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1.
Eur J Neurosci ; 54(7): 6633-6645, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34479401

RESUMO

Freezing of gait (FOG) is a common and complex manifestation of Parkinson's disease (PD) and is associated with impairment of attention. The purpose of this study was to evaluate the functional network connectivity (FNc) changes between the dorsal attention network (DAN) and the other seven intrinsic networks relevant to attention, visual-spatial, executive and motor functions in PD with or without FOG. Forty-three idiopathic PD patients (21 with FOG [FOG+] versus 22 without FOG [FOG-]) and 18 healthy controls (HC) were recruited in this study. The data-driven independent component analysis (ICA) method was used to extract and analyze the above-mentioned resting-state networks (RSNs). Compared with FOG-, FOG+ displayed decreased positive connectivity between the DAN and medial visual network (mVN) and sensory-motor network (SMN) and increased negative connectivity between the DAN and default mode network (DMN). The within-network connectivity in the SMN and visual networks were decreased, whereas the connectivity within DMN was increased significantly in FOG+. Correlation analysis showed that the clock drawing test (CDT) scores were positively correlated with the functional connectivity of mVN (r = 0.573, p = 0.008) and lateral visual network (lVN) (r = 0.510, p = 0.022), the Timed Up and Go Test (TUG) duration were negatively correlated with the connectivity of SMN (r = -0.629, p = 0.003), and the Frontal Assessment Battery (FAB) scores were negatively correlated with the connectivity of DMN in FOG+. Functional connectivity was changed in multiple intra-networks in patients with FOG. Inordinate inter-network connectivity between the DAN and other intrinsic networks may partly contribute to the mechanism of freezing.


Assuntos
Transtornos Neurológicos da Marcha , Doença de Parkinson , Mapeamento Encefálico , Marcha , Transtornos Neurológicos da Marcha/etiologia , Humanos , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Equilíbrio Postural , Estudos de Tempo e Movimento
2.
Neurochem Int ; 150: 105171, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34419525

RESUMO

Gastrodin, which is extracted from the Chinese herbal medicine Gastrodia elata Blume, can ameliorate neurogenesis after cerebral ischemia. However, it's possible underlying mechanisms remain still elusive. PDE9-cGMP-PKG signaling pathway is involved in the proliferation of neural stem cells (NSCs) after cerebral ischemia. In this study, we investigated whether the beneficial effect of gastrodin on hippocampal neurogenesis after cerebral ischemia is correlated with the PDE9-cGMP-PKG signaling pathway. Bilateral common carotid artery occlusion (BCCAO) in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary cultured hippocampal NSCs were used to mimic brain ischemic injury. The Morris water maze (MWM) test was executed to detect spatial learning and memory. Proliferation, differentiation, and mature neurons were examined using immunofluorescence. The survival and proliferation of NSCs were assessed by CCK-8 assay and BrdU immunofluorescence staining, respectively. ELISA and western blot were used to detect the level of the PDE9-cGMP-PKG signaling pathway. In BCCAO mice, administering gastrodin (50 and 100 mg/kg) for 14 d restored cognitive behaviors; meanwhile, neurogenesis in hippocampus was stimulated, and PDE9 was inhibited and cGMP-PKG was activated by gastrodin. Consistent with the results, administering gastrodin (from 0.01-1 µmol/L) for 48 h dose-dependently ameliorated the cell viability and promoted greatly the proliferation in primary hippocampal NSCs exposed to OGD/R. Gastrodin further decreased PDE9 activity and up-regulated cGMP-PKG level. KT5823, a PKG inhibitor, markedly abrogated the protective effects of gastrodin on OGD/R-injured NSCs, accompanied by the down-regulation of PKG protein expression, but had no effects on PDE9 activity and cGMP level. Gastrodin could accelerate hippocampal neurogenesis after cerebral ischemia, which is mediated, at least partly, by PDE9-cGMP-PKG signaling pathway.

