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1.
Neurotox Res ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499332

RESUMO

Aluminum is a widespread environmental neurotoxicant that can induce Alzheimer's disease (AD)-like damage, such as neuronal injury and impairment of learning and memory. Several studies have shown that aluminum could reduce the synaptic plasticity, but its molecular mechanism remains unclear. In this study, rats were treated with aluminum maltol (Al(mal)3) to establish a toxic animal model and PMA was used to interfere with the expression of PKC. The Morris water maze and open field test were used to investigate the behavioral changes of the rats. Western blotting and RT-PCR were used to detect the expression levels of NMDAR subunits, PKC and CaMKII. The results showed that Al(mal)3 damaged learning and memory function and reduced anxiety in rats. During this process, the expression of PKC was downregulated and it inhibited the expression of NMDARs through the phosphorylation of CaMKII.

2.
Bioresour Technol ; 341: 125841, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34523559

RESUMO

This study explored the effect of potassium ferrate (PF) combined with ultrasound (US) pretreatment on methane generation from sludge by a series of experiments and simulations. Batch experiments showed that the pretreatment of PF coupled with US exhibited positively synergy on the methane yield. And by the pretreatment of 0.05 g/g TSS (total suspended solids) PF cooperated with US (1 W/mL, 25 kHz, 15 min), the methane yield was enhanced from 180.62 ± 3.26 to 228.83 ± 4.76 mL/g VSS (volatile suspended solids). Mechanism studies confirmed that the co-pretreatment of PF and US efficiently promoted sludge disintegration, and the biodegradability of sludge organics was obviously enhanced. Microbial community analysis showed that the functional microorganisms participating in sludge anaerobic digestion were enriched by PF cooperated with US pretreatment, with the total abundance enhanced from 12.96% in the control to 17.96% in PF + US pretreated reactor.


Assuntos
Esgotos , Eliminação de Resíduos Líquidos , Anaerobiose , Reatores Biológicos , Compostos de Ferro , Metano , Compostos de Potássio
3.
Artigo em Inglês | MEDLINE | ID: mdl-34065212

RESUMO

For healthcare manufacturing firms, creating a crisis-prepared product and service portfolio and operational processes is essential for their long-term prosperity. In this paper, we examine how healthcare manufacturing firms cope with the operational disruptions and opportunities associated with the COVID-19 pandemic. We highlight the central role of organizational resilience and examine whether servitization and digitalization can improve the organizational resilience of healthcare manufacturing firms. On the basis of the organizational information processing theory, we suggest that servitization and digitalization can improve the stability and flexibility of operations, which make healthcare manufacturing firms more resilient to the COVID-19 pandemic. The hypotheses were tested using survey data from 163 manufacturing firms located in China. The results indicate that both servitization and digitalization improve the organizational resilience of healthcare manufacturing firms, leading to higher firm growth during the COVID-19 pandemic. Moreover, organizational resilience mediates the impacts of servitization and digitalization on firm growth. Environmental dynamism strengthens the relationship between digitalization and organizational resilience. This study offers new insights for healthcare manufacturing firms to prepare for crisis events and achieve sustainable development in a highly competitive environment.


Assuntos
COVID-19 , Pandemias , China/epidemiologia , Atenção à Saúde , Surtos de Doenças , Humanos , SARS-CoV-2
4.
Medicine (Baltimore) ; 100(20): e25928, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011065

