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1.
PLoS One ; 15(5): e0232233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365077

RESUMO

The physiological actions of orally ingested peptides on the brain remain poorly understood. This study examined the effects of 39 orally administered synthetic Tyr-containing dipeptides on the enhancement of brain norepinephrine metabolism in mice by comparing the concentration of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). Although Tyr-Tyr administration increased blood and cerebral cortex (Cx) Tyr concentrations the most, Tyr-Trp increased Cx MHPG concentration the most. The oral administration of Tyr-Trp ameliorated a short-term memory deficit of a mouse model of cognitive dysfunction induced by amyloid beta peptide 25-35. Gene expression profiling of mouse brain using a microarray indicated that Tyr-Trp administration led to a wide variety of changes in mRNA levels, including the upregulation of genes encoding molecules involved in catecholamine metabolism. A comparative metabolome analysis of the Cx of mice given Tyr-Trp or Tyr-Tyr demonstrated that Tyr-Trp administration yielded higher concentrations of Trp and kynurenine pathway metabolites than Tyr-Tyr administration, as well as higher L-dopa levels, which is the initial product of catecholamine metabolism. Catecholamines were not significantly increased in the Cx of the Tyr-Tyr group compared with the Tyr-Trp group, despite a marked increase in Tyr. Presumably, Tyr-Trp administration enhances catecholamine synthesis and metabolism via the upregulation of genes involved in Tyr and Trp metabolism as well as metabolites of Tyr and Trp. These findings strongly suggest that orally ingested Tyr-Trp modulates the brain metabolome involved in catecholamine metabolism and contributes to higher brain function.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Dipeptídeos/administração & dosagem , Memória de Curto Prazo/efeitos dos fármacos , Metoxi-Hidroxifenilglicol/análise , Administração Oral , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/efeitos adversos , Animais , Catecolaminas/biossíntese , Córtex Cerebral/química , Córtex Cerebral/efeitos dos fármacos , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Masculino , Metaboloma/efeitos dos fármacos , Camundongos , Fragmentos de Peptídeos/efeitos adversos
2.
Clin Chim Acta ; 494: 100-105, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30904545

RESUMO

BACKGROUND: Availability of appropriately established reference intervals for biochemical tests can be troublesome in pediatrics. Here we establish age-specific continuous reference intervals for catecholamine O-methylated metabolites in children evaluated for catecholamine producing tumors, particularly younger children with suspected neuroblastoma. METHODS: Plasma concentrations of 3-methoxytyramine, normetanephrine, metanephrine, and 3-O-methyldopa were analyzed by liquid chromatography tandem mass spectrometry in 533 children aged 2 days to 18 years. RESULTS: Concentrations of plasma free normetanephrine, 3-methoxytyramine and 3-O-methyldopa were higher in neonates up until six months of age, but thereafter declined steeply to levels after one year that were <38% those of neonatal concentrations and to further lower concentrations in teenagers that were <23% those in neonates. In contrast, concentrations of plasma free metanephrine showed a reciprocal pattern with 50% lower concentrations in infants below one year compared to later in childhood. CONCLUSION: The dynamic reciprocal changes in plasma concentrations of normetanephrine, 3-methoxytyramine and 3-O-methyldopa compared to metanephrine during early childhood suggest underlying developmental changes in extra-adrenal and adrenal chromaffin tissue that must be considered for pediatric reference intervals, particularly in infants. With such reference intervals at hand, biochemical testing for catecholamine producing tumors in young children is substantially improved.


Assuntos
Neoplasias das Glândulas Suprarrenais/sangue , Envelhecimento/sangue , Dopamina/análogos & derivados , Metanefrina/sangue , Normetanefrina/sangue , Paraganglioma/sangue , Feocromocitoma/sangue , Tirosina/análogos & derivados , Adolescente , Análise Química do Sangue , Catecolaminas/biossíntese , Criança , Pré-Escolar , Cromatografia Líquida , Dopamina/sangue , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Valores de Referência , Espectrometria de Massas em Tandem , Tirosina/sangue
3.
Can J Physiol Pharmacol ; 97(7): 685-690, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30773040