3.
Sleep Med ; 82: 125-133, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33915428

RESUMO

OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) frequently occurs in Parkinson's disease (PD), however, the exact pathophysiological mechanism underlying its occurrence is not clear. In this study, we explored whether there is abnormal spontaneous neuronal activities and connectivity maps in some brain areas under resting-state in PD patients with RBD. METHODS: We recruited 38 PD patients (19 PD with RBD and 19 PD without RBD), and 20 age- and gender-matched normal controls. We used resting-state functional magnetic resonance imaging (RS-fMRI) to analyze regional homogeneity (ReHo) and functional connectivity (FC), and further to reveal the neuronal activity in all subjects. RESULTS: Compared with the PD without RBD patients, the PD with RBD patients showed a significant increase in regional homogeneity in the left cerebellum, the right middle occipital region and the left middle temporal region, and decreased regional homogeneity in the left middle frontal region. The REM sleep behavioral disorders questionnaire scores were significantly positively correlated with the ReHo values of the left cerebellum. The functional connectivity analysis in which the four regions described above were used as regions of interest revealed increased functional activity between the left cerebellum and bilateral occipital regions, bilateral temporal regions and bilateral supplementary motor area. CONCLUSION: The pathophysiological mechanism of PD with RBD may be related to abnormal spontaneous neuronal activity patterns with strong synchronization of cerebellar and visual-motor relevant cortex, and the increased connectivity of the cerebellum with the occipital and motor regions.


Assuntos
Córtex Motor , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Encéfalo , Cerebelo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/diagnóstico por imagem
4.
Ther Adv Chronic Dis ; 12: 2040622321998139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796244

RESUMO

Background: Human bone marrow mesenchymal stem cells (hBMSCs) could differentiate into dopamine-producing cells and ameliorate behavioral deficits in Parkinson's disease (PD) models. Liver X receptors (LXRs) are involved in the maintenance of the normal function of central nervous system myelin. Therefore, the previous work of our team has found the induction of cocktail-induced to dopaminergic (DA) phenotypes from adult rat BMSCs by using sonic hedgehog (SHH), fibroblast growth factor 8 (FGF8), basic fibroblast growth factor (bFGF), and TO901317 (an agonist of LXRs) with 87.42% of efficiency in a 6-day induction period. But we did not verify whether the induced cells had the corresponding neural function. Methods: Expressions of LXRα, LXRß, and tyrosine hydroxylase (TH) were detected by immunofluorescence and western blot. Adenosine triphosphate-binding cassette transporter A1 (ABCA1) was detected by quantitative real-time PCR. The induced cells were transplanted into PD rats to study whether the induced cells are working. Results: The induced cells can release the dopamine transmitter; the maximum induction efficiency of differentiation of hBMSCs into DA neurons was 91.67% under conditions of combined use with TO901317 and growth factors (GF). When the induced-cells were transplanted into PD rats, the expression of TH in the striatum increased significantly, and the behavior of PD rats induced by apomorphine was significantly improved. Conclusion: The induced cells have the function of DA neurons and have the potential to treat PD. TO901317 promoted differentiation of hBMSCs into DA neurons, which may be related to activation of the LXR-ABCA1 signaling pathway.

5.
Eur J Neurosci ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33905578

RESUMO

Dexmedetomidine (Dex), an adrenergic α2 receptor agonist, is commonly used in deep-brain stimulation surgery for Parkinson's disease (PD). However, there is evidence that the use of anaesthetics may accelerate the progression of neurodegenerative diseases. The effect of Dex on PD remains unclear. Here, we cultured the all-trans-retinoicacid (ATRA) differentiated SH-SY5Y cells in vitro and then treated with MPP+ (1.5mM) with or without Dex (10nM) or Dex combined with Atipamezole (Ati,100nM, adrenergic α2 receptor inhibitor). The ratio of apoptotic cells, mitochondrial membrane potential (Δψm), reactive oxygen species (ROS), cell cycle and apoptotic markers (Cleaved caspase-3, 9) were analysed by flow cytometry and immunofluorescence. We found that the levels of apoptotic ratio and cleaved caspase-3, 9 increased, ROS accumulated, and mitochondrial membrane potential decreased after MPP+treatment, while these changes were partially reversed by Dex. Dex also prevented MPP+ induced cell arrest by increasing G1 phase cells, decreasing S phase cells, and decreasing the expression of cyclinD1 and Cdk4. Moreover the effects of Dex were partially reversed by Ati. These findings reveal that Dex attenuated MPP+ -induced apoptosis of SH-SY5Y cells by preventing the loss of Δψm, reducing ROS, and regulating the cell cycle. Our findings indicated that Dex is more likely to be a potential drug for the treatment of PD.

