at fishing sites could affect the risk of human illness from scombrotoxin (histamine) fish poisoning.

Asunto(s)

Enfermedades Transmitidas por los Alimentos , Histamina , Animales , Masculino , Humanos , Histamina/análisis , Golfo de México , ARN Ribosómico 16S , Calidad del Agua , Bacterias/genética , Enfermedades Transmitidas por los Alimentos/microbiología

RESUMEN

BACKGROUND: Cardiovascular diseases (CVD) are the major cause of mortality worldwide, whose most prominent risk factor is unhealthy eating habits, such as high fructose intake. Biogenic amines (BAs) perform important functions in the human body. However, the effect of fructose consumption on BA levels is still unclear, as is the association between these and CVD risk factors. OBJECTIVE: This study aimed to establish the association between BA levels and CVD risk factors in animals that consumed fructose. METHODS: Male Wistar rats received standard chow (n=8) or standard chow + fructose in drinking water (30%) (n=8) over a 24-week period. At the end of this period, the nutritional and metabolic syndrome (MS) parameters and plasmatic BA levels were analyzed. A 5% level of significance was adopted. RESULTS: Fructose consumption led to MS, reduced the levels of tryptophan and 5-hydroxitryptophan, and increased histamine. Tryptophan, histamine, and dopamine showed a correlation with metabolic syndrome parameters. CONCLUSION: Fructose consumption alters BAs associated with CVD risk factors.

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FUNDAMENTO: As doenças cardiovasculares (DCV) são a principal causa de mortalidade do mundo, e um de seus fatores de risco são os hábitos alimentares não saudáveis, tais como, o alto consumo de frutose. As aminas biogênicas (ABs) realizam funções importantes no corpo humano. Entretanto, o efeito do consumo de frutose nos níveis das ABs ainda não está claro, bem como a associação entre estes e os fatores de risco da DCV. OBJETIVO: Este estudo teve o objetivo de estabelecer a associação entre os níveis de ABs e os fatores de risco de DCV em animais que consumiram frutose. MÉTODOS: Ratos Wistar machos receberam ração convencional (n=8) ou ração convencional + frutose na água de beber (30%) (n=8) durante 24 semanas. Ao final, foram analisados os parâmetros nutricionais e da síndrome metabólica (SM) e os níveis plasmáticos das ABs. Foi adotado um nível de significância de 5%. RESULTADOS: O consumo de frutose levou à SM, reduziu os níveis de triptofano e 5-hidroxitriptofano e aumentou a histamina. Os níveis de triptofano, histamina e dopamina apresentaram correlação com parâmetros de síndrome metabólica. CONCLUSÃO: O consumo de frutose altera as ABs associadas a fatores de risco de doenças cardiovasculares.

Asunto(s)

Enfermedades Cardiovasculares , Síndrome Metabólico , Humanos , Ratas , Animales , Masculino , Ratas Wistar , Histamina , Enfermedades Cardiovasculares/etiología , Síndrome Metabólico/etiología , Triptófano , Aminas Biogénicas , Factores de Riesgo , Fructosa/efectos adversos

RESUMEN

Histamine is a biogenic amine found in fish-derived and fermented food products with physiological relevance since its concentration is proportional to food spoilage and health risk for sensitive consumers. There are various analytical methods for histamine quantification from food samples; however, a simple and quick enzymatic detection and quantification method is highly desirable. Histamine dehydrogenase (HDH) is a candidate for enzymatic histamine detection; however, other biogenic amines can change its activity or produce false positive results with an observed substrate inhibition at higher concentrations. In this work, we studied the effect of site saturation mutagenesis in Rhizobium sp. Histamine Dehydrogenase (Rsp HDH) in nine amino acid positions selected through structural alignment analysis, substrate docking, and proximity to the proposed histamine-binding site. The resulting libraries were screened for histamine and agmatine activity. Variants from two libraries (positions 72 and 110) showed improved histamine/agmatine activity ratio, decreased substrate inhibition, and maintained thermal resistance. In addition, activity characterization of the identified Phe72Thr and Asn110Val HDH variants showed a clear substrate inhibition curve for histamine and modified kinetic parameters. The observed maximum velocity (Vmax) increased for variant Phe72Thr at the cost of an increased value for the Michaelis-Menten constant (Km) for histamine. The increased Km value, decreased substrate inhibition, and biogenic amine interference observed for variant Phe72Thr support a tradeoff between substrate affinity and substrate inhibition in the catalytic mechanism of HDHs. Considering this tradeoff for future enzyme engineering of HDH could lead to breakthroughs in performance increases and understanding of this enzyme class.

