Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35
Filtrar
1.
Shock ; 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39194225

RESUMO

BACKGROUND: Acute lung injury (ALI) is a severe condition characterized by a high mortality rate, driven by an uncontrolled inflammatory response. Emerging evidence has underscored the crucial role of the ubiquitin system in ALI. However, due to their vast number, the specific functions of individual ubiquitination regulators remain unclear. MATERIALS AND METHODS: In this study, we established human lung organoids (HLOs) derived from human embryonic stem cells and subjected them to lipopolysaccharide (LPS) treatment to induce an inflammatory response, mimicking ALI. Subsequently, we detected the expression of inflammatory cytokines, including tumour necrosis factor alpha (TNF-α), interleukin 6, interleukin 18 (IL-18), and interleukin-1ß (IL-1ß), by qPCR experiments. We also detected changes in the mRNA expression of several USPs before and after HLOs treatment and thus screened for USPs that had significant changes in HLOs after LPS stimulation. After screening for USP, we silenced the USP in HLOs and then subjected them to LPS treatment, and TNF-α, IL-6, IL-18, and IL-1ß expressions were detected using qPCR assays. Meanwhile, Western blot was used to detect changes in NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and apoptosis-associated Speck-like protein containing a CARD (ASC) protein level in HLOs. RESULTS: Through screening the expression of 40 ubiquitin-specific proteases (USPs), which are responsible for removing ubiquitination, we identified several USPs that exhibited differential expression in LPS-treated HLOs compared to untreated HLOs. Notably, USP31 emerged as the most significantly upregulated USP, and the knockdown of USP31 markedly attenuated the inflammatory response of HLOs to LPS treatment. CONCLUSIONS: USP31 may play a facilitating role in the inflammatory response during ALI.

2.
Ren Fail ; 46(2): 2368088, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39108151

RESUMO

BACKGROUND: In various disease contexts, magnesium abnormalities are associated with acute kidney injury (AKI) incidence. However, this association remains unclear and has not been systematically investigated in patients with cirrhosis. Hence, we aimed to elucidate the association between admission serum magnesium levels and AKI incidence in intensive care unit (ICU)-admitted cirrhotic patients. METHODS: A retrospective cohort study was conducted using MIMIC-IV2.2 data, focusing on critically ill patients with cirrhosis. We employed univariable and multivariable logistic regression and restricted cubic spline analyses to robustly address our research objectives. To further substantiate the findings, subgroup and sensitivity analyses were also conducted. RESULTS: Among the 3,228 enrolled ICU-admitted cirrhotic patients, 34.4% were female, and the overall AKI incidence was 68.6% (2,213/3,228). Multivariable logistic regression analysis revealed an independent relationship between elevated serum magnesium levels and increased AKI risk (OR = 1.55 [95% CI = 1.15-2.09], p = 0.004). Compared with individuals with serum magnesium levels < 1.6 mg/dL, individuals with serum magnesium levels in Q2 (1.6-2.6 mg/dL) and Q3 (≥2.6 mg/dL) had adjusted ORs for AKI of 1.89 (95% CI = 1.34-2.65, p < 0.001) and 2.19 (95% CI = 1.27-3.75, p = 0.005), respectively. The restricted cubic spline analysis revealed that AKI risk increased linearly with increasing serum magnesium levels. Subgroup analysis revealed that the association between serum magnesium levels and AKI incidence was remarkably stable in subgroup analysis (all Pinteraction >0.05). CONCLUSIONS: High serum magnesium concentrations were significantly associated with an increased AKI risk in ICU-admitted patients with cirrhosis. Further randomized trials are needed to confirm this association.


