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1.
Genome Med ; 14(1): 46, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35501841

RESUMO

BACKGROUND: Natural killer (NK) cells are innate lymphoid cells that mediate antitumour and antiviral responses. However, very little is known about how ageing influences human NK cells, especially at the single-cell level. METHODS: We applied single-cell sequencing (scRNA-seq) to human lymphocytes and NK cells from 4 young and 4 elderly individuals and then analysed the transcriptome data using Seurat. We detected the proportion and phenotype of NK cell subsets in peripheral blood samples from a total of 62 young and 52 elderly healthy donors by flow cytometry. We also used flow cytometry to examine the effector functions of NK cell subsets upon IFN-α/IL-12+IL-15/K562/IL-2 stimulation in vitro in peripheral blood samples from a total of 64 young and 63 elderly healthy donors. We finally studied and integrated single-cell transcriptomes of NK cells from 15 young and 41 elderly COVID-19 patients with those from 12 young and 6 elderly healthy control individuals to investigate the impacts of ageing on NK cell subsets in COVID-19 disease. RESULTS: We discovered a memory-like NK subpopulation (NK2) exhibiting the largest distribution change between elderly and young individuals among lymphocytes. Notably, we discovered a unique NK subset that was predominantly CD52+ NK2 cells (NK2.1). These memory-like NK2.1 cells accumulated with age, exhibited proinflammatory characteristics, and displayed a type I interferon response state. Integrative analyses of a large-cohort COVID-19 dataset and our datasets revealed that NK2.1 cells from elderly COVID-19 patients are enriched for type I interferon signalling, which is positively correlated with disease severity in COVID-19. CONCLUSIONS: We identified a unique memory-like NK cell subset that accumulates with ageing and correlates with disease severity in COVID-19. Our results identify memory-like NK2.1 cells as a potential target for developing immunotherapies for infectious diseases and for addressing age-related dysfunctions of the immune system.


Assuntos
COVID-19 , Transcriptoma , Idoso , Envelhecimento/genética , Humanos , Imunidade Inata , Células Matadoras Naturais/metabolismo , Índice de Gravidade de Doença
2.
Nat Methods ; 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35577954

RESUMO

Spatial transcriptomics approaches have substantially advanced our capacity to detect the spatial distribution of RNA transcripts in tissues, yet it remains challenging to characterize whole-transcriptome-level data for single cells in space. Addressing this need, researchers have developed integration methods to combine spatial transcriptomic data with single-cell RNA-seq data to predict the spatial distribution of undetected transcripts and/or perform cell type deconvolution of spots in histological sections. However, to date, no independent studies have comparatively analyzed these integration methods to benchmark their performance. Here we present benchmarking of 16 integration methods using 45 paired datasets (comprising both spatial transcriptomics and scRNA-seq data) and 32 simulated datasets. We found that Tangram, gimVI, and SpaGE outperformed other integration methods for predicting the spatial distribution of RNA transcripts, whereas Cell2location, SpatialDWLS, and RCTD are the top-performing methods for the cell type deconvolution of spots. We provide a benchmark pipeline to help researchers select optimal integration methods to process their datasets.

5.
Signal Transduct Target Ther ; 6(1): 376, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34737296

RESUMO

Patients with chronic hepatitis B (CHB) undergoing interferon (IFN)-α-based therapies often exhibit a poor HBeAg serological response. Thus, there is an unmet need for new therapies aimed at CHB. This study comprised two clinical trials, including 130 CHB patients, who were treatment-naïve; in the first, 92 patients were systematically analyzed ex vivo for interleukin-2 receptor (IL-2R) expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-α therapy had failed, were treated with or without low-dose IL-2 for 24 weeks. We then examined the hepatitis B virus (HBV)-specific CD8+ T-cell response and the clinical outcome, in these patients. Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders, we observed a decrease in CD25 expression on their CD4+ T cells, suggesting that IFN-α therapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells (Tregs). Following sequential therapy with IL-2, we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1 (PD-1) expression. In addition, sequential IL-2 administration rescued effective immune function, involving signal transducer and activator of transcription 1 (STAT1) activation. Importantly, IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+ T cells, which translated into improved clinical outcomes, including HBeAg seroconversion, among the non-responder CHB patients. Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.


