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1.
J Toxicol Sci ; 45(7): 391-399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612007

RESUMO

This study was aimed at examining propofol- (a known anesthetic) induced emotion-related behavioral disorders in mice, and exploring the possible molecular mechanisms. A total of 60 mice were divided into two groups: control and propofol group. Mice were injected with propofol (150 mg/kg, ip) at 8:00 a.m. (once a day, lasting for 30 days). During the 30 days, loss of righting reflex (LORR) and return of righting reflex (RORR) of mice were recorded every day. At the 1st (T1) and 30th (T2) day of drug discontinuance (T2), 15 mice of each group were selected to perform the open field test; then the mice underwent perfusion fixation, and the midbrain and corpus striatum were separated for immunofluorescence assay with anti-tyrosine hydroxylase (Th) and anti- dopamine transporter (DAT) antibodies. Results showed that after propofol injection, LORR and RORR increased and decreased, respectively. Long-term use of propofol resulted in decreased activities of mice (activity trajectory, line crossing, rearing time, scratching times and defecating frequency). Immunofluorescence assay showed long-term use of propofol induced decrease of Th and DAT. Collectively, our present work suggested long-term abuse of propofol induces neuropsychiatric function impairments, and the possible mechanisms are related to dopamine dyssynthesis via down-regulating tyrosine hydroxylase and dopamine transporter.


Assuntos
Anestésicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Transtornos Mentais/induzido quimicamente , Propofol/toxicidade , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/patologia , Anestésicos/efeitos adversos , Animais , Neurônios Dopaminérgicos/metabolismo , Emoções/efeitos dos fármacos , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Camundongos Endogâmicos C57BL , Propofol/efeitos adversos , Reflexo de Endireitamento/efeitos dos fármacos
2.
PLoS One ; 15(7): e0236286, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702004

RESUMO

Functional brown adipose tissue (BAT) was identified in adult humans only in 2007 with the use of fluorodeoxyglucose positron emission tomography imaging. Previous studies have demonstrated a negative correlation between obesity and BAT presence in humans. It is proposed that BAT possesses the capacity to increase metabolism and aid weight loss. In rodents it is well established that BAT is stimulated by the sympathetic nervous system with the interscapular BAT being innervated via branches of intercostal nerves. Whilst there is evidence to suggest that BAT possesses beta-3 adrenoceptors, no studies have identified the specific nerve branch that carries sympathetic innervation to BAT in humans. The aim of this study was to identify and trace the peripheral nerve or nerves that innervate human BAT in the supraclavicular region. The posterior triangle region of the neck of cadaveric specimens were dissected in order to identify any peripheral nerve branches piercing and/or terminating in supraclavicular BAT. A previously undescribed branch of the cervical plexus terminating in a supraclavicular adipose depot was identified in all specimens. This was typically an independent branch of the plexus, from the third cervical spinal nerve, but in one specimen was a branch of the supraclavicular nerve. Histological analysis revealed the supraclavicular adipose depot contained tyrosine hydroxylase immunoreactive structures, which likely represent sympathetic axons. This is the first study that identifies a nerve branch to supraclavicular BAT-like tissue. This finding opens new avenues for the investigation of neural regulation of fat metabolism in humans.


Assuntos
Tecido Adiposo/inervação , Clavícula/inervação , Adipócitos/citologia , Tecido Adiposo/anatomia & histologia , Idoso , Cadáver , Forma Celular , Clavícula/anatomia & histologia , Dissecação , Humanos , Tirosina 3-Mono-Oxigenase/metabolismo
3.
Life Sci ; 257: 118019, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32629002

RESUMO

Parkinson's disease (PD) is a disease of the human nervous system with an onset, in the sixth and seventh decades of the human life. Chiefly perceived as progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) with the ensued loss of dopamine in the striatum and the presence of Lewy bodies, consisting of α-synuclein agglomeration. In which the neuronal bridge between substantia nigra and striatum plays an advent role in the motor system. Dilapidation of these neurons results in dopamine depletion which in-turn makes hay to PD. Eventually, the etiology and pathogenesis of PD were still on a hike of dilemma. Traditional Chinese medicine (TCM), including Chinese herbal remedies, acupuncture, and manipulative therapies, is commonly used as an adjunctive therapy in different diseases, particularly neurological diseases, in Asian countries. Additionally, TCM might improve the prognoses and the quality of life of patients with PD because it induces less adverse drug reactions. The present review describes research on the various neuroprotective components and herbal extracts from herbal medicines in the context of addressing the effects of PD.