RESUMO

ABSTRACT: Bilateral kidney damage in hypertensive patients is not parallel. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), as a commonly used antihypertensive drug, could protect kidney function and delay its deterioration. Most studies focused on overall renal function, but the researches on split renal function (SRF) are rare. We investigated the effects of ACEI/ARB on the SRF in patients with primary hypertension.Patients with primary hypertension (n = 429; male: 213; female: 216) admitted to our department between January 2014 and December 2016 were included in this study. The glomerular filtration rate (GFR) of split and total renal function were determined using diethylenetriaminepentaacetic acid tagged with 99mTc renal dynamic imaging method. For the same patient, the side with high GFR was considered as higher GFR kidney, whereas that with a low GFR was considered as lower GFR kidney. The split function score (Q value) was utilized to evaluate the differences of bilateral renal function. The patients were divided into 3 groups based on the Q values (Group 1, Q value <5%; Group 2, Q value of 5%-10%; Group 3, Q value ≥10%). All the patients received antihypertensive therapy based on ACEI/ARB. The renal dynamic imaging was performed in the 1-year follow-up to investigate the changes of the SRF.Compared with the baseline level, significant decline was noticed in the serum creatinine (Scr) in Group 2 and Group 3 (P < .05). The cystatin C in Group 3 showed significant decline (P < .05). Compared with the baseline, there was significant decline in the Q value in Group 2, whereas the GFR of lower GFR kidney showed significant increase (P < .05). No statistical differences were noticed in the Q value and split GFR in Group 1 and Group 3 (P > .05).In primary hypertension patients, ACEI/ARB therapy could improve the SRF of lower GFR kidney in the presence of certain differences between the SRF. As a result, the SRF difference was reduced. In case of Q value in a range of 5% to 10%, ACEI/ARB could improve the renal function effectively. It may be significant for the design of antihypertensive drugs.


Assuntos
Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Insuficiência Renal/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste/administração & dosagem , Creatinina/sangue , Cistatina C/sangue , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Humanos , Hipertensão/sangue , Hipertensão/complicações , Rim/diagnóstico por imagem , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/sangue , Insuficiência Renal/diagnóstico , Insuficiência Renal/etiologia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Resultado do Tratamento
5.
Chemosphere ; 278: 130484, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33838418

RESUMO

Aluminium (Al), not essential for biological activities, accumulates in the tissues. It exerts toxic effects on the nervous system, inducing in humans' irreversible cognitive impairment. In this study, a cluster sampling method was used to observe the cognitive function of long-term occupational Al-exposed workers in a large Al factory, and determine the expression of peripheral blood tumour necrosis factor receptor 1 (TNFR1), receptor-interacting protein 1 (RIP1), and RIP3. TNF-alpha, expressed in blood macrophages and microglia, with its receptors TNFR1, TR1 and TR3, enhances the necroptosis of neurons. Additionally, the relationship between the expression of TNFR1, RIP1, and RIP3 in the peripheral blood of long-term occupational Al-exposed workers and changes in their cognitive function was explored. The differences in the distributions of clock drawing test (CDT) scores among the three groups were statistically significant (P < 0.05). The results of correlation analysis showed that RIP1 and RIP3 protein contents were negatively correlated with mini-mental state examination (MMSE) and CDT scores (P < 0.05). Plasma Al content was positively correlated with other biological indicators (P < 0.05), and negatively correlated with MMSE and CDT scores (P < 0.05). Results showed that RIP3 protein had an incomplete mediation effect between plasma Al content and cognitive function. This suggests that Al may affect cognitive function by influencing the expression of TNFR1, RIP1, and RIP3 in the nervous system.


Assuntos
Alumínio , Disfunção Cognitiva , Apoptose , Cognição , Disfunção Cognitiva/induzido quimicamente , Humanos , Necroptose , Necrose , Receptores Tipo I de Fatores de Necrose Tumoral
6.
BMC Cardiovasc Disord ; 21(1): 194, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879070

