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1.
Adv Exp Med Biol ; 1232: 25-31, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893390

RESUMO

Hypoxic ischemic encephalopathy (HIE) leads to significant mortality and morbidity, and therapeutic hypothermia (TH) has become a standard of care following HIE. After TH, the body temperature is brought back to 37 °C. Early electroencephalography (EEG) is a reliable outcome biomarker following HIE. We hypothesized that changes in cerebral oxidative metabolism, measured as Δ[oxCCO], in relation to changes in brain tissue oxygenation (measured as Δ[HbD]) during rewarming will correlate with injury severity as evidenced on amplitude integrated EEG/EEG at initial presentation. Broadband near-infrared spectroscopy (NIRS) and systemic data were collected during rewarming from 14 infants following HIE over a mean period of 12.5 h. All infants were monitored with video EEG telemetry using a standard neonatal montage. aEEG and EEG background was classified into mild, moderate and severely abnormal groups based on the background pattern. Two infants had mild, 6 infants had moderate and another 6 infants had severe abnormality at presentation. The relationship between [oxCCO] and [HbD] was evaluated between two groups of infants with abnormal electrical activity (mild vs moderate to severe). A significant difference was noted between the groups in the relationship between [oxCCO] and [HbD] (as r2) (p = 0.02). This result indicates that the mitochondrial injury and deranged oxidative metabolism persists in the moderate to severely abnormal group during rewarming.


Assuntos
Eletroencefalografia , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Biomarcadores/análise , Encéfalo/metabolismo , Humanos , Hipóxia-Isquemia Encefálica/diagnóstico , Lactente , Recém-Nascido , Reaquecimento
2.
Adv Exp Med Biol ; 1232: 33-38, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893391

RESUMO

Monitoring of cerebral tissue oxygen saturation (StO2) by near-infrared spectroscopy (NIRS oximetry) has great potential to reduce the incidence of hypoxic and hyperoxic events and thus prevent long-term disabilities in preterm neonates. Since the light has to penetrate superficial layers (bone, skin and cerebrospinal fluid) before it reaches the brain, the question arises whether these layers influence cerebral StO2 measurement. We assessed this influence on the accuracy of cerebral StO2 values. For that purpose, we simulated light propagation with 'N-layered medium' software. It was found that with a superficial layer thickness of ≤6 mm, typical for term and preterm neonates, StO2 accurately reflects cerebral tissue oxygenation.


Assuntos
Oximetria , Oxigênio , Crânio , Encéfalo/metabolismo , Humanos , Hipóxia/diagnóstico , Recém-Nascido , Oximetria/normas , Crânio/anatomia & histologia , Espectroscopia de Luz Próxima ao Infravermelho
3.
Adv Exp Med Biol ; 1232: 339-345, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893429

RESUMO

We used a miniature broadband NIRS system to monitor concentration changes in brain oxygenation (oxy- and deoxy- haemoglobin [HbO2], [HHb]) and oxidised cytochrome-c-oxidase ([oxCCO]) during a high +Gz acceleration, induced by a human centrifuge, on two healthy experienced volunteers (2 male, 34 and 37 years). We performed a sequence of several +Gz exposures that were terminated at the onset of visual symptoms (loss of peripheral vision). Systemic parameters were recorded (i.e. heart rate, blood pressure and arterial saturation), and brain tissue blood volume changes ([HbT] = [HbO2] + [HHb]) and oxygen delivery ([HbDiff] = [HbO2] - [HHb]) were calculated. Volunteer 1 demonstrated a decrease in [HbT] of -3.49 ± 0.02 µMol and [HbDiff] of -3.23 ± 0.44 µMol, and an increase of [oxCCO] of 0.42 ± 0.01µMol. Volunteer 2 demonstrated a decrease in [HbDiff] of -4.37 ± 0.23 µMol, and no significant change in [HbT] (0.53 ± 0.06 µMol) and [oxCCO] (0.09 ± 0.06 µMol). The variability of the brain metabolic response was related to the level of ischaemia, suggesting that suppression of metabolism was due to lack of glucose substrate delivery rather than oxygen availability.