Assuntos
Medicina Tradicional Chinesa/métodos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/terapia , Animais , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Parte Compacta da Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
4.
Nucleic Acids Res ; 48(12): e67, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32421771

RESUMO

We designed and engineered a dye production cassette encoding a heterologous pathway, including human tyrosine hydroxylase and Amanita muscaria 4,5-DOPA dioxygenase, for the biosynthesis of the betaxanthin family of plant and fungal pigments in mammalian cells. The system does not impair cell viability, and can be used as a non-protein reporter system to directly visualize the dynamics of gene expression by profiling absorbance or fluorescence in the supernatant of cell cultures, as well as for fluorescence labeling of individual cells. Pigment profiling can also be multiplexed with reporter proteins such as mCherry or the human model glycoprotein SEAP (secreted alkaline phosphatase). Furthermore, absorbance measurement with a smartphone camera using standard application software enables inexpensive, low-tech reporter quantification.


Assuntos
Proteínas Fúngicas/metabolismo , Genes Reporter , Oxigenases/metabolismo , Ácidos Picolínicos/metabolismo , Análise de Célula Única/métodos , Absorção de Radiação , Animais , Células CHO , Cricetinae , Cricetulus , Proteínas Fúngicas/genética , Células HEK293 , Humanos , Microscopia de Fluorescência/métodos , Oxigenases/genética , Ácidos Picolínicos/efeitos da radiação , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Espectrometria de Fluorescência/métodos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Raios Ultravioleta
5.
Chemosphere ; 253: 126635, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32278909

RESUMO

Carbofuran, a carbamate pesticide, is widely used in developing countries to manage insect pests. Studies have found that carbofuran posed potential risks for the neurotransmitter systems of non-target species, we speculated that these disruptive effects on the neurotransmitter systems could trigger anxiety-like behaviors. In this study, female zebrafish were exposed to environmental levels (5, 50, and 500 µg/L) of carbofuran for 48 h to evaluate the effects of carbofuran on anxiety-like behaviors. Results showed that zebrafish exhibited more anxiety-like behaviors which proved by the observed higher bottom trend and more erratic movements in the novel tank after carbofuran treatment. In order to elucidate the underlying molecular mechanisms of carbofuran-induced anxiety-promoting effects, we measured the levels of neurotransmitters, precursors, and major metabolites, along with the level of gene expression and the enzyme activities involved in neurotransmitter synthesis and metabolism. The results demonstrated that acute carbofuran exposure stimulated the mRNA expression and enzyme activity of tyrosine hydroxylase, which sequentially induced the increased levels of dopamine and norepinephrine. Tyrosine hydroxylase inhibitor relieved the anxiety-related changes induced by carbofuran, confirming the overactive tyrosine hydroxylase-mediated accumulation of dopamine and norepinephrine in the brain was one of the main reasons for carbofuran-induced anxiety-like behaviors in the female zebrafish. Overall, our study indicated the environmental health risks of carbamate pesticide in inducing neurobehavioral disorders and provided novel insights into the investigation of the relevant underlying mechanisms.


Assuntos
Comportamento Animal/efeitos dos fármacos , Carbofurano/toxicidade , Inseticidas/toxicidade , Peixe-Zebra/fisiologia , Animais , Ansiedade/induzido quimicamente , Encéfalo/efeitos dos fármacos , Carbofurano/metabolismo , Dopamina/metabolismo , Feminino , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Peixe-Zebra/metabolismo
6.
Nat Commun ; 11(1): 1515, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251291