RESUMO

This study investigated the effects of melatonin treatment on adrenal catecholamine content, synthesis, uptake, and vesicular transport induced by the chronic unpredictable mild stress (CUMS) model of depression in rats. This entailed quantifying the norepinephrine, epinephrine, mRNA, and protein levels of tyrosine hydroxylase (TH), dopamine-ß-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), norepinephrine transporter (NET), and vesicular monoamine transporter 2 (VMAT2) in the adrenal medulla. CUMS caused a significant depletion of norepinephrine stores and protein levels of TH, DBH, and NET, whereas the gene expression of PNMT was increased. It was observed that melatonin treatment in the CUMS rats prevented the stress-induced decrease in norepinephrine content and the protein expression of TH, DBH, and NET in the adrenal medulla of chronically stressed rats. The present study demonstrates the stimulatory effect of melatonin on adrenomedullary synthesis, the uptake and content of catecholamine in the rat model of chronic stress-induced depression.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Catecolaminas/biossíntese , Depressão/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Melatonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Estresse Psicológico/complicações , Glândulas Suprarrenais/metabolismo , Animais , Doença Crônica , Depressão/etiologia , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Masculino , Melatonina/uso terapêutico , Ratos , Ratos Wistar
4.
Stress ; 22(3): 332-346, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30714474

RESUMO

Corticotropin-releasing-factor (CRF) is a key regulator of catecholamines (CATs) biosynthesis in the adrenal gland. Furthermore, miR-375 has been confirmed to be localized in the mouse adrenal gland. However, the relationships between miR-375 and CRF in regulating CATs biosynthesis remain to be established. This study was designed to investigate the relationship between CRF and miR-375 in the regulation of CATs biosynthesis in the porcine adrenal gland. Eight adult female pigs (four controls; four injected intracerebroventricularly with 50 µg of CRF) were used for the in vivo experiments in this study. The results showed that miR-375 was exclusively localized in porcine adrenal medullary cells. Functional studies showed that miR-375 negatively regulated CATs synthesis in primary cells by affecting the expression of the CATs synthetases tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine-N-methyltransferase (PNMT). CRF up-regulated the expression of CATs synthetase in primary adrenal medullary cells under basal conditions and upon endogenous miR-375 inhibition; the enhanced effects vanished when cellular miR-375 was overexpressed by transfecting miR-375-mic. CRF decreased the expression of miR-375 both in vivo and in vitro. Our in vitro results showed that CRF significantly decreased the expression of miR-375, perhaps by binding to CRFR1. miR-375 functions by directly binding to the 3'-UTR region of specificity protein 1 (Sp1), which is involved in regulating Th and Dbh expression. These data collectively indicate that miR-375 plays an important role in regulating CATs synthesis and mediates the CRF signaling pathway in porcine adrenal medullary cells.


Assuntos
Medula Suprarrenal/metabolismo , Catecolaminas/biossíntese , Hormônio Liberador da Corticotropina/metabolismo , MicroRNAs/metabolismo , MicroRNAs/fisiologia , Glândulas Suprarrenais/metabolismo , Animais , Dopamina beta-Hidroxilase/metabolismo , Feminino , Masculino , Camundongos , Feniletanolamina N-Metiltransferase , Transdução de Sinais , Estresse Psicológico , Suínos , Tirosina 3-Mono-Oxigenase/metabolismo
5.
Nature ; 564(7735): 273-277, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30542164

RESUMO

Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1-5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.


Assuntos
Catecolaminas/antagonistas & inibidores , Catecolaminas/metabolismo , Citocinas/efeitos adversos , Síndrome , Animais , Fator Natriurético Atrial/farmacologia , Complexo CD3/antagonistas & inibidores , Catecolaminas/biossíntese , Citocinas/imunologia , Epinefrina/metabolismo , Feminino , Humanos , Imunoterapia Adotiva , Técnicas In Vitro , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Norepinefrina/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , alfa-Metiltirosina/farmacologia
6.
Histochem Cell Biol ; 150(6): 703-709, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30250972

RESUMO

Recent advances in neurogastroenterology have extended and refined our knowledge on the roles monoamines play in physiology and pathophysiology of the gastrointestinal tract. The catecholamine noradrenaline, as the primary transmitter of postganglionic sympathetic neurons, orchestrates motility and secretory reflexes and controls arterial perfusion as well as immune functions. The catecholamine dopamine is produced by a subpopulation of enteric neurons which possibly use it as transmitter. Serotonin, largely produced by enterochromaffin cells and to a small extent by enteric neurons profoundly affects gut motility, enteric neuron development and is also involved in immunomodulation. However, its mode of action and the relative contribution of non-neuronal versus neuronal serotonin was recently subject to debate again. Histamine, although entirely of non-neuronal origin, is pivotal for gastrointestinal neuroimmunomodulation besides its paracrine effect in gastric HCl production.


