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Neuroinflammation is a process involved in a variety of central nervous system (CNS) diseases and is being increasingly recognized as a key mediator of cognitive impairments. Neuroinflammatory responses including glial activation, increased production of proinflammatory cytokines, and aberrant neuronal signaling, contribute to cognitive dysfunctions. Histamine is a key peripheral inflammatory mediator, but plays an important role in neuroinflammatory processes as well. The unique localization of histamine H3 receptor (H3R) in the CNS along with the modulation of the release of other neurotransmitters via its action on heteroreceptors on non-histaminergic neurons have led to the development of several H3R ligands for various brain diseases. H3R antagonists/ inverse agonists have revealed potential to treat diverse neuroinflammatory CNS disorders, including neurodegenerative diseases, attention-deficit hyperactivity syndrome and schizophrenia. In this mini review, we provide a brief overview on the crucial involvement of the histaminergic transmission in the neuroinflammatory processes underlying these cognitive disorders, with a special focus on H3R involvement. The anti-neuroinflammatory potential of single-targeted and multi-targeted H3R antagonists/inverse agonists for the treatment of these conditions is discussed here.

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Biogenic amines are signaling molecules with multiple roles in the central nervous system and in peripheral organs, including the gonads. A series of studies indicated that these molecules, their biosynthetic enzymes and their receptors are present in the testis and that they are involved in the regulation of male reproductive physiology and/or pathology. This mini-review aims to summarize the current knowledge in this field and to pinpoint existing research gaps. We suggest that the widespread clinical use of pharmacological agonists/antagonists of these signaling molecules, calls for new investigations in this area. They are necessary to evaluate the relevance of biogenic amines for human male fertility and infertility, as well as the potential value of at least one of them as an anti-aging compound in the testis.

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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.

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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.

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Fibromyalgia is a painful disorder of unknown aetiology that presents activation and recruitment of innate immune cells, including mast cells. Efforts have been made to understand its pathogenesis to manage it better. Thus, we explored the involvement of peripheral mast cells in an experimental model of fibromyalgia induced by reserpine. Reserpine (1 mg/kg) was subcutaneously (s.c.) injected once daily in the back of male Swiss mice for three consecutive days. We analysed mechanical and cold allodynia, muscle fatigue and number of mast cell in plantar tissue. The fibromyalgia induction produced mast cell infiltration (i.e., mastocytosis) in the mice's plantar tissue. The depletion of mast cell mediators with the compound 48/80 (0.5-4 mg/kg, intraperitoneal (i.p.)) or the mast cell membrane stabilizer ketotifen fumarate (10 mg/kg, oral route (p.o.) widely (80-90 %) and extensively (from 1 up to 10 days) prevented reserpine-induced mechanical and cold allodynia and muscle fatigue. Compound 48/80 also prevented the reserpine-induced mastocytosis. Finally, we demonstrated that PAR-2, 5-HT2A, 5-HT3, H1, NK1 and MrgprB2 receptors, expressed in neuronal or mast cells, seem crucial to mediate fibromyalgia-related cardinal symptoms since antagonists or inhibitors of these receptors (gabexate (10 mg/kg, s.c.), ENMD-1068 (10 mg/kg, i.p.), ketanserin (1 mg/kg, i.p.), ondansetron (1 mg/kg, p.o.), promethazine (1 mg/kg, i.p.), and L733,060 (5 mg/kg, s.c.), respectively) transiently reversed the reserpine-induced allodynia and fatigue. The results indicate that mast cells mediate painful and fatigue behaviours in this fibromyalgia model, representing potential therapy targets to treat fibromyalgia syndrome.

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Background: Fexofenadine emerged as one of the most representative second generation histamine H1 antagonist drugs since the 1990s, with an outstanding efficacy and appreciable safety for the treatment of allergic patients. While allergic rhino-conjunctivitis represents the most frequent atopic disease globally, an update of fexofenadine efficacy and safety on this entity was proposed as a surrogate of allergic condition. Methods: Double blind, placebo controlled, randomized clinical trials investigating the efficacy and safety of fexofenadine for the treatment of Allergic Rhinitis were searched in 5 major global databases. Eligibility criteria and characteristics, risk of bias, and validity assessment, data extraction and heterogeneity evaluation are described. Primary outcome selected corresponded to 12-reflective and instantaneous total symptom scores (TSS), besides morning instantaneous TSS and the frequency of reported adverse events (AEs); analysis was planned on the intention-to-treat population.Standardized mean differences of scoring systems were analyzed, and Cochran's Q statistic test and the I2 test were assessed for heterogeneity. Results: From the initial 83 identified records, 12 eligible studies were selected. In the evaluated patients, individuals receiving fexofenadine (1910) showed a significant reduction of TSS compared with those who received placebo (1777), change from baseline: standardized mean difference (SMD) -0.33; 95% CI-0.47 to -0.18, p < 0.0001. Morning instantaneous TSS also demonstrated lower symptoms (change from baseline: SMS -1.42; 95% CI -2.22 to -0.62, p = 0.0005). Heterogeneity was found across selected studies.Frequency of AEs was similar compared to placebo (OR = 1.04; 0.88-1.21), with no detection of heterogeneity across these 12 studies. Conclusions: According to this new evidence, fexofenadine maintains its beneficial profile on signs and symptoms of patients with allergic conditions, as well as its attributes as one of the major candidates for an ideal antihistamine medication (including special conditions such as pregnancy and pre-school age), providing support to its over-the-counter condition in several countries.