RESUMO

Hydroxytyrosol is an antioxidant free radical scavenger that is biosynthesized from tyrosine. In metabolic engineering efforts, the use of the mouse tyrosine hydroxylase limits its production. Here, we design an efficient whole-cell catalyst of hydroxytyrosol in Escherichia coli by de-bottlenecking two rate-limiting enzymatic steps. First, we replace the mouse tyrosine hydroxylase by an engineered two-component flavin-dependent monooxygenase HpaBC of E. coli through structure-guided modeling and directed evolution. Next, we elucidate the structure of the Corynebacterium glutamicum VanR regulatory protein complexed with its inducer vanillic acid. By switching its induction specificity from vanillic acid to hydroxytyrosol, VanR is engineered into a hydroxytyrosol biosensor. Then, with this biosensor, we use in vivo-directed evolution to optimize the activity of tyramine oxidase (TYO), the second rate-limiting enzyme in hydroxytyrosol biosynthesis. The final strain reaches a 95% conversion rate of tyrosine. This study demonstrates the effectiveness of sequentially de-bottlenecking rate-limiting steps for whole-cell catalyst development.


Assuntos
Evolução Molecular Direcionada/métodos , Escherichia coli/enzimologia , Depuradores de Radicais Livres/metabolismo , Engenharia Metabólica , Álcool Feniletílico/análogos & derivados , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Técnicas Biossensoriais , Vias Biossintéticas/genética , Corynebacterium glutamicum/enzimologia , Corynebacterium glutamicum/genética , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Estudos de Viabilidade , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Mutagênese Sítio-Dirigida , Mutação , Álcool Feniletílico/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Tirosina/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Ácido Vanílico/metabolismo
7.
PLoS One ; 15(3): e0230647, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210469

RESUMO

The beneficial effects of omega (ω)-3 polyunsaturated fatty acid (PUFA) supplementation on major depressive disorder have been actively studied, but the underlying mechanism remains unknown. The present study examined the involvement of the nucleus accumbens (NAc) dopaminergic systems in behavioral changes in mice fed a diet high in ω-3 PUFAs. Mice fed a diet containing about double the amount of ω-3 PUFAs (krill oil (KO) diet) exerted shorter immobility times in the forced swim test (FST) than mice fed a control diet, containing only α-linolenic acid (ALA) as ω-3 PUFAs. The shorter immobility times were observed in both male and female mice. A dopamine metabolite, 3,4-dihydroxyphenylacetic acid, increased in the NAc in male mice fed the KO diet when compared with those fed the control diet. In addition, dopamine, 3-methoxytyramine, and homovanillic acid increased in the NAc in female mice fed the KO diet. Notably, the effects of the KO diet on the immobility time in the FST were abolished by microinjection of sulpiride, an antagonist of D2-like receptors, into the NAc. A similar microinjection of an antagonist selective for D1-like receptors, SKF83566, also abolished the reduction in immobility in the FST. Moreover, we found that tyrosine hydroxylase-positive cells increased in the ventral tegmental area (VTA) in mice fed the KO diet. These results suggest that modulation of the VTA-NAc dopaminergic pathway is one of the mechanisms by which a KO diet rich in ω-3 PUFAs reduces the immobility behavior in the mouse FST.


Assuntos
Antidepressivos/farmacologia , Dieta , Ácidos Graxos Ômega-3/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Animais , Antidepressivos/química , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/análise , Monoaminas Biogênicas/metabolismo , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Ácidos Graxos Ômega-3/química , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/metabolismo , Receptores de Dopamina D2/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/enzimologia
8.
Endocrinology ; 161(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32166324

RESUMO

Genetic research has revealed pro-opiomelanocortin (POMC) to be a fundamental regulator of energy balance and body weight in mammals. Within the brain, POMC is primarily expressed in the arcuate nucleus of the hypothalamus (ARC), while a smaller population exists in the brainstem nucleus of the solitary tract (POMCNTS). We performed a neurochemical characterization of this understudied population of POMC cells using transgenic mice expressing green fluorescent protein (eGFP) under the control of a POMC promoter/enhancer (PomceGFP). Expression of endogenous Pomc mRNA in the nucleus of the solitary tract (NTS) PomceGFP cells was confirmed using fluorescence-activating cell sorting (FACS) followed by quantitative PCR. In situ hybridization histochemistry of endogenous Pomc mRNA and immunohistochemical analysis of eGFP revealed that POMC is primarily localized within the caudal NTS. Neurochemical analysis indicated that POMCNTS is not co-expressed with tyrosine hydroxylase (TH), glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), brain-derived neurotrophic factor (BDNF), nesfatin, nitric oxide synthase 1 (nNOS), seipin, or choline acetyltransferase (ChAT) cells, whereas 100% of POMCNTS is co-expressed with transcription factor paired-like homeobox2b (Phox2b). We observed that 20% of POMCNTS cells express receptors for adipocyte hormone leptin (LepRbs) using a PomceGFP:LepRbCre:tdTOM double-reporter line. Elevations in endogenous or exogenous leptin levels increased the in vivo activity (c-FOS) of a small subset of POMCNTS cells. Using ex vivo slice electrophysiology, we observed that this effect of leptin on POMCNTS cell activity is postsynaptic. These findings reveal that a subset of POMCNTS cells are responsive to both changes in energy status and the adipocyte hormone leptin, findings of relevance to the neurobiology of obesity.