Assuntos
Aminas/metabolismo , Sistema Nervoso Entérico/metabolismo , Catecolaminas/biossíntese , Catecolaminas/química , Humanos , Serotonina/biossíntese , Serotonina/química
7.
Endocr Pathol ; 29(4): 302-309, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30155766

RESUMO

In chromaffin cells, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine ß-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) are mainly involved in catecholamine synthesis. In this study, we evaluated the association between the status of catecholamine-synthesizing enzymes and histopathological features of pheochromocytoma and extraadrenal paraganglioma with special emphasis upon their postoperative clinical behavior. Immunohistochemical evaluation of TH, DBH, AADC, PNMT, Ki 67, and S-100 was performed in 29 pheochromocytoma and 10 extraadrenal paraganglioma and one lymph node harboring metastatic pheochromocytoma. Among these cases, metastasis was subsequently developed in three cases. Urinary normetanephrine (U-NM) levels were significantly higher in clinical metastatic cases than non-metastatic ones. Ki 67 labeling index was significantly higher in both clinical metastatic cases and the Adrenal Gland Scaled Score (PASS) score of ≧ 4 cases than PASS < 4 cases, although this score was originally used in pheochromocytoma. H-score of AADC and DBH were significantly lower in PASS ≧ 4 cases than those with < 4 cases, and in the cases associated with intratumoral necrosis (n = 4), the presence of spindle shaped tumor cells (n = 4), and large nests of cells or diffuse growth (n = 5). Lower status of intratumoral AADC could be related to poor differentiation of tumor cells in both catecholamine production and morphology and could be related to aggressive biological behavior of both pheochromocytoma and extraadrenal paraganglioma.


Assuntos
Neoplasias das Glândulas Suprarrenais/enzimologia , Catecolaminas/biossíntese , Paraganglioma Extrassuprarrenal/enzimologia , Feocromocitoma/enzimologia , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Descarboxilases de Aminoácido-L-Aromático/análise , Descarboxilases de Aminoácido-L-Aromático/metabolismo , Doenças do Sistema Nervoso Autônomo/metabolismo , Dopamina beta-Hidroxilase/análise , Dopamina beta-Hidroxilase/deficiência , Dopamina beta-Hidroxilase/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/análise , Norepinefrina/deficiência , Norepinefrina/metabolismo , Paraganglioma Extrassuprarrenal/patologia , Feniletanolamina N-Metiltransferase/análise , Feniletanolamina N-Metiltransferase/metabolismo , Feocromocitoma/patologia , Tirosina 3-Mono-Oxigenase/análise , Tirosina 3-Mono-Oxigenase/metabolismo
8.
J Clin Invest ; 128(9): 3866-3871, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-30080182

RESUMO

Hypoglycemia activates the counterregulatory response (CRR), a neural-endocrine reflex that restores euglycemia. Although effective if occasionally activated, repeated induction of the CRR leads to a decline in responsiveness and prolonged exposure to hypoglycemia. The mechanism underlying this impairment is not known. We found that the reduction in epinephrine release that characterizes a suppressed CRR involves a long-lasting form of sympatho-adrenal synaptic plasticity. Using optogenetically evoked catecholamine release, we show that recurrent hypoglycemia reduced the secretory capacity of mouse adrenal chromaffin cells. Single activation of the CRR increased the adrenal levels of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine synthesis, but this was prevented by repeated activation. In contrast, the level of neuropeptide Y (NPY), an adrenal cotransmitter, remained elevated after recurrent hypoglycemia. Inhibition of NPY or Y1 signaling, either transgenically or pharmacologically, prevented the attenuation of both TH expression and epinephrine release. These results indicate that impairment of the CRR involves suppressed activity at the adrenal level. Interfering with the peripheral NPY-dependent negative feedback loop may provide a way to avoid the pathophysiological consequences of recurrent hypoglycemia which are common in the diabetic state.


Assuntos
Glândulas Suprarrenais/metabolismo , Hipoglicemia/metabolismo , Animais , Catecolaminas/biossíntese , Células Cromafins/metabolismo , Epinefrina/metabolismo , Retroalimentação Fisiológica , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal , Neuropeptídeo Y/deficiência , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Recidiva , Tirosina 3-Mono-Oxigenase/metabolismo
9.
Int J Mol Sci ; 19(7)2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29996472