Asunto(s)

Agmatina , Rhizobium , Animales , Histamina/metabolismo , Especificidad por Sustrato , Rhizobium/metabolismo , Agmatina/análisis , Aminas Biogénicas/análisis , Calidad de los Alimentos , Ingeniería de Proteínas

RESUMEN

Abstract The authors report the case of a 71-year-old woman presented to the Emergency Department with acute ischemic stroke. She was treated with rt-PA and interventional endovascular revascularization and developed rapidly progressing angioedema that led to emergency intubation. The standard treatment was not very effective and the swelling improved after infusion of fresh frozen plasma. Angioedema after rt-PA infusion could be a life-threatening emergency that requires quick airway management by skilled professionals. As this condition is triggered by several factors, such as unregulated histamine and bradykinin production, the traditional treatment recommended by the guidelines may not be sufficient and the use of FFP can be considered as a safe and valuable aid.

Asunto(s)

Humanos , Femenino , Persona de Mediana Edad , Anciano , Accidente Cerebrovascular Isquémico/complicaciones , Angioedema/inducido químicamente , Angioedema/terapia , Plasma , Histamina , Manejo de la Vía Aérea

RESUMEN

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Currently, paclitaxel (PTX) represents the first-line therapy for TNBC; however it presents a hydrophobic behavior and produces severe adverse effects. The aim of this work is to improve the therapeutic index of PTX through the design and characterization of novel nanomicellar polymeric formulations composed of a biocompatible copolymer Soluplus® (S), surface-decorated with glucose (GS), and co-loaded either with histamine (HA, 5 mg/mL) and/or PTX (4 mg/mL). Their micellar size, evaluated by dynamic light scattering, showed a hydrodynamic diameter between 70 and 90 nm for loaded nanoformulations with a unimodal size distribution. Cytotoxicity and apoptosis assays were performed to assess their efficacy in vitro in human MDA-MB-231 and murine 4T1 TNBC cells rendering optimal antitumor efficacy in both cell lines for the nanoformulations with both drugs. In a model of TNBC developed in BALB/c mice with 4T1 cells, we found that all loaded micellar systems reduced tumor volume and that both HA and HA-PTX-loaded SG micelles reduced tumor weight and neovascularization compared with the empty micelles. We conclude that HA-PTX co-loaded micelles in addition to HA-loaded formulations present promising potential as nano-drug delivery systems for cancer chemotherapy.

Asunto(s)

Antineoplásicos Fitogénicos , Neoplasias de la Mama Triple Negativas , Ratones , Humanos , Animales , Paclitaxel , Histamina , Micelas , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Polietilenglicoles/química , Polímeros , Portadores de Fármacos/química , Ratones Endogámicos BALB C

RESUMEN

Histaminergic, orexinergic, and cannabinoid systems play a role in both physiologic and oncogenic mechanisms in digestive tissues. These three systems are important mediators of tumor transformation, as they are associated with redox alterations, which are key aspects in oncological disorders. The three systems are known to promote alterations in the gastric epithelium through intracellular signaling pathways, such as oxidative phosphorylation, mitochondrial dysfunction, and increased Akt, which might promote tumorigenesis. Histamine promotes cell transformation through redox-mediated alterations in the cell cycle, DNA repair, and immunological response. The increase in histamine and oxidative stress generates angiogenic and metastatic signals through the VEGF receptor and H2R-cAMP-PKA pathway. Immunosuppression in the presence of histamine and ROS is linked to a decrease in dendritic and myeloid cells in gastric tissue. These effects are counteracted by histamine receptor antagonists, such as cimetidine. Regarding orexins, overexpression of the Orexin 1 Receptor (OX1R) induces tumor regression through the activation of MAPK-dependent caspases and src-tyrosine. OX1R agonists are candidates for the treatment of gastric cancer by stimulating apoptosis and adhesive interactions. Lastly, cannabinoid type 2 (CB2) receptor agonists increase ROS, leading to the activation of apoptotic pathways. In contrast, cannabinoid type 1 (CB1) receptor agonists decrease ROS formation and inflammation in gastric tumors exposed to cisplatin. Overall, the repercussion of ROS modulation through these three systems on tumor activity in gastric cancer depends on intracellular and/or nuclear signals associated with proliferation, metastasis, angiogenesis, and cell death. Here, we review the role of these modulatory systems and redox alterations in gastric cancer.

Asunto(s)

Adenocarcinoma , Cannabinoides , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Histamina/metabolismo , Especies Reactivas de Oxígeno , Oxidación-Reducción , Receptor Cannabinoide CB2/metabolismo

RESUMEN

Diabetic rat embryos have increased cortical neurogenesis and neuron maturation, and their offspring presented altered neuron polarity, lamination, and diminished neuron excitability. The FOXP2 overexpression results in higher cortical neurogenesis by increasing the transition of radial glia to the intermediate progenitor. Similarly, histamine through H1-receptor activation increases cortical neuron differentiation. Indeed, blocking the H1-receptor by the systemic administration of chlorpheniramine to diabetic pregnant rats prevents increased neurogenesis. Here, we explore the relationship between the H1-receptor and FOXP2 on embryo neurogenesis from diabetic dams. Through qRT-PCR, Western blot, immunohistofluorescence, and flow cytometry, we showed an increased FOXP2 expression and nuclear localization, a reduced Nestin expression and -positive cells number, and a higher PKCα expression in the cortical neuroepithelium of fourteen-day-old embryos from diabetic rats. Interestingly, this scenario was prevented by the chlorpheniramine systemic administration to diabetic pregnant rats at embryo day twelve. These data, together with the bioinformatic analysis, suggest that higher H1-receptor activity in embryos under high glucose increases FOXP2 nuclear translocation, presumably through PKCα phosphorylation, impairing the transition of radial glia to intermediate progenitor and increasing neuron differentiation in embryos of diabetic rats.