Assuntos
Aceleração , Complexo IV da Cadeia de Transporte de Elétrons , Hemodinâmica , Espectroscopia de Luz Próxima ao Infravermelho , Adulto , Encéfalo/enzimologia , Encéfalo/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Estresse Oxidativo , Oximetria/instrumentação , Oxigênio/metabolismo
4.
Arch Insect Biochem Physiol ; 103(1): e21620, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31625196

RESUMO

Olfactory sensing and its modulation are important for the insects in recognizing diverse odors from the environment and in making correct decisions to survive. Identifying new genes involved in olfactory modulation and unveiling their mechanisms may lead us to understand decision making processes in the central nervous system. Here, we report a novel olfactory function of the cyclic nucleotide-gated (CNG) channel CG42260 in modulating ab3A olfactory sensory neurons, which specifically respond to food-derived odors in fruit fly Drosophila melanogaster. We found that two independent CG42260 mutants show reduced responses in the ab3A neurons. Unlike mammalian CNGs, CG42260 is not expressed in the odorant sensory neurons but broadly in the central nervous system including neuropeptide-producing cells. By using molecular genetic tools, we identified CG42260 expression in one pair of neuropeptide F (NPF) positive L1-l cells known to modulate food odor responsiveness. Knockdown of CG42260 in the NPF neurons reduced production of NPF in Ll-1 cells, which in turn, led to reduction of neuronal responses of the ab3A neurons. Our findings show the novel biological function of CG42260 in modulating olfactory responses to food odor through NPF.


Assuntos
Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Drosophila melanogaster/fisiologia , Neuropeptídeos/metabolismo , Neurônios Receptores Olfatórios/metabolismo , Animais , Encéfalo/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Fenômenos Eletrofisiológicos , Mutagênese Insercional , Neuropeptídeos/genética , Odorantes , Olfato/fisiologia
5.
Chemosphere ; 238: 124581, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31445333

RESUMO

Lead (Pb) pollution is one of the most serious environmental problems and has attracted worldwide attention. Pb causes hematological, central nervous system, as well as renal toxicity, and so on. Although many investigations about Pb in blood to evaluate pollution status and toxic effects have been reported, there are open question about biological behavior of Pb. In order to reveal any toxicological mechanisms or influences, we focused on the local distribution of Pb in mice organs. Lead acetate (100 mg/L and 1000 mg/L) in drinking water were given to the BALB/c mice (male, seven weeks of age, N = 24) for three weeks. Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) analysis revealed a homogenous distribution of Pb in the liver and inhomogeneous distribution in the kidney and brain. The hippocampus, thalamus, and hypothalamus had higher concentrations than other areas such as the white matter. Surprisingly, in the kidney, Pb tended to accumulate in the medulla rather than the cortex, strongly suggesting that high sensitivity areas and high accumulation areas differ. Moreover, distribution of stromal interacting protein 1 (STIM1) which is candidate gene of Pb pathway to the cells was homogenous in the liver and kidney whereas inhomogeneous in the brain. In contrast to our hypothesis, interestingly, Pb exposure under the current condition did not induce mRNA expressions for any candidate channel or transporter genes. Thus, further study should be conducted to elucidate the local distribution of Pb and other toxic metals, and pathway that Pb takes to the cells.


Assuntos
Química Encefálica/efeitos dos fármacos , Rim/química , Chumbo/análise , Fígado/química , Molécula 1 de Interação Estromal/análise , Animais , Encéfalo/metabolismo , Imuno-Histoquímica/métodos , Terapia a Laser , Masculino , Espectrometria de Massas/métodos , Camundongos , Camundongos Endogâmicos BALB C , Análise Espectral
6.
Biomed Khim ; 65(5): 385-387, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666410

RESUMO

The neurotransmitter systems of the brain are exposed to dysregulation during alcohol withdrawal. This contributes to the development of the pathological craving for alcohol in which corticotropin-releasing hormone receptors are may be involved. During the period of alcohol withdrawal, the level of CRFR2 mRNA in the ventral tegmental area of the brain on the seventh day of abstinence was significantly increased in comparison with the control group. This supports existing concepts on possible participation in the modulation of dopaminergic and GABA-neural neurons in the ventral tegmental area the brain.