RESUMO

Extracellular signal-regulated kinase 5 (ERK5) regulates diverse physiological responses such as proliferation, differentiation, and gene expression. Previously, we demonstrated that ERK5 is essential for neurite outgrowth and catecholamine biosynthesis in PC12 cells and sympathetic neurons. However, it remains unclear how ERK5 regulates the activity of ion channels, which are important for membrane excitability. Thus, we examined the effect of ERK5 on the ion channel activity in the PC12 cells that overexpress both ERK5 and the constitutively active MEK5 mutant. The gene and protein expression levels of voltage-dependent Ca2+ and K⁺ channels were determined by RT-qPCR or Western blotting. The A-type K⁺ current was recorded using the whole-cell patch clamp method. In these ERK5-activated cells, the gene expression levels of voltage-dependent L- and P/Q-type Ca2+ channels did not alter, but the N-type Ca2+ channel was slightly reduced. In contrast, those of Kv4.2 and Kv4.3, which are components of the A-type current, were significantly enhanced. Unexpectedly, the protein levels of Kv4.2 were not elevated by ERK5 activation, but the phosphorylation levels were increased by ERK5 activation. By electrophysiological analysis, the inactivation time constant of the A-type current was prolonged by ERK5 activation, without changes in the peak current. Taken together, ERK5 inhibits an inactivation of the A-type current by phosphorylation of Kv4.2, which may contribute to the neuronal differentiation process.


Assuntos
Proteína Quinase 7 Ativada por Mitógeno/genética , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Canais de Potássio Shal/genética , Canais de Potássio Shal/metabolismo , Animais , Catecolaminas/biossíntese , Diferenciação Celular , Regulação da Expressão Gênica , Potenciais da Membrana , Neurônios/citologia , Neurônios/metabolismo , Células PC12 , Técnicas de Patch-Clamp , Fosforilação , Ratos , Transdução de Sinais
10.
Sci Rep ; 8(1): 9645, 2018 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-29941879

RESUMO

Synovial adipose stem cells (sASC) can be differentiated into catecholamine-expressing sympathetic neuron-like cells to treat experimental arthritis. However, the pro-inflammatory tumor necrosis factor (TNF) is known to be toxic to catecholaminergic cells (see Parkinson disease), and this may prevent anti-inflammatory effects in inflamed tissue. We hypothesized that TNF exhibits inhibitory effects on human differentiated sympathetic tyrosine hydroxylase-positive (TH+) neuron-like cells. For the first time, iTH+ neuron-like sympathetic cells were generated from sACSs of rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. Compared to untreated controls in both OA and RA, TNF-treated iTH+ cells demonstrated a weaker staining of catecholaminergic markers in cell cultures of RA/OA patients, and the amount of produced noradrenaline was markedly lower. These effects were reversed by etanercept. Exposure of iTH+ cells to synovial fluid of RA patients showed similar inhibitory effects. In mixed synovial cells, significant effects of TNF on catecholamine release were observed only in OA. This study shows that TNF inhibits iTH+ synovial cells leading to the decrease of secreted noradrenaline. This might be a reason why discovered newly appearing TH+ cells in the synovium are not able to develop their possible full anti-inflammatory role in arthritis.


Assuntos
Artrite Reumatoide/patologia , Catecolaminas/biossíntese , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Osteoartrite/patologia , Sistema Nervoso Simpático/patologia , Fator de Necrose Tumoral alfa/farmacologia , Catecolaminas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neurônios/patologia , Norepinefrina/metabolismo , Líquido Sinovial/efeitos dos fármacos
11.
Artigo em Inglês | MEDLINE | ID: mdl-29730451

RESUMO

Monoamine neurotransmitters such as catecholamines [dopamine (DA), norepinephrine (NE) and epinephrine (E)] and serotonin have been shown to influence feeding in vertebrates. In order to better understand the role of monoamine neurotransmitters in the regulation of feeding in fish, we examined the effects of fasting on the brain and intestine gene expression of enzymes involved in their synthesis pathways (SPR: sepiapterin reductase; DHPR: dihydropteridine reductase; TH: tyrosine hydroxylase; TPH: tryptophan hydroxylase; AADC: aromatic l-amino acid decarboxylase; DBH: dopamine ß-hydroxylase) in goldfish. In order possible interactions between the monoaminergic pathways and appetite-regulating hormones, we examined the effects of intraperitoneal injections of orexin, CCK and irisin on the brain and intestine gene expression of these enzymes. Fasting increased the expressions of SPR, TH, DBH, TPH1 and DHPR in the brain but did not affect the intestinal expressions of any of the enzymes examined, suggesting that nutritional status might affect the synthesis of monoamines in the central nervous system. CCK injections decreased feeding and increased SPR, TH, and TPH expressions in both brain and intestine. Orexin injections increased feeding and SPR and AADC expressions in the brain but did not affect the expressions of any of the enzymes in the intestine. Irisin injections decreased feeding and increased TPH2 and AADC brain expressions and TH and SPR intestinal expressions, and decreased TPH1 brain expression and AADC intestinal expression. Our results suggest that feeding/fasting and appetite-regulating hormones modulate in part the catecholamine and serotonin synthesis pathways in goldfish.