Assuntos
Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Subunidade alfa de Receptor de Interleucina-2/genética , Interleucina-2/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Adolescente , Adulto , Idoso , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/sangue , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Humanos , Fator Gênico 3 Estimulado por Interferon/genética , Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/sangue , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Linfócitos T Reguladores/efeitos dos fármacos , Adulto Jovem
6.
Cell Rep ; 37(1): 109793, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34587478

RESUMO

The mortality risk of coronavirus disease 2019 (COVID-19) patients has been linked to the cytokine storm caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the inflammatory responses shared between COVID-19 and other infectious diseases that feature cytokine storms may therefore help in developing improved therapeutic strategies. Here, we use integrative analysis of single-cell transcriptomes to characterize the inflammatory signatures of peripheral blood mononuclear cells from patients with COVID-19, sepsis, and HIV infection. We identify ten hyperinflammatory cell subtypes in which monocytes are the main contributors to the transcriptional differences in these infections. Monocytes from COVID-19 patients share hyperinflammatory signatures with HIV infection and immunosuppressive signatures with sepsis. Finally, we construct a "three-stage" model of heterogeneity among COVID-19 patients, related to the hyperinflammatory and immunosuppressive signatures in monocytes. Our study thus reveals cellular and molecular insights about inflammatory responses to SARS-CoV-2 infection and provides therapeutic guidance to improve treatments for subsets of COVID-19 patients.


Assuntos
COVID-19/sangue , COVID-19/imunologia , Infecções por HIV/sangue , Leucócitos Mononucleares/metabolismo , SARS-CoV-2/imunologia , Sepse/sangue , Transcriptoma , COVID-19/virologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Análise de Dados , Conjuntos de Dados como Assunto , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Inflamação/sangue , Leucócitos Mononucleares/imunologia , Sepse/imunologia , Análise de Célula Única
7.
Cells ; 10(7)2021 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-34359979

RESUMO

Central nervous system (CNS) diseases are currently one of the major health issues around the world. Most CNS disorders are characterized by high oxidative stress levels and intense inflammatory responses in affected tissues. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein, plays a significant role in anti-inflammatory, antibacterial, antiviral, reactive oxygen species (ROS) modulator, antitumor immunity, and anti-apoptotic processes. Previous studies have shown that Lf is abnormally expressed in a variety of neurological diseases, especially neurodegenerative diseases. Recently, the promotion of neurodevelopment and neuroprotection by Lf has attracted widespread attention, and Lf could be exploited both as an active therapeutic agent and drug nanocarrier. However, our understanding of the roles of Lf proteins in the initiation or progression of CNS diseases is limited, especially the roles of Lf in regulating neurogenesis. This review highlights recent advances in the understanding of the major pharmacological effects of Lf in CNS diseases, including neurodegenerative diseases, cerebrovascular disease, developmental delays in children, and brain tumors.


Assuntos
Doenças do Sistema Nervoso Central/metabolismo , Lactoferrina/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/patologia , Criança , Desenvolvimento Infantil , Humanos , Transtornos do Neurodesenvolvimento/patologia
8.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202166

RESUMO

Copper (Cu) has been implicated in the progression of Alzheimer's disease (AD), and aggregation of Cu and amyloid ß peptide (Aß) are considered key pathological features of AD. Metal chelators are considered to be potential therapeutic agents for AD because of their capacity to reduce metal ion-induced Aß aggregation through the regulation of metal ion distribution. Here, we used phage display technology to screen, synthesize, and evaluate a novel Cu(II)-binding peptide that specifically blocked Cu-triggered Aß aggregation. The Cu(II)-binding peptide (S-A-Q-I-A-P-H, PCu) identified from the phage display heptapeptide library was used to explore the mechanism of PCu inhibition of Cu2+-mediated Aß aggregation and Aß production. In vitro experiments revealed that PCu directly inhibited Cu2+-mediated Aß aggregation and regulated copper levels to reduce biological toxicity. Furthermore, PCu reduced the production of Aß by inhibiting Cu2+-induced BACE1 expression and improving Cu(II)-mediated cell oxidative damage. Cell culture experiments further demonstrated that PCu had relatively low toxicity. This Cu(II)-binding peptide that we have identified using phage display technology provides a potential therapeutic approach to prevent or treat AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Proteínas de Transporte/metabolismo , Cobre/metabolismo , Peptídeos/metabolismo , Agregados Proteicos , Mapeamento de Interação de Proteínas , Sequência de Aminoácidos , Peptídeos beta-Amiloides/química , Animais , Proteínas de Transporte/química , Técnicas de Visualização da Superfície Celular , Humanos , Camundongos , Oxirredução , Estresse Oxidativo , Peptídeos/química , Agregação Patológica de Proteínas/metabolismo , Mapeamento de Interação de Proteínas/métodos
9.
ACS Chem Neurosci ; 12(12): 2110-2121, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34042421