Assuntos
Tronco Encefálico/metabolismo , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptores para Leptina/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colecistocinina/metabolismo , Colina O-Acetiltransferase/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo I/metabolismo , Nucleobindinas/metabolismo , Regiões Promotoras Genéticas , Receptores para Leptina/genética , Tirosina 3-Mono-Oxigenase/metabolismo
9.
Toxicol Lett ; 325: 1-13, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088201

RESUMO

Olfaction is often affected in parkinsonian patients and its disturbances precede the classical cognitive and locomotor dysfunction. The olfactory bulb might be the region of onset in Parkinson's disease (PD) pathogenesis, evidenced by the presence of disease-related protein aggregates and disturbed olfactory information processing. However, the underlying molecular mechanism that governs the olfactory bulb impairments remains unclear. This study was designed to investigate the relationship between olfactory bulb and inflammatory pathological alterations and the potential mechanisms. Here we found that rotenone led to typical parkinsonian symptoms and decreased tyrosine hydroxylase (TH)-positive neurons in the olfactory bulb. Additionally, increased NF-κB nuclear translocation and NLRP3 inflammasome components expressions caused by rotenone injection were observed accompanied by the activation of microglia and astrocytes in the olfactory bulb. Rotenone also triggered Drp1-mediated mitochondrial fission and this in turn caused mitochondrial damage. Furthermore, Mdivi-1(a selective Drp1 inhibitor) markedly ameliorated the morphologic disruptions of mitochondria and Drp1 translocation, inhibited the nuclear translocation of NF-κB, eventually blocked the downstream pathway of the NLRP3/caspase-1/IL-1ß axis and expression of iNOS. Overall, these findings suggest that Drp1-dependent mitochondrial fission induces NF-κB nuclear translocation and NLRP3 inflammasome activation that may further contribute to olfactory bulb disturbances.


Assuntos
Dinaminas/genética , Bulbo Olfatório/patologia , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/patologia , Rotenona/toxicidade , Desacopladores/toxicidade , Animais , Dinaminas/efeitos dos fármacos , Inflamassomos/genética , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/psicologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/patologia , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Doença de Parkinson Secundária/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Olfato/genética , Tirosina 3-Mono-Oxigenase/metabolismo
10.
Adv Exp Med Biol ; 1232: 401-408, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893437

RESUMO

Parkinson's disease, a progressive neurodegenerative disease, is caused by the loss of dopaminergic neurons in the substantia nigra (SN). It is characterized by the formation of intracytoplasmic Lewy bodies that are primarily composed of the protein alpha-synuclein (α-syn), along with dystrophic neurites. Acupuncture stimulation results in an enhanced survival of dopaminergic neurons in the SN in Parkinsonism animal models. We investigated the role of acupuncture in inhibiting the increase in α-syn expression that is related to dopaminergic cell loss in the SN in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonism mouse model. In this model, acupuncture stimulation at GB34 and LR3 attenuated the decrease in tyrosine hydroxylase in the SN. Moreover, acupuncture stimulation attenuated the increase in α-syn in SN. Acupuncture stimulation also maintained the phosphorylated α-syn on serine 129 at levels similar to the control group. Our findings indicate that the MPTP-mediated increase in α-syn, and the acupuncture-mediated inhibition of the increase in α-syn, may be responsible for the neuroprotective effects of acupuncture in the SN following damage induced by MPTP.