Assuntos
Alcoolismo , Encéfalo/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Síndrome de Abstinência a Substâncias , Animais , Encéfalo/efeitos dos fármacos , Etanol , RNA Mensageiro , Ratos
7.
Biomed Khim ; 65(5): 388-397, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666411

RESUMO

Fibrates are well-known agonists of the PPAR family (peroxisome proliferator-activated receptors). This class of drugs is used for the treatment of dyslipidemia and atherosclerosis. Fenofibrate is one of the members of this class of synthetic PPARα receptor ligands. The oral administration of 0.3% fenofibrate caused a decrease in strength due to loss of body weight in laboratory animals when improving behavioural features. Analysis of the mitochondrial DNA of liver cells showed a genotoxic effect of fenofibrate, due to accumulation of reactive oxygen species, which could be attributed to activation of peroxisomal ß-oxidation processes, as well as to the lack of increase in the expression of genes encoding antioxidant defense proteins. Treatment with fenofibrate did not cause brain mtDNA damage. It has been shown that fenofibrate induced mitochondrial ß-oxidation in the brain, as indicated by the increased expression of the Acadm and Cpt1a and Ppargc1a and Ppara. The study found no effect of fenofibrate on the increase of mitochondrial biogenesis in brain and liver cells. Thus, we can conclude that fenofibrate significantly affects lipid metabolism in the liver and brain, but in the liver it is associated with an increase of oxidative stress, resulting in mtDNA oxidative damage. However, fenofibrate-induced increase in the expression of Ppargc1a is not associated with an increase of mitochondrial biogenesis. This is consistent with the recent suggestion that PGC-1α might not be a master regulator of mitochondrial biogenesis.


Assuntos
Encéfalo/efeitos dos fármacos , Dano ao DNA , Ácidos Graxos/metabolismo , Fenofibrato/farmacologia , Fígado/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica , Fígado/metabolismo , Camundongos
8.
Biomed Khim ; 65(5): 407-417, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666414

RESUMO

Isatin (indol-2,3-dione), an endogenous biofactor found in the brain, peripheral tissues and biological body fluids of humans and animals, exhibits a wide range of biological and pharmacological activities. They are realized via interaction with numerous isatin-binding proteins. Some of these proteins identified during proteomic profiling of the brain are involved in the development of neurodegenerative pathology. In the context of the neuroprotective effect, the effect of isatin is comparable to the effects of deprenyl (selegiline), a pharmacological agent used for treatment of Parkinson's disease. In this study, we have investigated the effect of a single dose administration of isatin (100 mg/kg) and deprenyl (10 mg/kg) to mice on the profile of the brain isatin-binding proteins. Comparative proteomic analysis of brain isatin-binding proteins of mice treated with isatin or deprenyl resulted in identification of a representative group of proteins (n=200) sensitive to the administration of these substances. The change in the profile of isatin-binding proteins may be obviously attributed to accumulation of isatin and deprenyl in the brain and their interaction with target proteins; this prevents protein binding to the affinity sorbent. Thus identified brain isatin-binding proteins of the control animals obviously represent specific targets that interact directly with isatin (and also with deprenyl) in vivo. Isatin or deprenyl administered to animals interact with these proteins and thus inhibit their binding to the affinity sorbent (immobilized isatin analogue).


Assuntos
Encéfalo/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Isatina/farmacologia , Fármacos Neuroprotetores/farmacologia , Selegilina/farmacologia , Animais , Encéfalo/metabolismo , Camundongos , Proteômica
9.
Biochemistry (Mosc) ; 84(10): 1166-1176, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694512

RESUMO

The aim of this study was to evaluate changes in the content of sphingoid bases - sphingosine (SPH), sphinganine, and sphingosine-1-phosphate (SPH-1-P) - and in expression of genes encoding enzymes involved in their metabolism in the brain structures (hippocampus, cortex, and cerebellum) and spinal cord of transgenic FUS(1-359) mice. FUS(1-359) mice are characterized by motor impairments and can be used as a model of amyotrophic lateral sclerosis (ALS). Lipids from the mouse brain structures and spinal cord after 2, 3, and 4 months of disease development were analyzed by chromatography/mass spectrometry, while changes in the expression of the SPHK1, SPHK2, SGPP2, SGPL1, ASAH1, and ASAH2 genes were assayed using RNA sequencing. The levels of SPH and sphinganine (i.e., sphingoid bases with pronounced pro-apoptotic properties) were dramatically increased in the spinal cord at the terminal stage of the disease. The ratio of the anti-apoptotic SPH-1-P to SPH and sphinganine sharply reduced, indicating massive apoptosis of spinal cord cells. Significant changes in the content of SPH and SPH-1-P and in the expression of genes related to their metabolism were found at the terminal ALS stage in the spinal cord. Expression of the SGPL gene (SPH-1-P lyase) was strongly activated, while expression of the SGPP2 (SPH-1-P phosphatase) gene was reduced. Elucidation of mechanisms for the regulation of sphingolipid metabolism in ALS will help to identify molecular targets for the new-generation drugs.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Proteína FUS de Ligação a RNA/metabolismo , Esfingolipídeos/metabolismo , Medula Espinal/metabolismo , Animais , Camundongos , Camundongos Transgênicos , Esfingolipídeos/química
10.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 823-827, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750825