6.
Neuromolecular Med ; 23(4): 521-530, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33782855

RESUMO

tDCS, a new, safe, non-invasive physical therapy method, is often used in motor dysfunction rehabilitation. However, the effects and underlying mechanisms of tDCS on hippocampal neurogenesis after cerebral ischemia (CI) are still unclear. This study aimed to investigate the promotive effect and mechanism of repetitive anodal-tDCS on hippocampal neurogenesis after CI in mice. The CI model in mice was established using bilateral common carotid artery occlusion (BCCAO). The pathological changes in the hippocampal CA1 region and cognitive function were assessed by hematoxylin and eosin staining and Morris water maze test, respectively. Hippocampal neurogenesis was observed by immunofluorescence staining. The levels of expression of ephrinb1, EPHB2, MAP-2, and NMDAR in the hippocampi were analyzed by qRT-PCR and Western blotting. Compared with the sham mice, the model mice showed significant neuronal damage in the hippocampal CA1 region (P < 0.01), cognitive dysfunction (P < 0.01), and endogenous hippocampal neurogenesis (P < 0.01). These results suggested that the CI model was successfully established, and that CI could promote endogenous hippocampal neurogenesis, but this hippocampal neurogenesis was unable to recover cognitive dysfunction. Compared with the model mice, the tDCS mice had ameliorated pathological damage in the CA1 region (P < 0.01), improved cognitive function (P < 0.01), increased hippocampal neurogenesis (P < 0.01), and increased mRNA and protein expression of ephrinb1, EPHB2, MAP-2, and NMDAR (P < 0.05). Repetitive anodal-tDCS can promote hippocampal neurogenesis and improve cognitive function in CI mice. The effect may be related to the activation of the ephrinb1/EPHB2/MAP-2/NMDAR signaling pathway.

7.
BMC Neurol ; 21(1): 68, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33573615

RESUMO

BACKGROUND: Depression in essential tremor (ET) has been constantly studied and reported, while the associated brain activity changes remain unclear. Recently, regional homogeneity (ReHo), a voxel-wise local functional connectivity (FC) analysis of resting-state functional magnetic resonance imaging, has provided a promising way to observe spontaneous brain activity. METHODS: Local FC analyses were performed in forty-one depressed ET patients, 49 non-depressed ET patients and 43 healthy controls (HCs), and then matrix FC and clinical depression severity correlation analyses were further performed to reveal spontaneous neural activity changes in depressed ET patients. RESULTS: Compared with the non-depressed ET patients, the depressed ET patients showed decreased ReHo in the bilateral cerebellum lobules IX, and increased ReHo in the bilateral anterior cingulate cortices and middle prefrontal cortices. Twenty-five significant changes of ReHo clusters were observed in the depressed ET patients compared with the HCs, and matrix FC analysis further revealed that inter-ROI FC differences were also observed in the frontal-cerebellar-anterior cingulate cortex pathway. Correlation analyses showed that clinical depression severity was positively correlated with the inter-ROI FC values between the anterior cingulate cortex and bilateral middle prefrontal cortices and was negatively correlated with the inter-ROI FC values of the anterior cingulate cortex and bilateral cerebellum lobules IX. CONCLUSION: Our findings revealed local and inter-ROI FC differences in frontal-cerebellar-anterior cingulate cortex circuits in depressed ET patients, and among these regions, the cerebellum lobules IX, middle prefrontal cortices and anterior cingulate cortices could function as pathogenic structures underlying depression in ET patients.


Assuntos
Encéfalo/fisiopatologia , Depressão/etiologia , Depressão/fisiopatologia , Tremor Essencial/fisiopatologia , Tremor Essencial/psicologia , Adulto , Mapeamento Encefálico/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/fisiopatologia
8.
Stem Cell Res Ther ; 12(1): 22, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413637