Assuntos
Terapia por Acupuntura , Transtornos Parkinsonianos , Substância Negra , alfa-Sinucleína , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores , Transtornos Parkinsonianos/induzido quimicamente , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
11.
Am J Physiol Endocrinol Metab ; 318(4): E453-E461, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961706

RESUMO

Beige adipocytes have become a promising therapeutic target to combat obesity. Our senior author Dr. B. Xue previously discovered a transient but significant induction of beige adipocytes in mice during early postnatal development, which peaked at postnatal day (P) 20 and then disappeared thereafter. However, the physiological mechanism underlying the transient induction of the developmental beige cells remains mystery. Interestingly, there exists a postnatal surge of leptin in mice at P10 before the appearance of the developmental beige adipocytes. Given the neurotropic effect of leptin during neuronal development and its role in activating the sympathetic nervous system (SNS), we tested the hypothesis that postnatal leptin surge is required for the transient induction of developmental beige adipocytes through sympathetic innervation. Unlike wild-type (WT) mice that were able to acquire the developmentally induced beige adipocytes at P20, ob/ob mice had much less uncoupling protein 1 (UCP1)-positive multilocular cells in inguinal white adipose tissue at the same age. This was consistent with reduced expression of UCP1 mRNA and protein levels in white fat of ob/ob mice. In contrast, daily injection of ob/ob mice with leptin between P8 and P16, mimicking the postnatal leptin surge, largely rescued the ability of these mice to acquire the developmentally induced beige adipocytes at P20, which was associated with enhanced sympathetic nerve innervation assessed by whole mount adipose tissue immunostaining of tyrosine hydroxylase. Our data demonstrate that the postnatal leptin surge is essential for the developmentally induced beige adipocyte formation in mice, possibly through increasing sympathetic nerve innervation.


Assuntos
Adipócitos Bege/metabolismo , Tecido Adiposo/crescimento & desenvolvimento , Leptina/metabolismo , Adipócitos Bege/efeitos dos fármacos , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/inervação , Envelhecimento , Animais , Relação Dose-Resposta a Droga , Feminino , Leptina/farmacologia , Masculino , Camundongos , Camundongos Obesos , Sistema Nervoso Simpático , Tirosina 3-Mono-Oxigenase/metabolismo , Proteína Desacopladora 1/metabolismo
12.
Stem Cell Reports ; 14(1): 75-90, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31902706

RESUMO

Parkinson's disease (PD) is a complex and highly variable neurodegenerative disease. Familial PD is caused by mutations in several genes with diverse and mostly unknown functions. It is unclear how dysregulation of these genes results in the relatively selective death of nigral dopaminergic neurons (DNs). To address this question, we modeled PD by knocking out the PD genes PARKIN (PRKN), DJ-1 (PARK7), and ATP13A2 (PARK9) in independent isogenic human pluripotent stem cell (hPSC) lines. We found increased levels of oxidative stress in all PD lines. Increased death of DNs upon differentiation was found only in the PARKIN knockout line. Using quantitative proteomics, we observed dysregulation of mitochondrial and lysosomal function in all of the lines, as well as common and distinct molecular defects caused by the different PD genes. Our results suggest that precise delineation of PD subtypes will require evaluation of molecular and clinical data.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Genes Recessivos , Estudos de Associação Genética , Predisposição Genética para Doença , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Transdução de Sinais , Linhagem Celular , Técnicas de Introdução de Genes , Humanos , Mitocôndrias/metabolismo , Mutação , Doença de Parkinson/diagnóstico , Fenótipo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Proteoma , Proteômica/métodos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
13.
Life Sci ; 240: 117091, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760102

RESUMO

Mounting evidences indicated that elevated iron levels in the substantia nigra (SN) have been concerned as the underlying mechanisms of neurodegenerative diseases, including Parkinson's disease (PD). The present study used the 1-Methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine (MPTP)-treated cynomolgus monkeys for PD to evaluate the usability of SWI for assessing iron deposition in the cerebral nuclei of PD. The results showed that susceptibility-weighted imaging (SWI) phase values of the ipsilateral (MPTP-lesion side) SN of MPTP-treated monkeys were lower than those in the contralateral SN of MPTP-treated monkeys and the same side of Control monkeys, suggesting that iron deposition were elevated in the affected side SN of MPTP-treated monkeys. Whereas MPTP has not effects on the SWI phase values in other detected brain regions of monkeys, including red nucleus (RN), putamen (PUT) and caudate nucleus (CA). Furthermore, ICP-MS results showed that MPTP increased the iron levels in MPTP injection side, but no in the ipsilateral striatum. Additionally, MPTP treatment did not affect the calcium and manganese levels in the detected brain regions of monkeys. However, Pearson correlation analysis results indicated that there were not relationship between SWI phase values in MPTP-lesion side of SN with the behavioral score, tyrosine hydroxylase (TH)-positive cells number and iron levels in the MPTP-lesion side of midbrain. Taken together, the results confirm the involvement of SN iron accumulations in the MPTP-treated monkey models for PD, and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of PD.