RESUMO

BACKGROUND: Circulating monocytes and tissue macrophages play complex roles in the pathogenesis of hypertension and the resulting target organ damage. In this study, we observed alterations in the monocyte phenotype and inflammatory state of hypertensive patients with left ventricular hypertrophy (LVH) and studied the effects of irbesartan in these patients. This study might reveal a novel mechanism by which irbesartan alleviates LVH, and it could provide new targets for the prevention and treatment of hypertensive target organ damage. METHODS: CD163 and CD206 expression on monocytes and IL-10 and TNF-α levels in the serum of hypertensive patients with or without LVH and of healthy volunteers were detected. Furthermore, we treated monocytes from the LVH group with different concentrations of irbesartan, and then, CD163, CD206, IL-10 and TNF-α expression was detected. RESULTS: We found, for the first time, that the expression of CD163, CD206 and IL-10 in the LVH group was lower than that in the non-LVH group and healthy control group, but the TNF-α level in the LVH group was significantly higher. Irbesartan upregulated the expression of CD163 and CD206 in hypertensive patients with LVH in a concentration-dependent manner. Irbesartan also increased the expression of IL-10 and inhibited the expression of TNF-α in monocyte culture supernatants in a concentration-dependent manner. CONCLUSIONS: Our data suggest that inflammation was activated in hypertensive patients with LVH and that the monocyte phenotype was mainly proinflammatory. The expression of proinflammatory factors increased while the expression of anti-inflammatory factors decreased. Irbesartan could alter the monocyte phenotype and inflammatory status in hypertensive patients with LVH. This previously unknown mechanism may explain how irbesartan alleviates LVH. Trail registration The study protocols were approved by the Ethical Committee of the Second Affiliated Hospital of Dalian Medical University. Each patient signed the informed consent form.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/prevenção & controle , Irbesartana/farmacologia , Monócitos/efeitos dos fármacos , Idoso , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Pressão Sanguínea , Estudos de Casos e Controles , Células Cultivadas , Feminino , Humanos , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Interleucina-10/sangue , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Monócitos/metabolismo , Fenótipo , Receptores de Superfície Celular/sangue , Receptores Imunológicos/sangue , Fator de Necrose Tumoral alfa/sangue , Função Ventricular Esquerda , Remodelação Ventricular
7.
Neurotox Res ; 39(3): 634-644, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33464538

RESUMO

Aluminum demonstrates clear neurotoxicity and can cause Alzheimer's disease (AD)-like symptoms, including cognitive impairment. One toxic effect of aluminum is a decrease in synaptic plasticity, but the specific mechanism remains unclear. In this study, PC12 cells were treated with Al(mal)3 to construct a toxic cell model. (S)-3,5-Dihydroxyphenylglycine (DHPG), α-methyl-4-carboxyphenylglycine (MCPG), and mGluR1-siRNA were used to interfere with the expression of metabotropic glutamate receptor subtype 1 (mGluR1). Polymerase chain reaction and western blotting were used to investigate the expression of mGluR1, protein kinase C (PKC), and N-methyl-D-aspartate receptor (NMDAR) subunits. ELISA was used to detect PKC enzyme activity. In PC12 cells, mRNA and protein expressions of PKC and NMDAR subunits were inhibited by Al(mal)3. Aluminum may further regulate the expression of NMDAR1 and NMDAR2B through mGluR1 to regulate PKC enzyme activity, thereby affecting learning and memory functions. Furthermore, the results implied that the mGluR1-PKC-NMDAR signaling pathway may predominately involve positive regulation. These findings provide new targets for studying the neurotoxic mechanism of aluminum.

8.
Naunyn Schmiedebergs Arch Pharmacol ; 394(1): 151-164, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32444989

RESUMO

Psychiatric diseases and metabolic disorders frequently cooccur, yet the mechanisms underlying this interaction remain unknown. The aim of this study was to determine the role of glucocorticoid receptor (GR) phosphorylation in the comorbidity of metabolic and psychiatric disorders. Neonatal Sprague-Dawley rats were subcutaneously injected with monosodium glutamate (MSG) every 2 days for 10 days after birth. Metabolic and behavioral tests were performed 12 weeks later. Golgi staining and transmission electron microscopy (TEM) were performed to evaluate synaptic structural plasticity. Changes in GR phosphorylation and the BDNF/TrkB pathway were evaluated by western blotting and immunofluorescence. We found that MSG-treated rats displayed significant metabolic abnormalities accompanied by anxiogenic and depressive behaviors, an altered synaptic ultrastructure and the loss of dendritic spines. The expression of phosphorylated GR was reduced in the brain. Furthermore, a specific agonist of BDNF/TrkB significantly reversed the reduction in GR phosphorylation, as well as the metabolic and behavioral outcomes. These findings indicate that a decrease in BDNF/TrkB pathway-dependent GR phosphorylation is a long-term effect of MSG treatment that may contribute to metabolic and behavioral disturbances.