RESUMO

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disease with few disease-modifying treatments. A variety of peptide/protein drugs have neuroprotective effects, which brings new hope for the treatment of AD. However, the application of these drugs is limited because of their low specificity and difficulty in crossing the blood-brain barrier. Herein, using the phage display technology, we identified the Aß oligomer binding peptide (KH) and the brain targeting peptide (IS). We combined these peptides to develop a bifunctional nanoparticle (IS@NP/KH) for the delivery of Aß1-42 oligomer binding peptide into the brain. Intranasal administration of IS@NP/KH significantly attenuated the cognitive and behavioral deficits and reduced the Aß deposition in the brain of an AD animal model (APPswe/PS 1d9 double-transgenic mice). Our results suggest that intranasal IS@NP/KH administration could be a novel therapeutic strategy for the treatment of AD.


Assuntos
Doença de Alzheimer , Nanopartículas , Doenças Neurodegenerativas , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Agregados Proteicos
10.
Front Aging Neurosci ; 13: 660249, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935689

RESUMO

Alzheimer's disease (AD) is a type of neurodegenerative disease that is associated with the accumulation of amyloid plaques. Increasing non-amyloidogenic processing and/or manipulating amyloid precursor protein signaling could reduce AD amyloid pathology and cognitive impairment. D-penicillamine (D-Pen) is a water-soluble metal chelator and can reduce the aggregation of amyloid-ß (Aß) with metals in vitro. However, the potential mechanism of D-Pen for treating neurodegenerative disorders remains unexplored. In here, a novel type of chitosan-based hydrogel to carry D-Pen was designed and the D-Pen-CS/ß-glycerophosphate hydrogel were characterized by scanning electron microscopy and HPLC. Behavior tests investigated the learning and memory levels of APP/PS1 mice treated through the D-Pen hydrogel nasal delivery. In vivo and in vitro findings showed that nasal delivery of D-Pen-CS/ß-GP hydrogel had properly chelated metal ions that reduced Aß deposition. Furthermore, D-Pen mainly regulated A disintegrin and metalloprotease 10 (ADAM10) expression via melatonin receptor 1 (MTNR1α) and the downstream PKA/ERK/CREB pathway. The present data demonstrated D-Pen significantly improved the cognitive ability of APP/PS1 mice and reduced Aß generation through activating ADAM10 and accelerating non-amyloidogenic processing. Hence, these findings indicate the potential of D-Pen as a promising agent for treating AD.

11.
BMC Biol ; 19(1): 79, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863328

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that involves a variety of cell types. However, how the epigenetic dysregulations of peripheral immune cells contribute to the pathogenesis of RA still remains largely unclear. RESULTS: Here, we analysed the genome-wide active DNA regulatory elements of four major immune cells, namely monocytes, B cells, CD4+ T cells and CD8+ T cells, in peripheral blood of RA patients, osteoarthritis (OA) patients and healthy donors using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq). We found a strong RA-associated chromatin dysregulation signature in monocytes, but no other examined cell types. Moreover, we found that serum C-reactive protein (CRP) can induce the RA-associated chromatin dysregulation in monocytes via in vitro experiments. And the extent of this dysregulation was regulated through the transcription factor FRA2. CONCLUSIONS: Together, our study revealed a CRP-induced pathogenic chromatin dysregulation signature in monocytes from RA patients and predicted the responsible signalling pathway as potential therapeutic targets for the disease.


Assuntos
Artrite Reumatoide , Cromatina , Artrite Reumatoide/genética , Linfócitos T CD8-Positivos , Epigenômica , Humanos , Monócitos
12.
Cell ; 184(7): 1895-1913.e19, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33657410

RESUMO

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.