Assuntos
Ferro/metabolismo , Intoxicação por MPTP/metabolismo , Transtornos Parkinsonianos/metabolismo , Animais , Comportamento Animal , Encéfalo/diagnóstico por imagem , Cálcio/metabolismo , Intoxicação por MPTP/diagnóstico por imagem , Macaca fascicularis , Imagem por Ressonância Magnética , Masculino , Manganês/metabolismo , Espectrometria de Massas , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/diagnóstico por imagem , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
14.
Am J Physiol Renal Physiol ; 318(1): F260-F272, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31813250

RESUMO

Small intestinal Paneth cells play a critical role in acute kidney injury (AKI) and remote organ dysfunction by synthesizing and releasing IL-17A. In addition, intestine-derived norepinephrine is a major mediator of hepatic injury and systemic inflammation in sepsis. We tested the hypothesis that small intestinal Paneth cells synthesize and release norepinephrine to exacerbate ischemic AKI. After ischemic AKI, we demonstrated larger increases in portal venous norepinephrine levels compared with plasma norepinephrine in mice, consistent with an intestinal source of norepinephrine release after renal ischemia and reperfusion. We demonstrated that murine small intestinal Paneth cells express tyrosine hydroxylase mRNA and protein, a critical rate-limiting enzyme for the synthesis of norepinephrine. We also demonstrated mRNA expression for tyrosine hydroxylase in human small intestinal Paneth cells. Moreover, freshly isolated small intestinal crypts expressed significantly higher norepinephrine levels after ischemic AKI compared with sham-operated mice. Suggesting a critical role of IL-17A in Paneth cell-mediated release of norepinephrine, recombinant IL-17A induced norepinephrine release in the small intestine of mice. Furthermore, mice deficient in Paneth cells (SOX9 villin Cre mice) have reduced plasma norepinephrine levels after ischemic AKI. Finally, supporting a critical role for norepinephrine in generating ischemic AKI, treatment with the selective α-adrenergic antagonists yohimbine and phentolamine protected against murine ischemic AKI with significantly reduced renal tubular necrosis, inflammation, and apoptosis and less hepatic dysfunction. Taken together, we identify Paneth cells as a critical source of norepinephrine release that may lead to intestinal and liver injury and systemic inflammation after AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Isquemia/metabolismo , Rim/metabolismo , Norepinefrina/metabolismo , Celulas de Paneth/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose/fisiologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Isquemia/patologia , Rim/irrigação sanguínea , Rim/patologia , Camundongos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
15.
Arch Oral Biol ; 109: 104571, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31586907

RESUMO

OBJECTIVE: To study the innervation of the major sublingual gland by means of immunohistochemistry. DESIGN: Bioptic and autoptic specimens of the major sublingual gland of humans were examined for the presence of immunoreactivity to tyrosine hydroxylase and dopamine-ß-hydroxylase, on one hand, and choline acetyltransferase, on the other, to indicate adrenergic and cholinergic nerves, respectively. RESULTS: Acini and ducts were supplied by both divisions of the autonomic nervous system. CONCLUSIONS: Mucous and seromucous cells of the human major sublingual glands may respond with secretion not only to parasympathetic activity but also to sympathetic activity. The major sublingual gland is therefore a potential contributor to the mucin secretion recently reported in the literature in response to high sympathetic activity during physical exercise.