RESUMO

PURPOSE AND BACKGROUND: Previous studies have suggested that promoting endogenous neurogenesis has great significance for the recovery of cognitive dysfunction caused by cerebral ischemia (CI). Pharmacological inhibition of GABAB receptor can enhance neurogenesis in adult healthy and depressed mice. In the study, we intended to investigate the effects of GABAB receptor antagonists on cognitive function and hippocampal neurogenesis in mice following CI. METHODS: Adult mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min to induce CI and treated with CGP52432 (antagonist of GABAB receptor, CGP, 10 mg/kg intraperitoneal injection) starting 24 h after CI. The Morris water maze test was performed to test spatial learning and memory at day 28. Immunofluorescence was applied to detect neurogenesis in the DG region at day 14 and 28. In in vitro experiments, cell proliferation was detected by CCK8 and immunofluorescence, and the expression of cAMP/CREB signaling pathway-related proteins was detected by ELISA assay and Western blot. RESULTS: CGP significantly improved spatial learning and memory disorders caused by CI, and it enhanced the proliferation of neural stem cells (NSCs), the number of immature neurons, and the differentiation from newborn cells to neurons. In vitro experiments further confirmed that CGP dose-dependently enhanced the cell viability of NSCs, and immunofluorescence staining showed that CGP promoted the proliferation of NSCs. In addition, treatment with CGP increased the expression of cAMP, PKA, and pCREB in cultured NSCs. CONCLUSION: Inhibition of GABAB receptor can effectively promote hippocampal neurogenesis and improve spatial learning and memory in adult mice following CI.


Assuntos
Isquemia Encefálica , Neurogênese , Animais , Isquemia Encefálica/tratamento farmacológico , Cognição , Antagonistas de Receptores de GABA-B/farmacologia , Hipocampo , Aprendizagem em Labirinto , Camundongos , Ácido gama-Aminobutírico
9.
Brain Res ; 1751: 147197, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33160958

RESUMO

OBJECTIVES: To investigate whether curcumin promotes hippocampal neurogenesis in the cerebral ischemia (CI) mice via Wnt/ß-catenin signaling pathway. METHODS: Male C57BL/6 mice were randomly divided into groups: sham operation group (Sham), cerebral ischemic group (CI), curcumin treatment group (50, 100 mg/kg/d, i.p.) and curcumin (100 mg/kg/d) + DKK1 (a blocker of Wnt receptor, 200 ng/d, icv) group. CI was induced by bilateral common carotid arteries occlusion (BCCAO) for 20 min. The Morris water maze test was conducted to detect spatial learning and memory. Immunofluorescence staining was used to examine the proliferation and differentiation of immature neurons in the hippocampal dentate gyrus. The proteins involved in neurogenesis and Wnt signaling pathway were examined using Western blot assay. RESULTS: Curcumin significantly alleviated cognitive deficits induced by CI. Curcumin dose-dependently increased the proliferation of neural stem cells and promoted the differentiation and maturation of newly generated neural cells into neurons. Curcumin also increased the expression of proteins involved in neurogenesis (including Ngn2, Pax6 and NeuroD 1) and the Wnt/ß-catenin signaling pathway. Moreover, the forenamed effects of curcumin were abolished by pretreatment with DKK1, a blocker of Wnt receptor. CONCLUSION: Curcumin promotes hippocampal neurogenesis by activating Wnt/ß-catenin signaling pathway to ameliorate cognitive deficits after acute CI.

10.
Neurol Sci ; 42(7): 2937-2946, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33236247

RESUMO

BACKGROUND: Patients with akinetic-rigid Parkinson's disease (AR-PD) are more prone to cognitive decline and depressive symptoms than tremor-dominant PD (TD-PD) patients. The right fronto-insular cortex (rFIC), as a key node of salience network, plays a critical role in the switching between central executive network and default mode network. In this study, we explored the functional connectivity mode of rFIC with triple-brain networks, namely default mode network, salience network, and central executive network, in two motor subtypes of PD. METHODS: We recruited 44 PD patients (including the TD-PD group and AR-PD group) and 18 age-matched healthy controls (HCs). We performed functional connectivity (FC) analysis of resting-state functional MRI. RESULTS: Compared with TD-PD, decreased FC were found in the right insular cortex and bilateral anterior cingulate gyrus in AR-PD. Compared with HCs, decreased FC in the bilateral insula, the anterior cingulate gyrus, the precentral gyrus, and the right medial frontal gyrus were found; therein, the FC value of rFIC-precentral gyrus was positively correlated with the Unified Parkinson's Disease Rating Scale-II score in AR-PD (p = 0.0482, r = 0.4162). While TD-PD showed decreased FC in the left insula as well as bilateral anterior cingulate gyrus when compared with HCs, and the FC value of the rFIC-left insula was positively correlated with its Hamilton Depression Rating Scale score (p = 0.02, r = 0.50). CONCLUSION: The functional connectivity mode of rFIC in AR-PD differed from that in TD-PD. The decreased rFIC FC with the other nodes of salience network might be a potential indicator for AR-PD patients prone to develop cognitive decline and depressive symptoms.