Assuntos
Regulação do Apetite , Catecolaminas/biossíntese , Jejum , Carpa Dourada/fisiologia , Serotonina/biossíntese , Animais , Encéfalo/metabolismo , Comportamento Alimentar , Regulação Enzimológica da Expressão Gênica , Carpa Dourada/metabolismo , Injeções Intraperitoneais , Mucosa Intestinal/metabolismo , Neurotransmissores/metabolismo , Orexinas/administração & dosagem , RNA Mensageiro/metabolismo
12.
Mol Cell Endocrinol ; 470: 295-303, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29183807

RESUMO

A poor nutritional environment during early development has long been known to increase disease susceptibility later in life. We have previously shown that rats that are overfed as neonates (i.e. suckled in small litters (4 pups) relative to control conditions (12 pups)) show dysregulated hypothalamic-pituitary-adrenal axis responses to immune stress in adulthood, particularly due to an altered capacity of the adrenal to respond to an immune challenge. Here we hypothesised that neonatal overfeeding similarly affects the sympathomedullary system, testing this by investigating the biochemical function of tyrosine hydroxylase (TH), the first rate-limiting enzyme in the catecholamine synthesis. We also examined changes in adrenal expression of the leptin receptor and in mitogen-activated protein kinase (MAPK) signalling. During the neonatal period, we saw age-dependent changes in TH activity and phosphorylation, with neonatal overfeeding stimulating increased adrenal TH specific activity at postnatal days 7 and 14, along with a compensatory reduction in total TH protein levels. This increased TH activity was maintained into adulthood where neonatally overfed rats exhibited increased adrenal responsiveness 30 min after an immune challenge with lipopolysaccharide, evident in a concomitant increase in TH protein levels and specific activity. Neonatal overfeeding significantly reduced the expression of the leptin receptor in neonatal adrenals at postnatal day 7 and in adult adrenals, but did not affect MAPK signalling. These data suggest neonatal overfeeding alters the capacity of the adrenal to synthesise catecholamines, both acutely and long term, and these effects may be independent of leptin signalling.


Assuntos
Glândulas Suprarrenais/metabolismo , Catecolaminas/biossíntese , Comportamento Alimentar , Animais , Animais Recém-Nascidos , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases , Masculino , Fosforilação , Ratos Wistar , Receptores para Leptina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
13.
Toxicology ; 394: 84-92, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29246838

RESUMO

Imidacloprid is a neonicotinoid insecticide acting as an agonist of nicotinic acetylcholine receptors (nAChRs) in the target insects. However, questions about the safety to mammals, including human have emerged. Overactivation of mammalian peripheral catecholaminergic systems leads to onset of tachycardia, hypertension, vomiting, etc., which have been observed in acutely imidacloprid-poisoned patients as well. Physiological activation of the nAChRs is known to drive catecholamine biosynthesis and secretion in mammalian adrenal chromaffin cells. Yet, the impacts of imidacloprid on the catecholaminergic function of the chromaffin cells remain to be evaluated. In this study using PC12D cells, a catecholaminergic cell line derived from the medulla chromaffin-cell tumors of rat adrenal gland, we examined whether imidacloprid itself could impact the catecholamine-synthesizing ability. Imidacloprid alone did facilitate tyrosine hydroxylase (TH) transcription via activation of α3ß4 nAChR and the α7 subunit-comprising receptor. The insecticide showed the TH transcription-facilitating ability at the concentrations of 3 and 30 µM, at which acetylcholine is known to produce physiological responses, including catecholamine secretion through the nAChRs in adrenal chromaffin cells. The insecticide-facilitated TH transcription was also dependent on PKA- and RhoA-mediated signaling pathways. The insecticide coincidentally raised levels of TH and phenylethanolamine N-methyltransferase (PNMT) mRNA, and as a consequence, increased catecholamine production, although the efficacy of the neonicotinoid was lesser than that of nicotine, indicating its partial agonist-like action. Intriguingly, in cultured rat adrenal chromaffin cells, imidacloprid did increase levels of TH and PNMT protein. When the chromaffin cells were treated with nicotine in the presence of the insecticide, nicotine-elevated adrenaline production was enhanced due to facilitation of nicotine-increased TH and PNMT protein expression, and simultaneous enhancement of nicotine-elevated adrenaline secretion also took place. These findings thus suggest that imidacloprid may facilitate the physiological functions of adrenal glands in mammals.