Assuntos
Colina O-Acetiltransferase/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Glândula Sublingual/enzimologia , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto , Idoso , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade
16.
Gen Comp Endocrinol ; 285: 113289, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557469

RESUMO

Light intensity plays an important role in the regulation of growth, behavior, reproduction, and welfare of avian species. Light intensity preference behavior has been suggested to be involved in welfare of birds. This study aims to investigate the effects of different light intensity and dual light intensity choice (DLIC) lighting program on plasma corticosterone (CORT), and tryptophan hydroxylase 2 (TPH2, the rate-limiting enzyme of serotonin biosynthesis) and tyrosine hydroxylase (TH, the rate-limiting enzyme of dopamine biosynthesis) gene expression in the brainstem of male chickens. Day old broilers were housed in two commercial houses, and placed in 24 pens. All the treatment groups were provided with 23 h light (L) /1 h dark (D) and 30 lx (lx) light intensity during the first week and then 18L:6D (10 lx) from day 7 to 14. Blood and brain were sampled at 14 days of age (10 lx) before the onset of light treatments. On day 15, four treatments (2, 10, 20, and 100 lx), and DLIC treatment (2/20 lx) were initiated. Samples were collected on days 15, 16, 17, 30 and 41. TPH2 expression in the dorsal raphe nucleus (DRN) and caudal raphe nucleus (CRN) of brainstem, and TPH2 and TH expression in ventral tegmental areas (VTN) of the midbrain were determined by qPCR. Results showed that bright light and DLIC lighting program temporarily attenuated plasma CORT, suggesting the short-term stress attenuating effect of bright light and DLIC lighting program. Differential TPH2 expression in the DRN and CRN observed in the DLIC birds indicate a significant effect of DLIC lighting program on the serotonergic activity in the avian brainstem. At the 41 days of age, the significant downregulation of TPH2 and TH expression occurred in the VTA of DLIC treated birds compared to the other group of birds. Taken together, temporal and spatial regulation of TPH2 and TH expression by DLIC lighting program indicate that compensatory regulation of serotonergic and dopaminergic activities might be involved in the light intensity preference behavior of birds, suggesting a possible beneficial effect of the DLIC lighting program on broiler welfare.


Assuntos
Galinhas/sangue , Galinhas/metabolismo , Corticosterona/sangue , Dopamina/metabolismo , Luz , Serotonina/metabolismo , Animais , Tronco Encefálico/metabolismo , Tronco Encefálico/efeitos da radiação , Galinhas/crescimento & desenvolvimento , Regulação Enzimológica da Expressão Gênica/efeitos da radiação , Masculino , Núcleos da Rafe/metabolismo , Núcleos da Rafe/efeitos da radiação , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/metabolismo
17.
Exp Neurol ; 323: 113081, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655049

RESUMO

Phosphatase and tensin homolog (PTEN)-induced kinase 1 (Pink1) is involved in mitochondrial quality control, which is essential for maintaining energy production and minimizing oxidative damage from dysfunctional/depolarized mitochondria. Pink1 mutations are the second most common cause of autosomal recessive Parkinson's disease (PD). In addition to characteristic motor impairments, PD patients also commonly exhibit cognitive impairments. As the hippocampus plays a prominent role in cognition, we tested if loss of Pink1 in mice influences learning and memory. While wild-type mice were able to perform a contextual discrimination task, age-matched Pink1 knockout (Pink1-/-) mice showed an impaired ability to differentiate between two similar contexts. Similarly, Pink1-/- mice performed poorly in a delayed alternation task as compared to age-matched controls. Poor performance in these cognitive tasks was not the result of overt hippocampal pathology. However, a significant reduction in hippocampal tyrosine hydroxylase (TH) protein levels was detected in the Pink1-/- mice. This decrease in hippocampal TH levels was also associated with reduced DOPA decarboxylase and dopamine D2 receptor levels, but not post-synaptic dopamine D1 receptor levels. These presynaptic changes appeared to be selective for dopaminergic fibers as hippocampal dopamine beta hydroxylase, choline acetyltransferase, and tryptophan hydroxylase levels were unchanged in Pink1-/- mice. Administration of the dopamine D1 receptor agonist SKF38393 to Pink1-/- mice was found to improve performance in the context discrimination task. Taken together, our results show that Pink1 loss may alter dopamine signaling in the hippocampus, which could be a contributing mechanism for the observed learning and memory impairments.