Assuntos
Doença de Parkinson , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Tremor/diagnóstico por imagem , Tremor/etiologia
11.
J Neurochem ; 154(2): 205-217, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31602646

RESUMO

Cerebral ischemia (CI) leads to cognitive dysfunction due to the loss of hippocampal neurons. Liver X receptors (LXRs), including the LXRα and LXRß isoforms, are critical for neurogenesis, synaptic plasticity, neurodegeneration, and cholesterol metabolism. However, the potential role of LXRs in the pathogenesis of CI-induced cognitive impairment is unclear. Therefore, we investigated the effects of LXR activation on hippocampal neurogenesis and cognitive function in mice with CI. C57 mice were randomized into four groups that included a sham group and three treatment groups with CI [Vehicle, TO901317 (TO90, an agonist of LXRs) and GSK2033 (an antagonist of LXRs)]. Mice were subjected to bilateral common carotid artery occlusion for 20 min to induce transient CI. The Morris water maze test was executed to detect spatial learning and memory. Proliferation, differentiation, and immature neurons in the subgranular zone (SGZ) were examined using Immunofluorescence. Western blot assay was used to detect the expression of the Wnt/ß-catenin signaling pathway-associated protein. TO90 significantly improved spatial learning and memory deficits induced by CI on 28 days. It enhanced the proliferation of neural stem cells, the number of immature neurons and the differentiation from nascent cells to neurons. The expression of the Wnt/ß-catenin signaling pathway-associated protein level was totally increased. The forenamed effects of TO90 were decreased in GSK2033 group. Thus, our findings suggest that LXRs activation can improve long-term cognitive dysfunction caused by CI by increasing neurogenesis, and LXRs may serve as a potential therapeutic target for cerebral ischemia. Cover Image for this issue: doi: 10.1111/jnc.14753.


Assuntos
Isquemia Encefálica/metabolismo , Cognição/fisiologia , Hipocampo/metabolismo , Receptores X do Fígado/metabolismo , Neurogênese/fisiologia , Animais , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Recuperação de Função Fisiológica/fisiologia , Traumatismo por Reperfusão/metabolismo
12.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 36(4): 548-556, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31441254

RESUMO

Methods for achieving diagnosis of Parkinson's disease (PD) based on speech data mining have been proven effective in recent years. However, due to factors such as the degree of disease of the data collection subjects and the collection equipment and environment, there are different categories of sample aliasing in the sample space of the acquired data set. Samples in the aliased area are difficult to be identified effectively, which seriously affects the classification accuracy of the algorithm. In order to solve this problem, a partition bagging ensemble learning is proposed in this article, which measures the aliasing degree of the sample by designing the the ratio of sample centroid distance metrics and divides the training set into multiple subsets. And then the method of transfer training of misclassified samples is used to adjust the results of subset partitioning. Finally, the optimized weights of each sub-classifier are used to integrate the test results. The experimental results show that the classification accuracy of the proposed method is significantly improved on two public datasets and the increasement of mean accuracy is up to 25.44%. This method not only effectively improves the classification accuracy of PD speech dataset, but also increases the sample utilization rate, providing a new idea for the diagnosis of PD.


Assuntos
Mineração de Dados , Doença de Parkinson/diagnóstico , Fala , Algoritmos , Humanos , Aprendizado de Máquina
13.
Exp Cell Res ; 382(1): 111455, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163124