9.
J Trace Elem Med Biol ; 64: 126700, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33316730

RESUMO

BACKGROUND: Aluminum is an environmental neurotoxin widely exposed to animals and humans. Studies have shown that Alzheimer's disease (AD) is characterized by abnormally phosphorylated tau and Aß deposition, aluminum exposure can lead to abnormal phosphorylated tau and Aß deposition. Numerous epidemiological data and studies have confirmed that ApoEε4 is a risk factor for AD. However, whether there is an interaction effect between aluminum and ApoEε4 has yet to be verified. METHODS: SH-SY5Y cells were exposed with AlCl3 and transfected with ApoEε4 respectively. The experimental groups included the blank control group, the low dose group (200 µM AlCl3), the medium dose group (400 µM AlCl3), the high dose group (800 µM AlCl3), empty plasmid group, ApoEε4 group and 400 µM AlCl3+ApoEε4 group. The cell viability was determined by CCK-8 kit after transfection for 48 h.The contents of total tau proteins, tau-181, tau-231, tau-262, tau-396 and Aß42, were determined by ELISA kit. The interaction between AlCl3 and ApoEε4 was analyzed by factorial design. RESULTS: With the increase of aluminum exposure, SH-SY5Y cell viability decreased, and the expression of the total tau, tau-181, tau-231, tau-262, tau-396 and Aß content increased. The viability of cells transfected with ApoEε4 is significantly lower than control group, and the expressions of total tau, tau-181, tau-231, tau-262, tau-396 and Aß in ApoEε4 transfected cells were significantly higher than control group. The viability of cells treated with AlCl3 plus ApoEε4 was lower than those treated with, either AlCl3, or ApoEε4. The expression of total tau, tau-181, tau-231, tau-262, tau-396 and Aß in the cells treated with AlCl3 plus ApoEε4 were significantly higher than those in other groups (p < 0.05). Moreover, analyzing data based on the factorial design, there was existed an interaction between AlCl3 and ApoEε4 (p < 0.05). CONCLUSION: Al and ApoEε4 gene can cause morphological changes of SH-SY5Y cells, reduce cell activity, and have obvious cytotoxic effects, and increase the phosphorylation levels of tau and the deposition of Aß increases. In the presence of both Al and ApoEε4 genes, the two factors interact with each other and show a synergistic effect.


Assuntos
Cloreto de Alumínio/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Apolipoproteína E4/metabolismo , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Células Tumorais Cultivadas
10.
Exp Ther Med ; 20(6): 170, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33093907

