RESUMEN
Essential hypertension (HTN) is a disease where genetic and environmental factors interact to produce a high prevalent set of almost indistinguishable phenotypes. The weak definition of what is under the umbrella of HTN is a consequence of the lack of knowledge on the players involved in environment-gene interaction and their impact on blood pressure (BP) and mechanisms. The disclosure of these mechanisms that sense and (mal)adapt to toxic-environmental stimuli might at least determine some phenotypes of essential HTN and will have important therapeutic implications. In the present manuscript, we looked closer to the environmental sensor aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor involved in cardiovascular physiology, but better known by its involvement in biotransformation of xenobiotics through its canonical pathway. This review aims to disclose the contribution of the AHR-canonical pathway to HTN. For better mirror the complexity of the mechanisms involved in BP regulation, we privileged evidence from in vivo studies. Here we ascertained the level of available evidence and a comprehensive characterization of the AHR-related phenotype of HTN. We reviewed clinical and rodent studies on AHR-HTN genetic association and on AHR ligands and their impact on BP. We concluded that AHR is a druggable mechanistic linker of environmental exposure to HTN. We conclude that is worth to investigate the canonical pathway of AHR and the expression/polymorphisms of its related genes and/or other biomarkers (e.g. tryptophan-related ligands), in order to identify patients that may benefit from an AHR-centered antihypertensive treatment.
Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Humanos , Hipertensión/metabolismo , Receptores de Hidrocarburo de Aril/efectos de los fármacosRESUMEN
Accumulating evidence including studies of AHR-deficient mice and TCDD toxicity suggests multiple physiologic AHR functions. Challenges to identify responsible mechanisms are due to marked species differences and dependence upon cell type and cellular context. Transient AHR modulation is often necessary for physiologic functions whereas TCDD-mediated sustained receptor activation has been demonstrated to be responsible for toxic outcomes. To stimulate studies on responsible action mechanisms the commentary is focused on human AHR target genes and crosstalk with transcription factors. Discussed AHR functions include chemical and microbial defense, organ development, modulation of immunity and inflammation, reproduction, and NAD+-dependent energy metabolism. Obviously, much more work is needed to elucidate action mechanisms. In particular, studies of pathways leading to NAD+-dependent energy metabolism may shed light on the puzzling species differences of TCDD-mediated lethality and provide options for treatment of obesity and age-related degenerative diseases.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Receptores de Hidrocarburo de Aril/fisiología , Animales , Puntos de Control del Ciclo Celular/fisiología , Proliferación Celular/fisiología , Citocinas/metabolismo , Metabolismo Energético/fisiología , Humanos , Inactivación Metabólica/fisiología , Mastocitos/inmunología , Ratones , NAD/metabolismo , Dibenzodioxinas Policloradas/farmacocinética , Reproducción/fisiologíaRESUMEN
Despite decades of intense research physiologic aryl hydrocarbon receptor (AHR) functions have not been elucidated. Challenges include marked species differences and dependence on cell type and cellular context. A previous commentary on human AHR functions in skin and intestine has been extended to vascular tissue. Similar functions appear to be operating in vascular tissue including microbial defense, modulation of stem/progenitor cells as well as control of immunity and inflammation. However, AHR functions are Janus faced: Detrimental AHR functions in vascular tissue are well documented, e.g., upon exposure to polycyclic aromatic hydrocarbons in cigarette smoke leading to oxidative stress and generation of oxidized LDL. Modified LDL particles accumulate in macrophages and smooth muscle-derived pro-inflammatory foam cells, the hallmark of atherosclerosis. On the other hand, numerous anti-inflammatory AHR agonists have been identified including bilirubin and quercetin. Mechanisms as to how AHR produces pro- and anti-inflammatory responses in the vascular system need further investigation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Aterosclerosis/tratamiento farmacológico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/metabolismo , Aterosclerosis/metabolismo , Autoinmunidad , Bilirrubina/farmacología , Endotelio Vascular/metabolismo , Flavonoides/farmacología , Humanos , Lipoproteínas LDL/metabolismo , Hidrocarburos Policíclicos Aromáticos/toxicidad , Quercetina/farmacología , Transducción de SeñalRESUMEN
A large number of studies have focused on the role of serotonin as a neurotransmitter in the central nervous system, although only a small percentage of the body's serotonin (â¼5%) can be found in the mature brain of mammals. In the gut, the enterochromaffin cells are scattered in the enteric epithelium from the stomach through the colon and produce over 95% of the body's serotonin. Since the generation of tryptophan hydroxylase (Tph1 and Tph2) knockout mice, unsuspected roles have been identified for serotonin synthesized outside the brain. Moreover, the murine model deficient in peripheral serotonin (Tph1-/-) is a unique experimental tool for exploring the molecular and cellular mechanisms involving serotonin's local effects through microserotonergic systems. In this review, we focus on peripheral serotonin and its role on progenitor or stem cells as well as on hematopoietic progenitors. We discuss the possible role of serotonin in hematopoietic diseases, and whether targeting the serotonergic system could be of therapeutic value for the regulation of normal and pathological hematopoiesis.