RESUMO

Diabetic nephropathy (DN) is one of the most severe complications of diabetes mellitus. The pathomolecular events behind DN remain uncertain. Peroxisome proliferator-activated receptors (PPARs) play essential functions in the development of DN. Meanwhile, 20-hydroxyeicosatetraenoic acid (20-HETE) also plays central roles in the regulation of renal function. However, the relationship between PPARs and 20-HETE is rarely studied in DN. It was revealed in our study that both PPARs expression and CYP4A-20-HETE level were decreased under DN conditions in vivo and in vitro. Supplementation with bezafibrate, a PPAR pan-agonist, improved the damage of kidney in DN mice and in high glucose-induced NRK-52E cells, following the up-regulation of PPARs and the increase of CYP4A-20-HETE. PPARα antagonist (MK886), PPARß antagonist (GSK0660), and PPARγ antagonist (GW9662) reversed the protection of bezafibrate in NRK-52E, and abrogated the up-regulation of CYP4A-20-HETE produced by bezafibrate. Noteworthily, 20-HETE synthetase inhibitor, HET0016, also blocked the bezafibrate-mediated improvement of NRK-52E, and abolished the up-regulation of PPARs expression. Collectively, our data suggest that the concurrent down-regulation and interaction of PPARs and 20-HETE play crucial roles in the pathogenesis process of DN, and we provide a novel evidence that PPARs/20-HETE signaling may be served as a therapeutic target for DN patients.


Assuntos
Nefropatias Diabéticas/metabolismo , Ácidos Hidroxieicosatetraenoicos/fisiologia , PPAR alfa/fisiologia , PPAR gama/fisiologia , PPAR beta/fisiologia , Amidinas/farmacologia , Anilidas/farmacologia , Animais , Linhagem Celular , Citocromo P-450 CYP4A/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Regulação para Baixo/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/toxicidade , Ácidos Hidroxieicosatetraenoicos/biossíntese , Indóis/farmacologia , Túbulos Renais/citologia , Masculino , Camundongos , PPAR alfa/biossíntese , PPAR alfa/genética , PPAR gama/biossíntese , PPAR gama/genética , PPAR beta/biossíntese , PPAR beta/genética , Ratos , Sulfonas/farmacologia , Tiofenos/farmacologia
14.
Chem Biol Interact ; 307: 116-124, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31063766

RESUMO

Naringenin is a flavanone compound found in citrus fruits. Recent researches showed that naringenin has many potentially pharmacological effects. However, the therapeutic effect and the potential mechanism of naringenin on diabetic nephropathy (DN) remain to be elucidated. DN model was established by a high-fat diet combined with streptozotocin (STZ), which was confirmed by the levels of fasting blood glucose (FBG, more than 11.1 mmol/L) and urinary albumin (10 times higher than the normal mice). After 5 weeks of STZ injection, the DN was developed in model mice. Then naringenin (25 or 75 mg/kg·d) were supplemented for 4 weeks. At the end of the experiment, the injury of the renal function and structure was deteriorated. Concomitantly, peroxisome proliferators-activated receptors (PPARs) protein expression was down-regulated, and CYP4A expression and 20-hydroxyeicosatetraenoic acid (20-HETE) level were reduced in DN mice. Naringenin administration improved the renal damage of DN mice, and up-regulated PPARs expression, increased CYP4A-20-HETE level. Consistent with the results of in vivo, glucose at 30 mmol/L (high glucose, HG) significantly induced cell proliferation and hypertrophy in NRK-52E cells, following the reductive PPARs protein expression and the downward CYP4A-20-HETE level. Naringenin (0.01, 0.1, 1 µmol/L) reversed these changes induced by HG in a dose-dependent manner. HET0016, a selective inhibitor of 20-HETE synthase, partially blocked the effects of naringenin. In conclusion, naringenin has a therapeutic effect on DN, which may be, at least partly, related to the activation of CYP4A-20-HETE and the up-regulation of PPARs.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Flavanonas/uso terapêutico , Ácidos Hidroxieicosatetraenoicos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP4A/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Dieta Hiperlipídica , Feminino , Flavanonas/farmacologia , Glucose/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos , Ratos , Estreptozocina/toxicidade , Regulação para Cima/efeitos dos fármacos
15.
ACS Chem Neurosci ; 10(3): 1204-1208, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30682886

RESUMO

Parkinson's disease (PD) is a severe neurodegenerative disease and there is great need for developing a biochemical detection method to precisely diagnose it. Alpha-synuclein (α-syn) participates in the main pathology of PD and serves as an important biomarker of PD. Here, we identified peptoid ASBP-7 that had high affinity and specificity to α-syn by screening a peptoid library using the high-throughput surface plasmon resonance imaging method. We confirmed that ASBP-7 could significantly distinguish PD sera from the normal ones through identifying α-syn in the serum. We also demonstrated the high sensitivity of this system in detecting PD serum. This work provides a method for the blood-based, label-free, high-throughput analysis of PD serum, and holds great potential for the early diagnosis and dynamic monitoring of PD.