Assuntos
COVID-19/imunologia , Megacariócitos/imunologia , Monócitos/imunologia , RNA Viral , SARS-CoV-2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China , Estudos de Coortes , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/isolamento & purificação , Análise de Célula Única , Transcriptoma/imunologia , Adulto Jovem
13.
Cell Death Dis ; 12(1): 81, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441545

RESUMO

Iron deposition is present in main lesion areas in the brains of patients with Parkinson's disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.


Assuntos
Microglia/metabolismo , Substância Negra/metabolismo , alfa-Sinucleína/administração & dosagem , Administração Intranasal , Animais , Humanos , Macaca fascicularis , Masculino , Microglia/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Substância Negra/efeitos dos fármacos
14.
Cell Discov ; 7(1): 1, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33390590

RESUMO

Maintaining homeostasis of the decidual immune microenvironment at the maternal-fetal interface is essential for placentation and reproductive success. Although distinct decidual immune cell subpopulations have been identified under normal conditions, systematic understanding of the spectrum and heterogeneity of leukocytes under recurrent miscarriage in human deciduas remains unclear. To address this, we profiled the respective transcriptomes of 18,646 primary human decidual immune cells isolated from patients with recurrent pregnancy loss (RPL) and healthy controls at single-cell resolution. We discovered dramatic differential distributions of immune cell subsets in RPL patients compared with the normal decidual immune microenvironment. Furthermore, we found a subset of decidual natural killer (NK) cells that support embryo growth were diminished in proportion due to abnormal NK cell development in RPL patients. We also elucidated the altered cellular interactions between the decidual immune cell subsets in the microenvironment and those of the immune cells with stromal cells and extravillous trophoblast under disease state. These results provided deeper insights into the RPL decidual immune microenvironment disorder that are potentially applicable to improve the diagnosis and therapeutics of this disease.

16.
ACS Chem Neurosci ; 11(24): 4240-4253, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33284003

RESUMO

Tauopathies refer to a group of neurodegenerative disorders caused by the accumulation of insoluble hyperphosphorylated Tau protein in the brain. The inhibition and interruption of Tau aggregation are considered important strategies to ameliorate the neurodegenerative process. Previous work has shown that hexapeptide 306VQIVYK311 (PHF6) located in the repeat domain 3 of Tau protein drives Tau aggregation and itself forms a ß-sheet structure similar to those of Tau-oligomers and neurofibrillary tangles (NFTs). In this study, a mirror image phage display technology was used to screen protease-resistant and low-immunogenic d-enantiomeric peptides for their capacity to inhibit Tau aggregation. Following the preparation of d-enantiomeric PHF6 fibrils and M13 phage peptide library biopanning, 7 sets of high specificity peptides were obtained. Through ELISA and competition inhibition assays, we chose a highly specific peptide p-NH with the sequence N-I-T-M-N-S-R-R-R-R-N-H. The molecular docking results showed that p-NH interacted with PHF6 fibrils mainly through van der Waals forces and hydrogen bonding and could inhibit PHF6 aggregation in a d-configuration and concentration-dependent manner. In vitro, p-NH prohibited the formation of PHF6 fibrils and was able to enter into mouse neuroblastoma N2a cells (N2a cells) to inhibit Tau hyperphosphorylation and aggregation. Intranasal administration of p-NH reduced NFTs and improved the cognitive ability of TauP301S transgenic mice. These findings represent a straightforward methodology to find therapeutic peptides with potential applications in tauopathies.


Assuntos
Emaranhados Neurofibrilares , Proteínas tau , Animais , Camundongos , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Peptídeos , Proteínas Repressoras , Proteínas tau/genética
17.
Nat Commun ; 11(1): 5843, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203843

RESUMO

Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell-cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.


Assuntos
Cromatina/metabolismo , Células de Langerhans/patologia , Escleroderma Sistêmico/patologia , Pele/patologia , Estudos de Casos e Controles , Comunicação Celular , Cromatina/genética , Epigenoma , Fibrose , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Pele/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição
18.
Scanning ; 2020: 6685299, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33214800