Assuntos
Catecolaminas/biossíntese , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nicotina/farmacologia , Nitrocompostos/farmacologia , Feniletanolamina N-Metiltransferase/genética , RNA Mensageiro/genética , Tirosina 3-Mono-Oxigenase/genética , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Animais , Catecolaminas/genética , Células Cultivadas , Células Cromafins/efeitos dos fármacos , Células Cromafins/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Sinergismo Farmacológico , Epinefrina/biossíntese , Epinefrina/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células PC12 , Feniletanolamina N-Metiltransferase/biossíntese , RNA Mensageiro/biossíntese , Ratos , Transcrição Genética/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/biossíntese , Proteínas rho de Ligação ao GTP/metabolismo
14.
Intern Med ; 57(9): 1253-1257, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29279477

RESUMO

We herein report the case of a 37-year-old man with both pheochromocytoma and visceral fat accumulation and describe the sequential changes in his adiponectin levels throughout the clinical course from catecholamine crisis until the follow-up for adrenalectomy. His adiponectin level decreased during catecholamine crisis and increased after adrenalectomy. However, his adiponectin level decreased again at two years postoperatively when his visceral fat area greatly increased. This case suggests that catecholamines and visceral fat volume may affect adiponectin metabolism in subjects with pheochromocytoma, which may precipitate cardiovascular complications in this endocrine disease.


Assuntos
Adiponectina/sangue , Neoplasias das Glândulas Suprarrenais/complicações , Catecolaminas/biossíntese , Obesidade/complicações , Feocromocitoma/complicações , Adrenalectomia , Adulto , Humanos , Gordura Intra-Abdominal/metabolismo , Masculino
15.
J Biomol Struct Dyn ; 36(3): 609-620, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28132600

RESUMO

The objective of the present study was to evaluate the effects of propolis, pollen, and caffeic acid phenethyl ester (CAPE) on tyrosine hydroxylase (TH) activity and total RNA levels of Nω-nitro-L-arginine methyl ester (L-NAME) inhibition of nitric oxide synthase in the heart, adrenal medulla, and hypothalamus of hypertensive male Sprague dawley rats. The TH activity in the adrenal medulla, heart, and hypothalamus of the rats was significantly increased in the L-NAME group vs. control (p < 0.05). Treatment with L-NAME led to a significant increase in blood pressure (BP) in the L-NAME group compared to control (p < 0.05). These data suggest that propolis, pollen, and CAPE may mediate diminished TH activity in the heart, adrenal medulla, and hypothalamus in hypertensive rats. The decreased TH activity may be due to the modulation and synthesis of catecholamines and BP effects. In addition, the binding mechanism of CAPE within the catalytic domain of TH was investigated by means of molecular modeling approaches. These data suggest that the amino acid residues, Glu429 and Ser354 of TH may play a pivotal role in the stabilization of CAPE within the active site as evaluated by molecular dynamics (MD) simulations. Gibbs binding free energy (ΔGbinding) of CAPE in complex with TH was also determined by post-processing MD analysis approaches (i.e. Poisson-Boltzmann Surface Area (MM-PBSA) method).


Assuntos
Hipertensão/tratamento farmacológico , Hipertensão/enzimologia , Óxido Nítrico Sintase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/genética , Medula Suprarrenal/efeitos dos fármacos , Medula Suprarrenal/metabolismo , Animais , Ácidos Cafeicos/administração & dosagem , Domínio Catalítico , Catecolaminas/biossíntese , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Humanos , Hipertensão/genética , Hipertensão/patologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico Sintase/química , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/análogos & derivados , Pólen/efeitos adversos , Própole/administração & dosagem , Ratos , Tirosina 3-Mono-Oxigenase/química
16.
J Mol Cell Biol ; 9(5): 422-434, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29087480

RESUMO

Type 2 immune response has been shown to facilitate cold-induced thermogenesis and browning of white fat. However, whether alternatively activated macrophages produce catecholamine and substantially promote adaptive thermogenesis in adipose tissue remains controversial. Here, we show that tyrosine hydroxylase (TyrH), a rate-limiting enzyme of catecholamine biosynthesis, was expressed and phosphorylated in adipose-resident macrophages. In addition, the plasma level of adrenaline was increased by cold stress in mice, and treatment of macrophages with adrenaline stimulated phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and TyrH. Genetic and pharmacological inhibition of CaMKII or PKA signaling diminished adrenaline-induced phosphorylation of TyrH in primary macrophages. Consistently, overexpression of constitutively active CaMKII upregulated basal TyrH phosphorylation, while suppressing the stimulatory effect of adrenaline on TyrH in macrophages. Myeloid-specific disruption of CaMKIIγ suppressed both the cold-induced production of norepinephrine and adipose UCP1 expression in vivo and the stimulatory effect of adrenaline on macrophage-dependent activation of brown adipocytes in vitro. Lack of CaMKII signaling attenuated catecholamine production mediated by cytokines IL-4 and IL-13, key inducers of type 2 immune response in primary macrophages. Taken together, these results suggest a feedforward mechanism of adrenaline in adipose-resident macrophages, and that myeloid CaMKII signaling plays an important role in catecholamine production and subsequent beige fat activation.