RESUMO

The current study aimed to investigate whether sarpogrelate and rosuvastatin possess anti-arterial injury, and attempted to elucidate the mechanism of action underlying this activity. Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is extensively used to prevent arterial thrombosis; however, its effects on atherosclerosis remain unknown. In the present study, sarpogrelate combined with rosuvastatin or rosuvastatin alone were administered to male ApoE-/- mice fed a high-fat diet (HFD) for 8 weeks. Metabolic parameters in the blood samples were analyzed using an automatic analyzer. Aortic tissues were stained with hematoxylin and eosin for morphological analysis. The expression levels of oxidized-low density lipoprotein (LDL) specific scavenging receptors, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 68 were detected via immunostaining. mRNA expression levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α were determined via reverse transcription-quantitative PCR analysis, while protein expression levels of LOX-1 and phosphor(p)-ERK were determined via western blot analysis. The results demonstrated that sarpogrelate combined with rosuvastatin treatment significantly decreased total cholesterol and LDL cholesterol levels in the serum, and alleviated intimal hyperplasia and lipid deposition, accompanied by decreased inflammatory cell infiltration and lower expression levels of inflammatory cytokines, compared with rosuvastatin monotherapy or HFD treatment. Furthermore, sarpogrelate combined with rosuvastatin treatment significantly decreased the expression levels of LOX-1 and p-ERK. Taken together, these results suggest that the positive effects of sarpogrelate combined with rosuvastatin treatment on aortic injury may be associated with the regulation of the LOX-1/p-ERK signaling pathway. Sarpogrelate and rosuvastatin synergistically decreased aortic damage in ApoE-/- HFD mice, and thus provide a basis for the treatment of aortic injury caused by hyperlipidemia with sarpogrelate.

11.
Transl Psychiatry ; 10(1): 240, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681009

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

12.
Biomed Pharmacother ; 129: 110364, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32531678

RESUMO

Cardiac hypertrophy and remodeling are among the major health challenges facing countries around the world today. Neohesperidin plays an important role in influencing cell apoptosis, cell growth, tumorigenesis and tumor microenvironment, but the mechanism and role of Neohesperidin in cardiac hypertrophy and remodeling caused by Angiotensin II has not been fully elucidated. This study used Angiotensin II to induce cardiac hypertrophy and cardiac remodeling in mice. Echocardiography was used to evaluate cardiac function, H&E and Masson trichrome staining were used to detect myocardial histological changes. Cardiac cell size was determined by WGA staining. The protein content of the signaling pathway was detected by Western blot, and the mRNA expression of fibrosis and hypertrophy markers was detected by qPCR. DHE staining was used to detect oxidative stress. We also observed the effect of Neohesperidin on Ang II-induced NRCMs. The results showed that neohesperidin can significantly inhibit Ang II-induced myocardial contractile dysfunction, cardiac hypertrophy, myocardial fibrosis, myocardial oxidative stress and inflammation. These results suggest that Neohesperidin can alleviate cardiac hypertrophy and remodeling caused by Ang II, and its mechanism may be related to the inhibition of multiple signaling pathways.


Assuntos
Angiotensina II , Hesperidina/análogos & derivados , Hipertrofia Ventricular Esquerda/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica , Hesperidina/farmacologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais
13.
Transl Psychiatry ; 10(1): 181, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513932

RESUMO

Stroke is a leading reason of death and long-term disability, and most studies mainly focus on efforts to protect neurons. However, failed clinical trials suggest that therapies against single target in neurons may not be sufficient and the involvement of endothelial cells and glial cells have been underestimated. Astrocytes are the major source of ApoE in the brain and endothelial cells express high level of ApoE receptors. Thus, ApoE may mediate the interaction between astrocytes and endothelial cells. To address whether and how ApoE-mediated astrocytes-endothelial cells interaction contributes to the pathogenesis of stroke, we used oxygen and glucose deprivation-reoxygenation (OGD-R) as a stroke model and investigated the effects of OGD-R on astrocytes-endothelial cell co-cultures in the current study. We find that OGD-R leads to various damages to endothelial cells, including compromised cell viability, increased ROS level, enhanced caspase activity, and higher apoptotic rate. Meanwhile, mouse astrocytes could secrete ApoE to activate PI3K/eNOS signaling in endothelial cells to prevent OGD-R induced injuries. In addition, OGD-R induces down-regulation of ApoE in astrocyte-endothelial cell co-cultures while melatonin restores astrocytic ApoE expression via pCREB pathway and protects endothelial cell in OGD-R treated co-cultures. Our study provides evidence that astrocytes could protect endothelial cells via ApoE in OGD-R condition and Melatonin could induce ApoE expression to protect endothelial cells.