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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.

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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.

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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.

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INTRODUCTION: Oral H1 antihistamines are the first-line treatment for patients with allergic rhinitis, while it is uncertain which kind and dosage of the antihistamines are more effective in improving symptoms of patients. OBJECTIVE: To evaluate the efficacy of different oral H1 antihistamine treatments on patients with allergic rhinitis by performing a network meta-analysis. METHODS: The search was executed in PubMed, Embase, OVID, the Cochrane Library and ClinicalTrials.gov for relevant studies. The network meta-analysis was performed by using Stata 16.0, and the outcome measures of the analysis were symptom score reductions of patients. Relative risks with 95% Confidence Intervals were used in the network meta-analysis to compare the clinical effect of treatments involved, and Surface Under the Cumulative Ranking Curves (SUCRAs) were also calculated to rank the treatments' efficacy. RESULTS: 18 eligible randomized controlled studies, involving a total of 9419 participants, were included in this meta-analysis. All the antihistamine treatments outperformed placebo in total symptom score reduction and each individual symptom score reduction. According to the results of SUCRA, rupatadine 20 mg and rupatadine 10 mg were ranked relatively high in reductions of total symptom score (SUCRA: 99.7%, 76.3%), nasal congestion score (SUCRA: 96.4%, 76.4%), rhinorrhea score (SUCRA: 96.6%, 74.6%) and ocular symptom score (SUCRA: 97.2%, 88.8%); rupatadine 20 mg and levocetirizine 5 mg were ranked relatively high in reductions of nasal itching score (SUCRA: 84.8%, 83.4%) and sneezing score (SUCRA: 87.3%, 95.4%); loratadine 10 mg was ranked the lowest in each symptom score reduction besides placebo. CONCLUSION: This study suggests that rupatadine is the most effective in alleviating symptoms of patients with allergic rhinitis among different oral H1 antihistamine treatments involved, and rupatadine 20 mg performs better than rupatadine 10 mg. While loratadine 10 mg has inferior efficacy for patients to the other antihistamine treatments.

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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.

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Abstract Objective: We aimed to evaluate the effect of radiofrequency turbinate reduction as an initial treatment on clinical improvement, inflammatory mediators, and remodeling process. Methods: Between July 2018- February 2020, 32 patients with moderate-severe persistent AR were randomly divided into 2 groups. Intervention group received radiofrequency turbinate reduction followed by intranasal steroid and Antihistamine H-1 (AH-1), control group received intranasal steroid and AH-1. Both groups were evaluated for clinical improvement (using visual analogue scale based on total nasal symptoms score, peak nasal inspiratory flow, and turbinate size using imageJ) after 4 and 8 weeks of treatment. Inflammatory mediators (ELISA from nasal secretions was performed to measure ECP, IL-5, and HSP-70) and remodeling markers (nasal biopsy followed by immunohistochemistry examination was performed to evaluate MMP-9, TIMP-1, and PAI-1) were evaluated in week 4. Results: Three patients dropped out of the study, resulting in 16 patients in intervention group and 13 patients in control group. At week 4, clinical response improved significantly in the intervention group compared to control group (Chi-Square test, p<0.05). Compared to control, intervention group experienced a reduction of IL-5 and no significant change in ECP level (Mann Whitney test, p>0.05). Reduction in the ratio of MMP-9/TIMP-1 were significantly higher in intervention group (unpaired t-test, p< 0,05). Meanwhile, increase in HSP-70 in the intervention group was slightly lower than in control group, but the difference with control group was not significant (Mann Whitney test, p>0.05). Conclusion: Early radiofrequency turbinate reduction followed by pharmacotherapy given to persistent moderate-severe AR patients give more improvement only in early clinical symptoms and reduce MMP-9/TIMP-1 ratio, thus it might be suggested as one of the adjuvant therapies for the management of moderate-severe persistent AR. However, further investigation with a larger sample size and longer follow-up period is needed. Level of evidence: 1B.

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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.

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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.

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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.

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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.

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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.

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The influence of under-fermented (UF) cocoa (0 to 65 %) on bioactive amines in chocolate and their in vitro bioaccessibility was investigated. The same amines were found in all treatments; however, treatments were divided into two groups regarding total amines [0 & 20 % UF (34 mg/kg) and 35 to 65 % UF (17 mg/kg)] and phenolic levels [lower and higher, respectively]. Serotonin, tyramine, putrescine, cadaverine, agmatine and phenylethylamine were higher in chocolate with ≤ 20 % UF cocoa. Histamine and spermidine were not affected. Digestibility studies indicated that low levels of amines were present in the oral phase. Gastric digestion was effective in releasing tyramine, spermidine and phenylethylamine from conjugates. Serotonin and agmatine were not detected after in vitro digestion of chocolate with ≥ 35 % UF cocoa. Histamine was released during in vitro intestinal digestion. By adding different proportions of UF cocoa during chocolate production, the levels and bioaccessibility of amines can be modulated.