Assuntos
Adrenérgicos/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Catecolaminas/biossíntese , Células Mieloides/metabolismo , Transdução de Sinais , Adaptação Biológica , Adipócitos Bege/metabolismo , Animais , Temperatura Baixa , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Metabolismo Energético , Epinefrina/sangue , Macrófagos/metabolismo , Camundongos , Fosforilação , Estresse Fisiológico/genética , Termogênese , Tirosina 3-Mono-Oxigenase/metabolismo
17.
Endocr Regul ; 51(2): 73-83, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28609288

RESUMO

OBJECTIVE: Fos protein expression in catecholamine-synthesizing neurons of the substantia nigra (SN) pars compacta (SNC, A8), pars reticulata (SNR, A9), and pars lateralis (SNL), the ventral tegmental area (VTA, A10), the locus coeruleus (LC, A6) and subcoeruleus (sLC), the ventrolateral pons (PON-A5), the nucleus of the solitary tract (NTS-A2), the area postrema (AP), and the ventrolateral medulla (VLM-A1) was quantitatively evaluated aft er a single administration of asenapine (ASE) (designated for schizophrenia treatment) in male Wistar rats preconditioned with a chronic unpredictable variable mild stress (CMS) for 21 days. Th e aim of the present study was to reveal whether a single ASE treatment may 1) activate Fos expression in the brain areas selected; 2) activate tyrosine hydroxylase (TH)-synthesizing cells displaying Fos presence; and 3) be modulated by CMS preconditioning. METHODS: Control (CON), ASE, CMS, and CMS+ASE groups were used. CMS included restraint, social isolation, crowding, swimming, and cold. Th e ASE and CMS+ASE groups received a single dose of ASE (0.3 mg/kg, s.c.) and CON and CMS saline (300 µl/rat, s.c.). The animals were sacrificed 90 min aft er the treatments. Fos protein and TH-labeled immunoreactive perikarya were analyzed on double labeled histological sections and enumerated on captured pictures using combined light and fluorescence microscope illumination. RESULTS: Saline or CMS alone did not promote Fos expression in any of the structures investigated. ASE alone or in combination with CMS elicited Fos expression in two parts of the SN (SNC, SNR) and the VTA. Aside from some cells in the central gray tegmental nuclei adjacent to LC, where a small number of Fos profiles occurred, none or negligible Fos occurrence was detected in the other structures investigated including the LC and sLC, PON-A5, NTS-A2, AP, and VLM-A1. CMS preconditioning did not infl uence the level of Fos induction in the SN and VTA elicited by ASE administration. Similarly, the ratio between the amount of free Fos and Fos colocalized with TH was not aff ected by stress preconditioning in the SNC, SNR, and the VTA. CONCLUSIONS: Th e present study provides an anatomical/functional knowledge about the nature of the acute ASE treatment on the catecholamine-synthesizing neurons activity in certain brain structures and their missing interplay with the CMS preconditioning.


Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Condicionamento Psicológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Estresse Psicológico/metabolismo , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Animais , Área Postrema/citologia , Área Postrema/efeitos dos fármacos , Área Postrema/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Catecolaminas/biossíntese , Imuno-Histoquímica , Locus Cerúleo/citologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Bulbo/citologia , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Microscopia de Fluorescência , Neurônios/metabolismo , Parte Compacta da Substância Negra/citologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/metabolismo , Parte Reticular da Substância Negra/citologia , Parte Reticular da Substância Negra/efeitos dos fármacos , Parte Reticular da Substância Negra/metabolismo , Ponte/citologia , Ponte/efeitos dos fármacos , Ponte/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Estresse Psicológico/psicologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo
18.
J Pharmacol Sci ; 133(4): 268-275, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28433565