Asunto(s)
Hematopoyesis , Serotonina/fisiología , Células Madre/fisiología , Animales , Desarrollo Embrionario , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Despite the increased morbidity of ulcerative colitis (UC) in recent years, available treatments remain unsatisfactory. Pogostemon cablin has been widely applied to treat a variety of gastrointestinal disorders in clinic for centuries, in which patchouli alcohol (PA, C15H26O) has been identified as the major active component. This study attempted to determine the bioactivity of PA on dextran sulfate sodium (DSS)-induced mice colitis and clarify the mechanism of action. Acute colitis was induced in mice by 3% DSS for 7 days. The mice were then given PA (10, 20 and 40mg/kg) or sulfasalazine (SASP, 200mg/kg) as positive control via oral administration for 7 days. At the end of study, animals were sacrificed and samples were collected for pathological and other analysis. In addition, a metabolite profiling and a targeted metabolite analysis, based on the Ultra-Performance Liquid Chromatography coupled with mass spectrometry (UPLC-MS) approach, were performed to characterize the metabolic changes in plasma. The results revealed that PA significantly reduced the disease activity index (DAI) and ameliorated the colonic injury of DSS mice. The levels of colonic MPO and cytokines involving TNF-α, IFN-γ, IL-1ß, IL-6, IL-4 and IL-10 also declined. Furthermore, PA improved the intestinal epithelial barrier by enhancing the level of colonic expression of the tight junction (TJ) proteins, for instance ZO-1, ZO-2, claudin-1 and occludin, and by elevating the levels of mucin-1 and mucin-2 mRNA. The study also demonstrated that PA inhibited the DSS-induced cell death signaling by modulating the apoptosis related Bax and Bcl-2 proteins and down-regulating the necroptosis related RIP3 and MLKL proteins. By comparison, up-regulation of IDO-1 and TPH-1 protein expression in DSS group was suppressed by PA, which was in line with the declined levels of kynurenine (Kyn) and 5-hydroxytryptophan (5-HTP) in plasma. The therapeutic effect of PA was evidently reduced when Kyn was given to mice. In summary, the study successfully demonstrated that PA ameliorated DSS-induced mice acute colitis by suppressing inflammation, maintaining the integrity of intestinal epithelial barrier, inhibiting cell death signaling, and suppressing tryptophan catabolism. The results provided valuable information and guidance for using PA in treatment of UC.
Asunto(s)
Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colon/efectos de los fármacos , Sulfato de Dextran , Sesquiterpenos/uso terapéutico , Triptófano/metabolismo , Animales , Colitis/metabolismo , Colitis/patología , Colon/metabolismo , Colon/patología , Citocinas/análisis , Masculino , Ratones Endogámicos BALB C , Pogostemon/química , Sesquiterpenos/químicaRESUMEN
A Box-Behnken design was used in conjunction with multiresponse optimization based on the desirability function to carry out the simultaneous separation of tryptophan and 15 derivatives by Ultra Performance Liquid Chromatography. The gradient composition of the mobile phase and the flow rate were optimized with respect to the resolution of severely overlapping chromatographic peaks and the total run time. Two different stationary phases were evaluated (hybrid silica and a solid-core-based C18 column). The methods were validated and a suitable sensitivity was found for all compounds in the concentration range 1-100µgL-1 (R2>0.999). High levels of repeatability and intermediate precision (CV less than 0.25% and 1.7% on average for the retention time and the signal area, respectively) were obtained. The new method was applied to the determination tryptophan and its derivatives in black pigmented glutinous and non-glutinous rice grain samples.