Assuntos
Doença de Parkinson/sangue , alfa-Sinucleína/sangue , Idoso , Biomarcadores/sangue , Análise Química do Sangue/métodos , Diagnóstico Precoce , Feminino , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Análise em Microsséries , Simulação de Acoplamento Molecular , Peptoides , Ressonância de Plasmônio de Superfície
16.
Zhongguo Zhong Yao Za Zhi ; 44(24): 5451-5456, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-32237394

RESUMO

This paper was aimed to investigate the effect of gastrodin( GAS) on hippocampal neurogenesis after cerebral was chemic and to explore its mechanism of action related to NO. The cerebral ischemia model of C57 BL/6 mice was established by bilateral common carotid artery occlusion. The pathological changes in hippocampal CA1 region and the cognitive function of mice were assessed by HE staining and Morris water maze test,respectively. The count of Brd U/Neu N positive cells in dentate gyrus was detected by immunofluorescence assay. The NOS activity and the NO content were determined by colorimetric and nitrate reduction methods,respectively.The level of c GMP was measured by ELISA kit,and the PKG protein expression was tested by Western blot. On postoperative day 8,the hippocampal CA1 pyramidal neurons of mice showed irregular structure,with obvious nuclear pyknosis,loose cell arrangement and obvious decrease in the number of neurons. On postoperative day 29,the spatial learning ability and memory were decreased. These results indicated cerebral ischemia in mice. Meanwhile,the Brd U/Neu N positive cells were increased significantly in ischemic mice,indicating that neurogenesis occurred in hippocampus after cerebral ischemia. Treatment with different doses of gastrodin( 50 and 100 mg·kg-1) significantly ameliorated the pathological damages in the CA1 region,improved the ability of learning and memory,and promoted hippocampal neurogenesis. At the same time,both the NOS activity and the NO concentration were decreased in model group,but the c GMP level was increased,and the PKG protein expression was up-regulated. Gastrodin administration activated the NOS activity,promoted NO production,further increased c GMP level and up-regulated PKG protein expression. These results suggested that gastrodin can promote hippocampal neurogenesis after cerebral ischemia and improve cognitive function in mice,which may be related to the activation of NO-cGMP-PKG signaling pathway.


Assuntos
Álcoois Benzílicos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Região CA1 Hipocampal/efeitos dos fármacos , Glucosídeos/uso terapêutico , Neurogênese , Transdução de Sinais , Animais , Cognição , Camundongos , Camundongos Endogâmicos C57BL
17.
Neural Regen Res ; 13(8): 1375-1383, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30106049

RESUMO

Genistein, a potent antioxidant compound, protects dopaminergic neurons in a mouse model of Parkinson's disease. However, the mechanism underlying this action remains unknown. This study investigated human SH-SY5Y cells overexpressing the A53T mutant of α-synuclein. Four groups of cells were assayed: a control group (without any treatment), a genistein group (incubated with 20 µM genistein), a rotenone group (treated with 50 µM rotenone), and a rotenone + genistein group (incubated with 20 µM genistein and then treated with 50 µM rotenone). A lactate dehydrogenase release test confirmed the protective effect of genistein, and genistein remarkably reversed mitochondrial oxidative injury caused by rotenone. Western blot assays showed that BCL-2 and Beclin 1 levels were markedly higher in the genistein group than in the rotenone group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling revealed that genistein inhibited rotenone-induced apoptosis in SH-SY5Y cells. Compared with the control group, the expression of NFE2L2 and HMOX1 was significantly increased in the genistein + rotenone group. However, after treatment with estrogen receptor and NFE2L2 channel blockers (ICI-182780 and ML385, respectively), genistein could not elevate NFE2L2 and HMOX1 expression. ICI-182780 effectively prevented genistein-mediated phosphorylation of NFE2L2 and remarkably suppressed phosphorylation of AKT, a protein downstream of the estrogen receptor. These findings confirm that genistein has neuroprotective effects in a cell model of Parkinson's disease. Genistein can reduce oxidative stress damage and cell apoptosis by activating estrogen receptors and NFE2L2 channels.