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OBJECTIVE: We aimed to evaluate the effect of radiofrequency turbinate reduction as an initial treatment on clinical improvement, inflammatory mediators, and remodeling process. METHODS: Between July 2018-February 2020, 32 patients with moderate-severe persistent AR were randomly divided into 2 groups. Intervention group received radiofrequency turbinate reduction followed by intranasal steroid and Antihistamine H-1 (AH-1), control group received intranasal steroid and AH-1. Both groups were evaluated for clinical improvement (using visual analogue scale based on total nasal symptoms score, peak nasal inspiratory flow, and turbinate size using imageJ) after 4 and 8 weeks of treatment. Inflammatory mediators (ELISA from nasal secretions was performed to measure ECP, IL-5, and HSP-70) and remodeling markers (nasal biopsy followed by immunohistochemistry examination was performed to evaluate MMP-9, TIMP-1, and PAI-1) were evaluated in week 4. RESULTS: Three patients dropped out of the study, resulting in 16 patients in intervention group and 13 patients in control group. At week 4, clinical response improved significantly in the intervention group compared to control group (Chi-Square test, p < 0.05). Compared to control, intervention group experienced a reduction of IL-5 and no significant change in ECP level (Mann Whitney test, p > 0.05). Reduction in the ratio of MMP-9/TIMP-1 were significantly higher in intervention group (unpaired t-test, p < 0,05). Meanwhile, increase in HSP-70 in the intervention group was slightly lower than in control group, but the difference with control group was not significant (Mann Whitney test, p > 0.05). CONCLUSION: Early radiofrequency turbinate reduction followed by pharmacotherapy given to persistent moderate-severe AR patients give more improvement only in early clinical symptoms and reduce MMP-9/TIMP-1 ratio, thus it might be suggested as one of the adjuvant therapies for the management of moderate-severe persistent AR. However, further investigation with a larger sample size and longer follow-up period is needed. LEVEL OF EVIDENCE: 1B.

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The term food intolerance has been used non-specifically to define a wide range of disorders related to food intake. Recently, the use of the term "non-immunological adverse reactions to foods" (RANIAs) was recommended as a more correct clinical definition. The pathophysiological mechanisms can be diverse, sometimes unknown, and there are no validated diagnostic tests, making it difficult to obtain accurate data. The clinical manifestations of non-immunological adverse reactions to foods affect more than one organ or system; and gastrointestinal symptoms (pain, abdominal distension, flatulence, and diarrhea) are the most common. Non-immunological adverse reactions to foods are divided into independent and dependent on host factors. Foods may contain chemicals with pharmacological activity and be present naturally, such as vasoactive amines (histamine) and salicylates, or added for preservation, to improve appearance or flavor (monosodium glutamate, tartrazine, sulfites, and benzoates). In some cases, these types of reactions may be like to hypersensitivity reactions. Concomitant alcohol consumption may worsen symptoms by inhibiting histamine breakdown and increasing intestinal permeability. In patients diagnosed with non-immunological adverse reactions to foods, it is important to rule out some psychological problems: aversions or eating disorders.

El término intolerancia alimentaria se ha utilizado de manera inespecífica para definir una amplia gama de trastornos relacionados con la ingesta de alimentos. Recientemente se recomendó el uso de la expresión "reacciones adversas no inmunológicas a alimentos" (RANIAs) como una definición clínica más correcta. Los mecanismos fisiopatológicos pueden ser diversos, a veces desconocidos, y no existen pruebas diagnósticas validadas, por lo que es difícil obtener datos certeros. Las manifestaciones clínicas de las reacciones adversas no inmunológicas a alimentos afectan a más de un órgano o sistema; y los síntomas gastrointestinales (dolor, distensión abdominal, flatulencias y diarrea) son los más frecuentes. Las reacciones adversas no inmunológicas a alimentos se dividen en independientes y dependientes de factores del huésped. Los alimentos pueden contener productos químicos con actividad farmacológica y estar presentes en forma natural, como las aminas vasoactivas (histamina) y los salicilatos, o añadirse para su conservación, mejorar la apariencia o el sabor (glutamato monosódico, tartrazina, sulfitos y benzoatos). En algunos casos, este tipo de reacciones pueden ser similares, desde el punto de vista clínico, a las reacciones de hipersensibilidad. El consumo de alcohol concomitante puede empeorar los síntomas, al inhibir la degradación de la histamina y aumentar la permeabilidad intestinal. En pacientes con diagnóstico de reacciones adversas no inmunológicas por alimentos es importante descartar algunos problemas de índole psicológica: aversiones o trastornos de la conducta alimentaria.

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