RESUMO

Extract of pine nodules (matsufushi) formed by bark proliferation on the surface of trees of Pinus tabulaeformis or Pinus massoniana has been used as an analgesic for joint pain, rheumatism, neuralgia, dysmenorrhea and other complaints in Chinese traditional medicine. Here we report the effects of matsufushi extract and its components on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that matsufushi extract (0.0003-0.005%) and its component, SJ-2 (5-hydroxy-3-methoxy-trans-stilbene) (0.3-100 µM), but not the other three, concentration-dependently inhibited catecholamine secretion induced by acetylcholine, a physiological secretagogue. Matsufushi extract (0.0003-0.005%) and SJ-2 (0.3-100 µM) also inhibited 45Ca2+ influx induced by acetylcholine in a concentration-dependent manner, similar to its effect on catecholamine secretion. They also suppressed 14C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine. In Xenopus oocytes expressing α3ß4 nicotinic acetylcholine receptors, matsufushi extract (0.00003-0.001%) and SJ-2 (1-100 µM) directly inhibited the current evoked by acetylcholine. The present findings suggest that SJ-2, as well as matsufushi extract, inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.


Assuntos
Acetilcolina/farmacologia , Medula Suprarrenal/citologia , Medula Suprarrenal/metabolismo , Catecolaminas/biossíntese , Catecolaminas/metabolismo , Pinus/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Acetilcolina/antagonistas & inibidores , Animais , Cálcio/metabolismo , Bovinos , Células Cultivadas , Relação Dose-Resposta a Droga , Antagonistas Nicotínicos , Extratos Vegetais/isolamento & purificação , Receptores Nicotínicos/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Xenopus
19.
G Ital Cardiol (Rome) ; 18(2): 164-168, 2017 Feb.
Artigo em Italiano | MEDLINE | ID: mdl-28398370

RESUMO

Pheochromocytoma is a rare tumor, usually benign, potentially lethal in case of crisis with acute release of catecholamines. The heart is a target and the clinical presentation can mimic various cardiac conditions, thus rendering diagnosis elusive. Cardiac magnetic resonance is a valuable non-invasive diagnostic tool for the evaluation of cardiomyopathies; it allows the identification of catecholamine-induced myocarditis pattern and, in some cases, it can detect the primary tumor. The definitive treatment of pheochromocytoma is surgical, while the acute crisis may require mechanical support to circulation. We here report a case of pheochromocytoma in a 25-year-old man complicated by catecholamine-induced myocarditis and heart failure.


Assuntos
Neoplasias das Glândulas Suprarrenais/metabolismo , Catecolaminas/efeitos adversos , Catecolaminas/biossíntese , Insuficiência Cardíaca/induzido quimicamente , Miocardite/induzido quimicamente , Feocromocitoma/metabolismo , Neoplasias das Glândulas Suprarrenais/complicações , Adulto , Humanos , Masculino , Feocromocitoma/complicações
20.
Am J Physiol Cell Physiol ; 312(5): C663-C672, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28356269

RESUMO

The adrenal gland is an important endocrine gland in balancing homeostasis and the response to stress by synthesizing and secreting catecholamines (CATs), and it has been confirmed that microRNA-375 (miR-375) is highly expressed in adrenal medulla. However, up to now there are few reports about the functions and related mechanisms in adrenal medulla. The present study was thus designed to study the roles and related mechanisms in rat adrenal medulla. Our results showed that miR-375 was specifically expressed in rat adrenal medulla chromaffin cells, and its expression was downregulated when rats were exposed to stress. The further functional studies demonstrated that the inhibition of endogenous miR-375 induced the secretion of CATs in primary rat medulla chromaffin cells and PC12 cells, whereas miR-375 overexpression resulted in a decline of CAT secretion. In addition, our results showed that miR-375 negatively regulated tyrosine hydroxylase (TH) and dopamine-ß-hydroxylase (DBH) and mediated adrenomedullary CAT biosynthesis. These functions of miR-375 were accomplished by its binding to the 3'-untranslated region of Sp1, which was involved in the regulation of TH and DBH expressions. These novel findings suggest that miR-375 acts as a potent negative mediator in regulating the synthesis and secretion of CATs in the adrenal medulla during the maintenance of homeostasis under stress.


Assuntos
Medula Suprarrenal/metabolismo , Catecolaminas/metabolismo , Células Cromafins/metabolismo , MicroRNAs/metabolismo , Fator de Transcrição Sp1/metabolismo , Animais , Catecolaminas/biossíntese , Dopamina beta-Hidroxilase/metabolismo , Regulação para Baixo/fisiologia , Regulação da Expressão Gênica/fisiologia , Masculino , Células PC12 , Ligação Proteica , Ratos , Ratos Wistar , Distribuição Tecidual , Tirosina 3-Mono-Oxigenase/metabolismo
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