RESUMO

Objective To study the characteristics of the expression of aquaporin-4 (AQP4) in the brains and astrocytes of rats with thermoplegia. Methods Sixty healthy male Sprague-Dawley rats weighing (250±30) g were randomly divided into control group and model group. The quiet exposure method with high temperature (40DegreesCelsius) and high humidity (70%) was used to make a typical rat model of thermoplegia to monitor rectal temperature and record onset time every 10 minutes. When the temperature of stressed rats reached 42.5 DegreesCelsius, it was regarded as onset time of the disease. The rats in both groups were placed at 26DegreesCelsius with humidity 60% later. After 5-hour observation and their behavior evaluation, the rats were killed and their brain tissues were taken for measuring the water content of the tissues. The astrocytes of the rats were cultured at 37DegreesCelsius and 41DegreesCelsius. AQP4 mRNA and protein expression were detected by reverse-transcription PCR and Western blot analysis. Results Compared with the control group, the expression of AQP4 mRNA and protein were significantly lower in the model group than in the control group. Conclusion High temperature may lead to the destruction of blood-brain barrier and the down-regulation of AQP4 mRNA and protein expression in experimental rats, which can induce the occurrence and development of cerebral edema in experimental rats.


Assuntos
Aquaporina 4/metabolismo , Barreira Hematoencefálica , Edema Encefálico/patologia , Golpe de Calor/patologia , Animais , Astrócitos , Encéfalo/metabolismo , Temperatura Alta , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
11.
Biochemistry (Mosc) ; 84(11): 1359-1374, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760923

RESUMO

The review summarizes the data of our research and published studies on the ubiquitination of brain mitochondrial proteins and its changes during the development of experimental parkinsonism and administration of the neuroprotector isatin (indole-2,3-dione) with special attention to the mitochondrial ubiquitin-conjugating system and location of ubiquitinated proteins in these organelles. Incubation of brain mitochondrial fraction with biotinylated ubiquitin in vitro resulted in the incorporation of biotinylated ubiquitin in both mitochondrial and mitochondria-associated proteins. According to the interactome analysis, the identified non-ubiquitinated proteins are able to form tight complexes with ubiquitinated proteins or their partners and components of mitochondrial membranes, in which interactions of ubiquitin chains with the ubiquitin-binding protein domains play an important role. The studies of endogenous ubiquitination in the total brain mitochondrial fraction of C57Bl mice performed in different laboratories have shown that mitochondrial proteins represent about 30% of all ubiquitinated proteins. However, comparison of brain subproteomes of mitochondrial ubiquitinated proteins reported in the literature revealed significant differences both in their composition and involvement of identified ubiquitinated proteins in biological processes listed in the Gene Ontology database. The development of experimental parkinsonism in C57Bl mice induced by a single-dose administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in a decrease in the total number of mitochondrial ubiquitinated proteins and increase in the number of oxidized mitochondrial proteins containing the ubiquitin signature (K-ε-GG). Comparison of ubiquitinated proteins associated with the mouse brain mitochondrial fraction and mouse brain mitochondrial proteins bound to the proteasome ubiquitin receptor (Rpn10 subunit) did not reveal any common proteins. This suggests that ubiquitination of brain mitochondrial proteins is not directly related to their degradation in the proteasomes. Proteomic profiling of brain isatin-binding proteins identified enzymes involved in the ubiquitin-conjugating system functioning. Mapping of the identified isatin-binding proteins to known metabolic pathways indicates their participation in the parkin (E3 ubiquitin ligase)-associated pathway (CH000000947). The functional links involving brain mitochondrial ubiquitinated proteins were found only in the group of animals with the MPTP-induced parkinsonism, but not in animals treated with MPTP/isatin or isatin only. This suggests that the neuroprotective effect of isatin may be associated with the impaired functional relationships of proteins targeted to subsequent degradation.