Asunto(s)

Diabetes Mellitus Experimental , Células-Madre Neurales , Animales , Femenino , Embarazo , Ratas , Clorfeniramina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Factores de Transcripción Forkhead/metabolismo , Histamina/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis/fisiología , Proteína Quinasa C-alfa/metabolismo , Telencéfalo/metabolismo , Receptores Histamínicos H1

RESUMEN

The motor activity of the epididymis duct is an essential process for male fertility and it is regulated by hormonal, neuronal and epithelial mechanisms. However, although there is evidence for the presence of histamine in the epididymis, its effects on epididymal motor activity are unknown. This study sought to evaluate the contractile effects of histamine on the rat distal cauda epididymis duct. Segments of the distal cauda epididymis duct from male Wistar rats were isolated and used in isolated organ bath experiments to evaluate the contractile effects of histamine in the absence or presence of antagonists of histamine receptors, α1-adrenoceptors and muscarinic acetylcholine receptors. The effects of histamine on noradrenaline induced contractions were also investigated. Histamine was able to induce phasic contractions on rat distal cauda epididymis duct which were prevented by promethazine 10-1000 nM (H1 receptor antagonist), ranitidine 1-100 µM (H2 receptor antagonist), atropine 100 nM (muscarinic antagonist), and prazosin 100 nM (α1-adrenoceptor antagonist). In addition, histamine was also able to modify noradrenaline-induced contractions possibly via activation of H1 and H2 receptors. In conclusion, this study demonstrates that histamine can induce phasic contractions of rat distal cauda epididymis via H2 receptors and autonomic neurotransmitters. Histamine may also exert modulatory actions on contractions of rat distal cauda epididymis duct induced by adrenergic receptor agonists. Further studies are necessary to unveil the localization of histamine receptors within the epididymal duct and the consequences of manipulation of the histaminergic system on epididymal function and male fertility.

Asunto(s)

Epidídimo , Histamina , Ratas , Masculino , Animales , Ratas Wistar , Histamina/farmacología , Prazosina/farmacología , Norepinefrina/farmacología , Receptores Adrenérgicos alfa 1

RESUMEN

Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer's disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine N-methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme-drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC50 = 72.89 µM and 45.01 µM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies.

Asunto(s)

Histamina , Transferasas , Histamina/metabolismo , Histamina N-Metiltransferasa/metabolismo , Clorhidrato de Vilazodona , Simulación del Acoplamiento Molecular , Reposicionamiento de Medicamentos , Dihidroergotamina

RESUMEN

Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H3 and dopamine D3 receptors (H3R and D3R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H3R and D3R was done at 1 or 10 µM and 100 µM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the Ki and IC50 values. Results showed that several compounds were ligands at H3R (n = 10), D3R (n = 6), AChE (n = 3), and BChE (n = 9). Compounds LINS05006 (Ki H3R 2.8 µM; D3R 0.7 µM; IC50 BChE 26.3 µM) and LINS05015 (Ki H3R 1.1 µM; D3R 3.1 µM; IC50 AChE 97.8 µM; BChE 43.7 µM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties.

Asunto(s)

Disfunción Cognitiva , Receptores Histamínicos H3 , Humanos , Histamina , Dopamina , Ligandos , Butirilcolinesterasa/metabolismo , Receptores Histamínicos H3/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Inhibidores de la Colinesterasa/química , Relación Estructura-Actividad

RESUMEN

The authors report the case of a 71-year-old woman presented to the Emergency Department with acute ischemic stroke. She was treated with rt-PA and interventional endovascular revascularization and developed rapidly progressing angioedema that led to emergency intubation. The standard treatment was not very effective and the swelling improved after infusion of fresh frozen plasma. Angioedema after rt-PA infusion could be a life-threatening emergency that requires quick airway management by skilled professionals. As this condition is triggered by several factors, such as unregulated histamine and bradykinin production, the traditional treatment recommended by the guidelines may not be sufficient and the use of FFP can be considered as a safe and valuable aid.

Asunto(s)

Angioedema , Accidente Cerebrovascular Isquémico , Femenino , Humanos , Anciano , Accidente Cerebrovascular Isquémico/complicaciones , Angioedema/inducido químicamente , Angioedema/terapia , Manejo de la Vía Aérea , Histamina , Plasma