Assuntos
Glucose , Melatonina , Animais , Apolipoproteínas E , Astrócitos , Células Cultivadas , Células Endoteliais , Melatonina/farmacologia , Camundongos , Oxigênio
14.
Environ Toxicol Pharmacol ; 78: 103406, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32438325

RESUMO

The main symptoms of Alzheimer's disease (AD) is the loss of learning and memory ability, of which biological basis is synaptic plasticity. Aluminium has been found to cause changes in synaptic plasticity, but its molecular mechanism was unclear. In this study, Sprague-Dawley rats were injected with aluminium maltol (Al(mal)3) through the lateral ventricle to establish an AD-like model. Y-maze, electrophysiological measurements, Golgi staining, scanning electron microscopy, quantitative real-time polymerase chain reaction, and western blot techniques were used to investigate regulation of the metabolic glutamate receptor 1 (mGluR1) in synaptic plasticity impairment induced by Al(mal)3. The results showed that Al(mal)3 inhibited the induction and maintenance of long-term potentiation in the hippocampal CA1 region. During this process, the expression of mGluR1 was up-regulated and it inhibited the expression and phosphorylation of the N-methyl-D-aspartic acid receptors (NMDARs). This mainly affected NMDAR1 and NMDAR2B but did not affect protein kinase C expression.


Assuntos
Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Pironas/toxicidade , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Hipocampo/fisiologia , Hipocampo/ultraestrutura , Masculino , Microscopia Eletrônica de Transmissão , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Proteína Quinase C/metabolismo , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
15.
Biochem Biophys Res Commun ; 526(3): 553-559, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32245616

RESUMO

BACKGROUND: Inflammasome activation and followed by the release of proinflammatory cytokines play a pivotal role in the development and progression of depression. However, the involvement of gasdermin D (GSDMD)-mediated pyroptosis in inflammasome-associated depression has not been studied. The present study aimed to determine the involvement of pyroptosis in the development of depression. METHODS: The rat depressive model was established by the administration of monosodium glutamate (MSG) in postnatal rats. Minocycline (an anti-inflammatory agent) and VX-765 (a specific inhibitor of caspase-1) were given as intervention treatments when rats were two-month-old. Rat depressive behaviors were evaluated by behavioral tests, including open field test, sucrose preference test, and forced swim test. Rat hippocampi were collected for western blotting and immunofluorescence examination. RESULTS: MSG administration induced depressive-like behavior in rats. MSG upregulated protein presences of caspase-1, GSDMD, interleukin-1ß (IL-1ß), interleukin-18 (IL-18), NLR pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), high mobility group box 1 protein (HMGB1), and the receptor for advanced glycation end products (RAGE) in the hippocampus. Protein presences of HMGB1, NLRP3 and GSDMD were upregulated in Olig2+ oligodendrocytes in the hippocampus. The data suggest that both HMGB1/RAGE/NLRP3 signalings and GSDMD-dependent pyroptosis were activated. Both minocycline and VX-765 treatments improved depressive-like behaviors. Minocycline treatment significantly reduced both HMGB1/RAGE/NLRP3 inflammasome signalings and GSDMD-dependent pyroptosis. VX-765 downregulated GSDMD-dependent pyroptosis, but not HMGB1/RAGE signalings, indicating that GSDMD-dependent pyroptosis is a key player in the progress of depression. CONCLUSION: In rats hippocampus, NLRP3 inflammasome activates GSDMD mediated-pyroptosis in the hippocampus of MSG-induced depressive rats.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Inflamassomos/metabolismo , Minociclina/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Transtorno Depressivo/induzido quimicamente , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Glutamato de Sódio
16.
Neurotox Res ; 37(4): 835-846, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31721047