Assuntos
Encéfalo/metabolismo , Transtornos Parkinsonianos/patologia , Ubiquitina/metabolismo , Animais , Autofagia , Redes e Vias Metabólicas , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/veterinária , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitinação
12.
Biochemistry (Mosc) ; 84(11): 1411-1423, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760927

RESUMO

Ischemic stroke and neonatal hypoxic-ischemic encephalopathy are two of the leading causes of disability in adults and infants. The energy demands of the brain are provided by mitochondrial oxidative phosphorylation. Ischemia/reperfusion (I/R) affects the production of ATP in brain mitochondria, leading to energy failure and death of the affected tissue. Among the enzymes of the mitochondrial respiratory chain, mitochondrial complex I is the most sensitive to I/R; however, the mechanisms of its inhibition are poorly understood. This article reviews some of the existing data on the mitochondria impairment during I/R and proposes two distinct mechanisms of complex I damage emerging from recent studies. One mechanism is a reversible dissociation of natural flavin mononucleotide cofactor from the enzyme I after ischemia. Another mechanism is a modification of critical cysteine residue of complex I involved into the active/deactive conformational transition of the enzyme. I describe potential effects of these two processes in the development of mitochondrial I/R injury and briefly discuss possible neuroprotective strategies to ameliorate I/R brain injury.


Assuntos
Encéfalo/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Flavinas/química , Flavinas/metabolismo , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Compostos de Sulfidrila/química
13.
Psychiatr Danub ; 31(3): 290-307, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31596822

RESUMO

Temperament traits of Novelty Seeking, Harm Avoidance, Reward Dependence, and Persistence, are well defined in terms of their neural circuitry, neurochemical modulators, and patterns of associative learning. When heritably excessive, each of these traits may become a mechanistically fundamental biogenetic trait vulnerability for personality disorder. The other main risk factor for personality disorder is environmental, notably abuse, neglect, and psychological trauma. The emerging concept of mechanism-based pharmacotherapy aims to activate the brain's homeostasis as the only available delivery system to re-calibrate complex neurophysiological participants in each of the temperament traits. In a positive feedback, a homeostasis-driven improvement of excessive temperament is expected to facilitate maturation of neocortical networks of cognition, most reliably in expert psychotherapy (Part I of this paper) and, ultimately, thereby improve top-down cortical control of subcortical affect reactivity. As an emerging concept informed by neuroscience and clinical research, mechanism-based pharmacotherapy has the potential to be superior to traditional symptom-based treatments. Such mechanism-based approach illustrates what the pharmacological treatment of Research Domain Criteria (RDoC) might look like.


Assuntos
Modelos Psicológicos , Transtornos da Personalidade/tratamento farmacológico , Temperamento , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição , Humanos , Personalidade , Transtornos da Personalidade/psicologia
14.
Chem Commun (Camb) ; 55(86): 12932-12935, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31599282

RESUMO

Here, we report the development of novel PET radiotracer ([11C]CW22) of BET proteins. In vivo imaging results in rodents and nonhuman primates (NHP) demonstrate that [11C]CW22 has excellent brain uptake, good specificity, good selectivity, suitable metabolism, appropriate kinetics and distribution in the brain. Our studies demonstrated that [11C]CW22 exhibits ideal properties as a PET imaging probe of BET proteins for further validation.


Assuntos
Encéfalo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Animais , Barreira Hematotesticular/metabolismo , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Cristalografia por Raios X , Cinética , Macaca , Camundongos , Conformação Molecular , Proteínas do Tecido Nervoso/química , Neurônios , Domínios Proteicos , Compostos Radiofarmacêuticos/metabolismo , Receptores de Superfície Celular/química
15.
Adv Exp Med Biol ; 1141: 407-466, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571171

RESUMO

Blood-brain interfaces comprise the cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-cerebrospinal fluid barrier (BCSFB). Their main functions are to impede free diffusion between brain fluids and blood; to provide transport processes for essential nutrients, ions, and metabolic waste products; and to regulate the homeostasis of central nervous system (CNS), all of which are attributed to absent fenestrations, high expression of tight junction proteins at cell-cell contacts, and expression of multiple transporters, receptors, and enzymes. Existence of BBB is an important reason that systemic drug administration is not suitable for the treatment of CNS diseases. Some diseases, such epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and diabetes, alter BBB function via affecting tight junction proteins or altering expression and function of these transporters. This chapter will illustrate function of BBB, expression of transporters, as well as their alterations under disease status.