Assuntos
Injúria Renal Aguda , Unidades de Terapia Intensiva , Cirrose Hepática , Magnésio , Humanos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Feminino , Magnésio/sangue , Estudos Retrospectivos , Masculino , Pessoa de Meia-Idade , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Unidades de Terapia Intensiva/estatística & dados numéricos , Incidência , Idoso , Fatores de Risco , Estado Terminal , Modelos Logísticos , Bases de Dados Factuais , Adulto
3.
Neurosci Res ; 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39214315

RESUMO

This study aimed to elucidate the expression patterns of miR-33 and ARC in both a rat model of temporal lobe epilepsy (TLE) and human TLE patients, to explore the role of miR-33 in epilepsy onset through its regulation of ARC expression in the hippocampus. Our findings, supported by a Dual-Luciferase reporter assay, suggest that miR-33 can bind to the 3' UTR region of ARC. We observed that miR-33 levels were reduced at 1 hour and 60 days post-seizure, while ARC expression notably increased at these time points. In the hippocampal CA1 and CA3 regions of post-seizure rats, ARC expression significantly exceeded that of control groups. Following the transfection of HEK cells with a miR-33 mimic, there was a decrease in both ARC mRNA and protein levels, whereas the group treated with a miR-33 inhibitor displayed the opposite effect. RNA sequencing in TLE patients revealed a similar miR-33 and ARC interaction. The regulation of Arc expression by miR-33 suggests that Arc may be a target gene of miR-33 in the context of epilepsy. Our findings indicate that miR-33 downregulation could contribute to the dysregulation of Arc expression observed in TLE, potentially influencing the disease process. Further studies are required to establish the exact role of miR-33-mediated Arc regulation in the development of epilepsy.

4.
Biosens Bioelectron ; 264: 116667, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39146772

RESUMO

Developing the portable CRP detection technologies that are suitable for point-of-care (POC) and primary care management is of utmost importance, and advancing the electrochemical immunosensors hold promise for POC implementation. Nevertheless, non-specific adsorption of numerous interfering proteins in complex biological media contaminates immunosensors, thereby restricting the reliability in detection efficacy. In this study, a three-dimensional flower-leaf shape amyloid bovine serum albumin/gold nanoparticles/polyaniline (AL-BSA/AuNPs/PANI) coating on the surface of the electrode was developed, which demonstrated strong anti-adsorption properties against bovine serum albumin, plasma, and cells. The immunosensor exhibited a good linear relationship to CRP response, featuring a detection limit of 0.09 µg/mL, consistent with clinical reference range. In addition, the CRP immunosensor demonstrated excellent specificity in other inflammation-related proteins and commendable anti-interference performance for CRP detection in plasma and whole blood tests. Importantly, by combining the development of a USB flash disk-type portable electrochemical workstation with a reagent-free mode, the developed CRP electrochemical immunosensor delivered ideal results in clinical samples. The anti-fouling performance, sensitivity and specificity of the immunosensor, as well as its flexible test modes in clinical samples, provide important scientific basis for developing POC detection technologies of vital biomarkers in complex biological media.


Assuntos
Compostos de Anilina , Técnicas Biossensoriais , Proteína C-Reativa , Técnicas Eletroquímicas , Ouro , Limite de Detecção , Nanopartículas Metálicas , Soroalbumina Bovina , Ouro/química , Proteína C-Reativa/análise , Técnicas Biossensoriais/instrumentação , Humanos , Nanopartículas Metálicas/química , Soroalbumina Bovina/química , Técnicas Eletroquímicas/métodos , Compostos de Anilina/química , Imunoensaio/métodos , Imunoensaio/instrumentação , Sistemas Automatizados de Assistência Junto ao Leito , Animais , Bovinos , Anticorpos Imobilizados/química
6.
Ann Hum Biol ; 51(1): 2342531, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38771661