RESUMO

The brain is one of organs vulnerable to aluminum insult. Aluminum toxicity is involved in neurobehavioral deficit, neuronal cell dysfunction, and death. The aim of this study are as follows: (1) to evaluate the repairing efficiency of Necrostatin-1 (Nec-1), a cell death inhibitor, and Z-VAD-FMK, a pan-caspase inhibitor, on Al-induced neurobehavioral deficit and neuronal cell death, in order to evidence the cell death inducing ability of aluminum, and (2) to primarily explore the possibility of treating neuronal cell loss-related disease, such as Alzheimer's disease, with Nec-1 and Z-VAD in Al-induced dementia animal model. We found Nec-1 and Z-VAD-FMK alone or in combination could reduce aluminum-induced learning and memory impairment in mice. Pathohistological results indicated that Nec-1 and Z-VAD-FMK can decrease Al-induced neuronal death cell. In addition, some cell death-associated proteins in cell death signal pathway were inhibited by Nec-1 and Z-VAD-FMK in Al-exposed mice. In conclusions, Nec-1 and Z-VAD-FMK can repair the injury of learning and memory induced by aluminum in mice. Furthermore, Nec-1 was more obvious to repair the injury of learning and memory function compared with Z-VAD-FMK. Nec-1 and Z-VAD-FMK can repair the Al-induced morphological injury of cell and reduce the amounts of dead cell, and repairing effects were more significant at higher doses. The effect of Nec-1 was stronger than Z-VAD-FMK, though their mechanism was different. The combination of them had the strongest effect. Our study evidenced Al-induced neuronal necroptosis and apoptosis existing in animal model and suggested potential therapeutic effects of Nec-1 and Z-VAD-FMK on neuronal cell death in neurodegenerative diseases.


Assuntos
Alumínio/toxicidade , Clorometilcetonas de Aminoácidos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Imidazóis/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Relação Dose-Resposta a Droga , Reação de Fuga/efeitos dos fármacos , Reação de Fuga/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos
17.
Phytother Res ; 33(9): 2329-2336, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31243840

RESUMO

Bilobalide (BB), a constituent of the Ginkgo biloba extract, is a neuroprotective agent with multiple mechanisms of action. To further explore the potential therapeutic effects of BB in stroke, we investigated its effects on primary astrocytes using the oxygen and glucose deprivation-reoxygenation (OGD-R) model. Cell viability was measured by lactate dehydrogenase release assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell death was measured by annexin 5 conjgated with fluorescein isothiocyanate (V-FITC) assay, and reactive oxygen species (ROS) production was measured by 2',7'-Dichlorodihydrofluorescein Diacetate (DCFH-DA) probe. Manganese superoxide dismutase (MnSOD) expression was measured by western blot and immunofluorescence. Mitochondrial membrane potential was monitored using JC-1 staining. Our results show that OGD-R downregulated MnSOD and impaired mitochondrial function, which further enhanced ROS production in primary astrocytes. As a result, cell viability was compromised, and cell death increased. BB treatment protected astrocytes from those injuries mainly by restoring MnSOD level as MnSOD inhibitor abolished the effects of BB. In conclusion, we demonstrated that OGD-R induced astrocytic injury, but BB increased the expression of MnSOD, the ROS scavenger, to reverse the exacerbated astrocytic injury.


Assuntos
Astrócitos/efeitos dos fármacos , Ciclopentanos/uso terapêutico , Furanos/uso terapêutico , Ginkgolídeos/uso terapêutico , Glucose/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Oxigênio/metabolismo , Extratos Vegetais/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Ciclopentanos/farmacologia , Furanos/farmacologia , Ginkgolídeos/farmacologia , Humanos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia
18.
Mol Ther Nucleic Acids ; 16: 302-312, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959405