Assuntos
Barreira Hematoencefálica , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo
16.
J Biol Regul Homeost Agents ; 33(5): 1359-1367, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31659887

RESUMO

To study the expression changes of inflammatory factors heme oxygenase-1 (HO-1), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) in intracerebral hemorrhage (ICH), brain tissues surrounding hematoma were collected from ICH patients. The expressions of HO-1, TNF-α, IL- 1ß, and other genes were examined at different time points of ICH. Changes in HO-1, TNF-α, and IL-1ß positive cell numbers after ICH were detected by immunohistochemical staining. The results showed that the expressions of HO-1, TNF-α, and IL-1ß had no significant changes in brain tissues surrounding hematoma within 6 hours after ICH (P > 0.05). Their expressions during 6-24 hours and 24-72 hours after ICH increased constantly. After reaching the peak, they remained steady or slightly decreased after 72 hours. The dynamic expression changes of HO-1, TNF-α, and IL-1ß were observed and their development trends were interfered timely to alleviate the secondary neurological impairment after ICH, which was significant to prevent ICH.


Assuntos
Encéfalo/metabolismo , Hemorragia Cerebral/patologia , Hematoma/metabolismo , Heme Oxigenase-1/metabolismo , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Encéfalo/patologia , Hematoma/patologia , Humanos
17.
Clin Nucl Med ; 44(11): e597-e601, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584490

RESUMO

AIM: In this study, we investigated the relationship of cerebral tau deposition (F-tau-AD-ML 104 PET/CT) with glucose metabolism (F-FDG PET/CT) and cognitive function in patients with Alzheimer disease (AD). PATIENTS AND METHODS: Seventy subjects (Mini Mental State Examination [MMSE] score <18 = 37 [AD]; MMSE score, 18-24 = 16 [early AD]) and 17 controls were included in this study. All participants underwent detailed neurological and neuropsychological evaluation, followed by F-tau-AD-ML 104 and F-FDG PET/CT imaging. Region-wise SUVmax ratios at 50 to 60 minutes postinjection were calculated for F-tau-AD-ML 104 and F-FDG, using the cerebellar cortex as the reference region. Linear models were used to investigate the association of regional F-tau-AD-ML 104 retention with F-FDG uptake and cognition (MMSE scores). RESULTS: F-Tau-AD-ML 104 retention was observed in the parietal lobe, temporal lobe, hippocampus, parahippocampus, frontal lobe, anterior and posterior cingulate, and precuneus in advanced and early AD patient as compared with normal controls with regional hypometabolism in overlapping regions on F-FDG PET. Significant negative association was found between F-tau-AD-ML 104 regional retention and glucose metabolism in the parietal lobe, temporal lobe, hippocampus, parahippocampus, frontal lobe, anterior and posterior cingulate, and precuneus among patients with advanced and early AD. In advanced and early AD patients, a negative association was found between F-tau-AD-ML 104 regional retention (precuneus) and cognition (MMSE score), whereas a positive association was observed between F-FDG regional uptake (precuneus) and cognition (MMSE score). CONCLUSIONS: Tau pathology overlapped with areas of hypometabolism on FDG PET in the brains of AD patients. Tau deposition was found to have negative association with cognitive scores in these patients.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Cognição , Glucose/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
18.
Nature ; 574(7779): 559-564, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645735

RESUMO

Although glucose-sensing neurons were identified more than 50 years ago, the physiological role of glucose sensing in metazoans remains unclear. Here we identify a pair of glucose-sensing neurons with bifurcated axons in the brain of Drosophila. One axon branch projects to insulin-producing cells to trigger the release of Drosophila insulin-like peptide 2 (dilp2) and the other extends to adipokinetic hormone (AKH)-producing cells to inhibit secretion of AKH, the fly analogue of glucagon. These axonal branches undergo synaptic remodelling in response to changes in their internal energy status. Silencing of these glucose-sensing neurons largely disabled the response of insulin-producing cells to glucose and dilp2 secretion, disinhibited AKH secretion in corpora cardiaca and caused hyperglycaemia, a hallmark feature of diabetes mellitus. We propose that these glucose-sensing neurons maintain glucose homeostasis by promoting the secretion of dilp2 and suppressing the release of AKH when haemolymph glucose levels are high.