RESUMO

Shale ash (SA) as the carrier, the ratio of Cu to Ni in the Cu-Ni transition metal salt being, respectively, 1 : 0, 2 : 1, 1 : 1, 1 : 2, 0 : 1, the double transition metal salt catalyst (CumNin/SA) was prepared to explore the effect of such catalysts on the pyrolysis behavior and characteristics of Fushun OS. The research results show that the temperature (T max) corresponding to the maximum weight loss rate decreased by 12.9°C, 4.0°C, and 3.6°C; and the apparent activation energy decreased by 35.2%, 33.9%, and 29.6%, respectively, after adding catalysts Cu0Ni1/SA in pyrolysis. The addition of Cu0Ni1/SA and Cu2Ni1/SA further improves the shale oil (SO) yield of 3.5% and 3.1%, respectively. Cu0Ni1/SA produces more aromatic hydrocarbons, which, however, weakens the stability of SO and is of toxicity in use. After analyzing the pyrolysis product-semicoke (SC) and SO-with ATR-FTIR and GC-MS methods, CumNin/SA promotes the secondary cracking and aromatization of OS pyrolysis, increasing the content of the compound of olefins and aromatics in SO, and hastening the decomposition of long-chain aliphatic hydrocarbons to short-chain aliphatic hydrocarbons.

19.
Medicine (Baltimore) ; 99(47): e23244, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33217843

RESUMO

BACKGROUND: Diabetic neuropathic pain (DNP) is a common complication of diabetes mellitus, it severely affects the quality of life of Diabetic patients. Acupuncture is proofed to have favorable effects in treating DNP, however, evidence needs to be gathered and interpreted. We will make a comprehensive review of clinical trials concerning acupuncture in treating DNP and do meta-analysis if possible. METHOD: The following databases will be searched from the inception to September 2020: PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Wan-Fang Database, and Chinese Scientific Journal Database. RCTs that evaluated acupuncture for patients with DNP will be included. The primary outcome will be patient-reported pain intensity using validated scales or verbal reporting. The secondary outcomes including the Toronto clinical scoring system, Sensory Nerve Conduction Velocity, Motor Nerve Conduction Velocity, and quality of life. The study selection, data extraction, and study quality evaluation will be performed independently by 2 researchers. A meta-analysis will be performed using RevMan V5.3 statistical software if possible; otherwise, descriptive analysis or subgroup analysis will be conducted. The quality of evidence for outcomes will be assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: This study will evaluate the effect and safety of acupuncture in treating DNP. CONCLUSIONS: The evidence we generated from the present study will provide more options for DNP management in clinical practice. SYSTEMATIC REVIEW REGISTRATION: INPLASY202090043.


Assuntos
Terapia por Acupuntura , Neuropatias Diabéticas/terapia , Neuralgia/terapia , Neuropatias Diabéticas/complicações , Humanos , Metanálise como Assunto , Neuralgia/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto
20.
Free Radic Biol Med ; 161: 139-149, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33068737

RESUMO

Vitamin D (VD) deficiency is prevalent among aging people and Alzheimer's disease (AD) patients. However, the roles of VD deficiency in the pathology of AD remain largely unexplored. In this study, APP/PS1 mice were fed a VD-deficient diet for 13 weeks to evaluate the effects of VD deficiency on the learning and memory functions and the neuropathological characteristics of the mice. Our study revealed that VD deficiency accelerated cognitive impairment in the APP/PS1 mice. Mechanistic studies revealed that VD deficiency promoted glial activation and increased inflammatory factor secretion. Furthermore, VD deficiency increased the production and deposition of Aß by elevating the expression levels of amyloid precursor protein (APP) and ß-site APP cleavage enzyme 1 (BACE1). In addition, VD deficiency increased the phosphorylation of Tau at Thr181, Thr205 and Ser396 by increasing the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3α/ß (GSK3α/ß) and promoted synaptic dystrophy and neuronal loss. All these effects of VD deficiency may be ascribed to enhanced oxidative stress via the downregulation of superoxide dismutase 1 (SOD1), glutathione peroxidase 4 (GPx4) and cystine/glutamate exchanger (xCT). Taken together, our data suggest that VD deficiency exacerbates Alzheimer-like pathologies via promoting inflammatory stress, increasing Aß production and elevating Tau phosphorylation by decreasing antioxidant capacity in the brains of APP/PS1 mice. Hence, rescuing the VD status of AD patients should be taken into consideration during the treatment of AD.


Assuntos
Doença de Alzheimer , Deficiência de Vitamina D , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Antioxidantes , Ácido Aspártico Endopeptidases , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Presenilina-1 , Proteínas tau/genética
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