RESUMO

ß-amyloid (Aß) plays an essential role in the pathogenesis of Alzheimer's disease (AD). Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is indispensable for Aß production, and knockout of BACE1 has no overt phenotypes in mouse. Thus, fine modulation of BACE1 may be a safe and effective treatment for AD patients. However, the large active site of BACE1 makes it challenging to target BACE1 with classical small-molecule inhibitors. DNA aptamer can have high affinity and specificity against diverse targets, and it provides an alternative strategy to target BACE1. In this study, we used a novel cell-systematic evolution of ligands by exponential enrichment (SELEX) strategy to select specific DNA aptamers optimized to target BACE1 under physiological status. After 17 rounds of selection, we identified two DNA aptamers against BACE1: BI1 and BI2. The identified aptamers interacted with BACE1 in pull-down assay, inhibited BACE1 activity in in vitro fluorescence resonance energy transfer (FRET) assay and HEK293-APP stable cell line, reduced Aß in the culture medium of HEK293-amyloid protein precursor (APP) stable cell line and APP-PS1 primary cultured neurons, and rescued Aß-induced neuronal deficiency in APP-PS1 primary cultured neurons. In contrast, the identified aptamers had no effect on α- or γ-secretase. In addition, cholesteryl tetraetylene glycol (TEG) modification further improved the potency of the identified aptamers. Our study suggests that it is feasible and effective to target BACE1 with DNA aptamers, and the therapeutic potential of the identified aptamers deserves further investigation.

19.
Artigo em Inglês | MEDLINE | ID: mdl-30498516

RESUMO

Objects: Sheng-Di-Da-Huang Decoction was used as an effective hemostatic agent in ancient China. However, its therapeutic mechanism is still not clear. Inflammatory injury plays a critical role in ICH-induced secondary brain injury. After hemolysis, hematoma components are released, inducing microglial activation via TLR4, which initiates the activation of transcription factors (such as NF-κB) to regulate expression of proinflammatory cytokine genes. This study aimed to verify the anti-inflammatory effects of Sheng-Di-Da-Huang Decoction on ICH rats. Materials and Methods: Intracerebral hemorrhage was induced by injection of bacterial collagenase (0.2 U) in rats. Neurological deficits, brain water content, Evans blue extravasation, expression of TLR4, NF-κB, Iba-1 positive cells (activated microglia), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) were examined 1, 3, 7, and 14 days after collagenase injection. MR images were also studied. Results: Sheng-Di-Da-Huang Decoction remarkably improved neurological function, reduced brain water content as well as Evans blue extravasation, downregulated expression of TLR4, NF-κB, TNF-α, and IL-1ß, and inhibited microglial activation. Conclusions: Sheng-Di-Da-Huang Decoction reduced inflammation reaction after ICH through inhibited inflammation expressed in microglia.

20.
Sci Rep ; 8(1): 9886, 2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29959371

RESUMO

As a classical prescription of Traditional Chinese medicine, the Jia-Jian-Di-Huang-Yin-Zi (JJDHYZ) decoction has long been used to treat movement disorders. The present study evaluated the effects of JJDHYZ on dopaminergic (DA) neurons and their survival-enhancing microenvironment as well as the possible mechanisms involved using a mouse model of Parkinson's disease. In MPTP-lesioned mice, a high dosage of JJDHYZ (34 g/kg/day) attenuated the loss of DA neurons, reversed the dopamine depletion, and improved the expression of glial-derived neurotrophic factor (GDNF) compared to the untreated model group. JJDHYZ also protected the ultrastructure of the blood-brain barrier (BBB) and tight junction proteins by inhibiting the activation of microglia and astrocytes besides the increase in three types of matrix metalloproteinases in the substantia nigra. In conclusion, the JJDHYZ-high dosage (JJDHYZ-H) group exhibited the neuroprotection of DA neurons, and the underlying mechanism may be related to the survival-enhancing microenvironment of the DA neurons.


Assuntos
Microambiente Celular/efeitos dos fármacos , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Antioxidantes/metabolismo , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/ultraestrutura , Quimiocina CCL2/metabolismo , Quimiocina CCL4/metabolismo , Claudina-5/metabolismo , Neurônios Dopaminérgicos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Interleucina-23/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Ocludina/metabolismo , Permeabilidade/efeitos dos fármacos
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