Assuntos
Hipocampo/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia , Proteínas Quinases/deficiência , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Aprendizagem/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos Parkinsonianos/metabolismo , Receptores de Dopamina D1/metabolismo
18.
Exp Neurol ; 323: 113089, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31697941

RESUMO

Serotonin axons in the adult rodent brain can regrow and recover their function following several forms of injury including controlled cortical impact (CCI), a neocortical stab wound, or systemic amphetamine toxicity. To assess whether this capacity for regrowth is unique to serotonergic fibers, we used CCI and stab injury models to assess whether fibers from other neuromodulatory systems can also regrow following injury. Using tyrosine-hydoxylase (TH) immunohistochemistry we measured the density of catecholaminergic axons before and at various time points after injury. One week after CCI injury we observed a pronounced loss, across cortical layers, of TH+ axons posterior to the site of injury. One month after CCI injury the same was true of TH+ axons both anterior and posterior to the site of injury. This loss was followed by significant recovery of TH+ fiber density across cortical layers, both anterior and posterior to the site of injury, measured three months after injury. TH+ axon loss and recovery over weeks to months was also observed throughout cortical layers using the stab injury model. Double label immunohistochemistry revealed that nearly all TH+ axons in neocortical layer 1/2 are also dopamine-beta-hyroxylase+ (DBH+; presumed norepinephrine), while TH+ axons in layer 5 are a mixture of DBH+ and dopamine transporter+ types. This suggests that noradrenergic axons can regrow following CCI or stab injury in the adult mouse neocortex and leaves open the question of whether dopaminergic axons can do the same.


Assuntos
Axônios/metabolismo , Lesões Encefálicas/fisiopatologia , Catecolaminas/metabolismo , Neocórtex/fisiologia , Regeneração Nervosa/fisiologia , Animais , Dopamina/metabolismo , Camundongos , Norepinefrina/metabolismo , Serotonina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
19.
J Cell Physiol ; 235(2): 869-879, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31232473

RESUMO

Lack of dopamine production and neurodegeneration of dopaminergic neurons in the substantia nigra are considered as the major characteristics of Parkinson's disease, a prevalent movement disorder worldwide. DJ-1 mutation leading to loss of its protein functions is a genetic factor of PD. In this study, our results illustrated that DJ-1 can directly interact with Ca2+ /calmodulin-dependent protein kinase kinase ß (CaMKKß) and modifies the cAMP-responsive element binding protein 1 (CREB1) activity, thus regulates tyrosine hydroxylase (TH) expression. In Dj-1 knockout mouse substantia nigra, the levels of TH and the phosphorylation of CREB1 Ser133 are significantly decreased. Moreover, Dj-1 deficiency suppresses the phosphorylation of CaMKIV (Thr196/200) and CREB1 (Ser133), subsequently inhibits TH expression in vitro. Furthermore, Knockdown of Creb1 abolishes the effects of DJ-1 on TH regulation. Our data reveal a novel pathway in which DJ-1 regulates CaMKKß/CaMKIV/CREB1 activities to facilitate TH expression.


Assuntos
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Doença de Parkinson/patologia , Proteína Desglicase DJ-1/metabolismo , Tirosina 3-Mono-Oxigenase/biossíntese , Animais , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Knockout , Fosforilação , Transdução de Sinais , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
20.
Int J Mol Sci ; 20(24)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835787

RESUMO

This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson's disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA presynaptic parameters begins significantly earlier in male than female MP mice. This was correlated with behavioral gender differences of both forced and spontaneous motor behavior. The degeneration of the nigrostriatal DA system in MP mice is earlier and more marked than that of the mesolimbic DA system, with male MP mice again being more strongly affected than female MP mice. After ovariectomy, DA presynaptic and behavioral changes in female mice become very similar to those of male animals. Our results suggest that estrogen, either directly or indirectly, is neuroprotective in the midbrain DA system. Our results are compatible with epidemiological data on incidence and symptom progression in PD, showing that men are more strongly affected than women at early ages.


Assuntos
Dopamina/metabolismo , Atividade Motora , Doença de Parkinson/fisiopatologia , Animais , Comportamento Animal , Modelos Animais de Doenças , Estimulação Elétrica , Feminino , Masculino , Camundongos Endogâmicos C57BL , Ovariectomia , Probabilidade , Tirosina 3-Mono-Oxigenase/metabolismo
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