18.
Neurol Sci ; 39(11): 1847-1856, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30019200

RESUMO

OBJECTIVE: Constipation is among the most frequently delineated nonmotor symptoms (NMS) with a high occurrence in Parkinson's disease (PD). The purpose of our study was to investigate whether PD with comparatively integrated intestinal function (without constipation) in the early stage had different clinical features compared to constipated PD. METHOD: We conducted a study of 105 consecutive de novo as well as early treated (treated for shorter than 3 months), aged 50 years or older outpatients. Subjects were administered motor and nonmotor questionnaires as well as constipation associated examinations. Then, we explored the distinctive features of nonconstipated contrasted to constipated PD by using univariate, multiple regression analysis and correlation analysis. RESULTS: Nonconstipated PD tended to have fewer motor deficits, as well as lower Hoehn and Yahr (H&Y) stage and they mainly presented as tremor-dominant (TD), while constipated group had a higher occurrence of posture instability and gait difficulty (PIGD); nonconstipated patients were inclined to live in urban area, the NMSloads and prevalence of NMS were lower compared to constipated ones. Correlation analysis found a discord between NMSloads and disease severity based on H&Y stage and motor scores in nonconstipated PD. CONCLUSIONS: These results suggest that PD without constipation in early stage may represent a unique clinical phenotype, which may be more benign than PD with constipation.


Assuntos
Constipação Intestinal/etiologia , Enteropatias/etiologia , Doença de Parkinson/complicações , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Análise de Regressão , Índice de Gravidade de Doença , Inquéritos e Questionários
19.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 34(6): 942-948, 2018 Feb 01.
Artigo em Chinês | MEDLINE | ID: mdl-29761992

RESUMO

Diagnosis of Parkinson's disease (PD) based on speech data has been proved to be an effective way in recent years. However, current researches just care about the feature extraction and classifier design, and do not consider the instance selection. Former research by authors showed that the instance selection can lead to improvement on classification accuracy. However, no attention is paid on the relationship between speech sample and feature until now. Therefore, a new diagnosis algorithm of PD is proposed in this paper by simultaneously selecting speech sample and feature based on relevant feature weighting algorithm and multiple kernel method, so as to find their synergy effects, thereby improving classification accuracy. Experimental results showed that this proposed algorithm obtained apparent improvement on classification accuracy. It can obtain mean classification accuracy of 82.5%, which was 30.5% higher than the relevant algorithm. Besides, the proposed algorithm detected the synergy effects of speech sample and feature, which is valuable for speech marker extraction.

20.
Oncotarget ; 9(1): 576-590, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29416637

RESUMO

Dopaminergic (DA) neurons derived from bone marrow derived mesenchymal stem cells (BMSCs) maybe a valuable source for cell replacement therapy in Parkinson disease. Recent studies showed that new functions of LXR and their ligands have been proposed to prevent PD in the adult nervous system. The present study was designed to observe the effect of liver X receptors (LXR) agonist on differentiation of rat BMSCs into DA neurons. Expressions of the neuronal markers (Tuj1 and Nestin), the specific marker of DA neurons (tyrosine hydroxylase, TH), LXR α and LXR ß were measured by immunocytochemical assay and TH/Tuj1 positive cells were determined by quantitative cell count analyses. mRNA expressions of LXR α, LXR ß, TH, DAT, Nurr1, Pitx3, En1 and Lmx1b were measured by qPCR. Compared with growth factors (GF) treated group, combined use of LXR and GF induced rat BMSCs to TH-expressing cells with 87.42% of efficiency in 6 days of period of induction. LXR agonist alone did not induce the differentiation. Compared with GF alone, combined use of LXR and GF increased expressions of LXR α and LXR ß protein and mRNA and TH, DAT, Nurr1, and Pitx3 mRNA, decreased expressions of En1 and Lmx1b mRNA. Our experimental results indicated that LXR activation leads to improve induction efficiency and shorten induction period of rat BMSCs into DA neuron-like cells through regulating DA development-related genes expressions and that LXR can be considered as a candidate target for drug development to improve differentiation of BMSCs into DA neurons.

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