Assuntos
Encéfalo/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Glucagon/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Neurônios/metabolismo , Animais , Axônios/metabolismo , Encéfalo/anatomia & histologia , Drosophila melanogaster/anatomia & histologia , Glucose/análise , Hormônios de Inseto/metabolismo , Masculino , Inibição Neural , Vias Neurais , Neuropeptídeos/química , Neuropeptídeos/metabolismo , Neurotransmissores/metabolismo , Oligopeptídeos/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/metabolismo
19.
Life Sci ; 237: 116929, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610210

RESUMO

LncRNA small nucleolar RNA host gene 3 (Snhg3) has been involved in cell proliferation and migration in malignant cells. However, its role in regulating functions of non-malignant cells has been hardly reported. Here, we found Snhg3 expression was sharply induced in primary brain microvascular endothelial cells (BMVECs) treated with oxygen-and-glucose-deprivation (OGD) plus hemin, an in vitro model of intracerebral hemorrhage (ICH). Downregulation of Snhg3 by siRNA transfection improved cell proliferation and migration abilities and reduced cell apoptosis and monolayer permeability in BMVECs under treatment with OGD plus hemin. Snhg3 overexpression suppressed cell proliferation and migration and increased cell apoptosis and monolayer permeability under normal condition. In ICH rats, downregulation of Snhg3 by siRNA injection improved behavioral and histological manifestations, including number of right turns, limb placement score, integrity of blood-brain barrier (BBB), brain water content and cell apoptosis in vivo. In the mechanism exploration, we found that, TWEAK and Snhg3 displayed a positive correlation with each other. Snhg3 overexpression increased expression of TWEAK protein and its receptor Fn14, that were also induced by OGD plus hemin, activating the downstream neuroinflammatory pathway STAT3 and enhancing the secretion of MMP-2/9. Finally, the TWEAK-siRNA, the Fn14 inhibitor ATA and the STAT3 blocker AG490 were respectively used to treat BMVECs under treatment with OGD plus hemin. Our results showed either TWEAK downregulation, Fn14 inhibition, or STAT3 blockade, could rescue Snhg3-induced impairment of BMVEC functions. In conclusion, the lncRNA Snhg3 contributes to dysfunction of cerebral microvascular cells in ICH rats by activating the TWEAK/Fn14/STAT3 pathway.


Assuntos
Encéfalo/patologia , Hemorragia Cerebral/patologia , Citocina TWEAK/metabolismo , Endotélio Vascular/patologia , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/metabolismo , Receptor de TWEAK/metabolismo , Animais , Comportamento Animal , Encéfalo/metabolismo , Células Cultivadas , Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , Circulação Cerebrovascular/fisiologia , Citocina TWEAK/genética , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Masculino , Microvasos/metabolismo , Microvasos/patologia , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Receptor de TWEAK/genética , Cicatrização
20.
Life Sci ; 235: 116844, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31499069

RESUMO

AIMS: 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a new derivative of ginkgolide B, has drawn great attention for its potent bioactivities against ischemia-induced injury. The purpose of this study was to further investigate the effect of XQ-1H against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO/R) injuries in mice. MAIN METHODS: Treatment of XQ-1H (78 or 39 mg/kg, i.g., bid) 2 h after MCAO improved motor skills and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes and the activation of a pro-apoptotic protein Cleaved-Caspase-3, which in turn induced anti-apoptotic Bcl-xL. Through introducing Wnt/ß-catenin signaling inhibitor XAV-939, XQ-1H was proven to intensively promoted neurogenesis in the peri-infarct cortex, subventricular area (SVZ) and the dentate gyrus (DG) subgranular area (SGZ) in a Wnt signal dependent way by compromising the activation of GSK3ß, which in turn upregulated Wnt1, ß-catenin, Neuro D1 and Cyclin D1, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KEY FINDINGS: We conclude that XQ-1H preserved the motor functions, limited apoptosis, and concomitantly promoted neurogenesis-related protein expression by Wnt signaling-dependently compromising GSK3ß/Caspase-3 activity and enhancing the expression of Wnt1/ß-catenin/Neuro D1/Cyclin D1 and Bcl-xL. SIGNIFICANCE: This research may benefit the development of stroke therapeutics targeting neurogenesis through Wnt upregulation by XQ-1H.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Ginkgolídeos/farmacologia , Ginkgolídeos/uso terapêutico , Lactonas/farmacologia , Lactonas/uso terapêutico , Neurogênese/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Caspase 3/metabolismo , Ciclina D1/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Fator de Crescimento Neural/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Regulação para Cima/efeitos dos fármacos , Proteína bcl-X/metabolismo
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