RESUMO

BACKGROUND: Cuproptosis, a type of cell death involving copper ion accumulation and oxidative stress, has been implicated in the development of Alzheimer's disease (AD). AIM: This study aimed to explore the potential mechanisms and roles of cuproptosis-related genes (CRGs), long non-coding RNAs (lncRNAs), and immune cells in the development of cuproptosis in AD. SUBJECTS AND METHODS: Gene expression profiles of AD were acquired from the Gene Expression Omnibus (GEO) database, and differential analysis was conducted to identify CRGs. Random Forest (RF) modelling was employed to select the most crucial CRGs, which were subsequently validated in the test set. A nomogram model was created to predict AD risk and categorise AD subtypes based on the identified CRGs. A lncRNA-related ceRNA network was built, and immune cell infiltration analysis was conducted. RESULTS: Twelve differentially expressed CRGs were identified in the AD dataset. The RF model pinpointed the five most critical CRGs, which were validated in the test set with an AUC of 0.90. A lncRNA-related ceRNA network was developed, and immune cell infiltration analysis revealed high levels of M1 macrophages and mast cells, along with low levels of memory B cells in AD samples. Correlation analysis unveiled associations between CRGs, lncRNAs, and differentially infiltrating immune cells. CONCLUSION: This research offers insights into the potential mechanisms and roles of CRGs, lncRNAs, and immune cells in the development of cuproptosis in AD. The identified CRGs and lncRNAs may serve as potential therapeutic targets for AD, and the nomogram model may assist in early AD diagnosis and subtyping.


Assuntos
Doença de Alzheimer , RNA Longo não Codificante , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , RNA Longo não Codificante/genética , Humanos , Cobre
7.
Int Immunopharmacol ; 115: 109720, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37724956

RESUMO

Aseptic loosening caused by inflammatory osteolysis is one of the most frequent and serious long-term complications after total joint arthroplasty (TJA). Development of a new therapeutic drug is required due to the lack of effective therapy and serious adverse effects. This study aimed to explore the pharmacological properties of zingerone (ZO) in attenuating osteoclast-mediated periprosthetic osteolysis and how ZO modulates osteoclastogenesis. The nontoxic concentration of ZO was clarified by the CCK-8 method. Then, we explored the efficacy of ZO on suppressing osteoclast differentiation, F-actin ring formation, bone resorption, and NF-κB luciferase activity in vitro as well as osteoprotection in vivo. Polymerase chain reaction and western blotting were applied to detect the underlying mechanisms involved in osteoclastogenesis. ZO showed an obvious inhibitory effect on osteoclastogenesis and bone resorption in a dose-dependent manner by mainly suppressing the activation of NF-κB signaling pathways. Furthermore, ZO administration successfully attenuated titanium (Ti) particle-stimulated periprosthetic osteolysis and osteoporosis by regulating osteoclast formation. Our findings demonstrated the pharmacological properties of ZO in inhibiting osteoclast formation and function by downregulation of NF-κB signaling activation. As a result, these findings could be expected to provide a novel reagent for regulating inflammatory osteolysis caused by prosthetic loosening.


Assuntos
NF-kappa B , Osteólise , Humanos , Titânio , Osteoclastos , Osteólise/tratamento farmacológico , Transdução de Sinais
8.
Front Aging Neurosci ; 15: 1105690, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36875702

RESUMO

Background: Alzheimer's disease (AD) is the most common form of dementia characterized by a prominent cognitive deterioration of sufficient magnitude to impair daily living. Increasing studies indicate that non-coding RNAs (ncRNAs) are involved in ferroptosis and AD progression. However, the role of ferroptosis-related ncRNAs in AD remains unexplored. Methods: We obtained the intersection of differentially expressed genes in GSE5281 (brain tissue expression profile of patients with AD) from the GEO database and ferroptosis-related genes (FRGs) from the ferrDb database. Least absolute shrinkage and selection operator model along with weighted gene co-expression network analysis screened for FRGs highly associated with AD. Results: A total of five FRGs were identified and further validated in GSE29378 (area under the curve = 0.877, 95% confidence interval = 0.794-0.960). A competing endogenous RNA (ceRNA) network of ferroptosis-related hub genes (EPT1, KLHL24, LRRFIP1, CXCL2 and CD44) was subsequently constructed to explore the regulatory mechanism between hub genes, lncRNAs and miRNAs. Finally, CIBERSORT algorithms were used to unravel the immune cell infiltration landscape in AD and normal samples. M1 macrophages and mast cells were more infiltrated whereas memory B cells were less infiltrated in AD samples than in normal samples. Spearman's correlation analysis revealed that LRRFIP1 was positively correlated with M1 macrophages (r = -0.340, P < 0.001) whereas ferroptosis-related lncRNAs were negatively correlated with immune cells, wherein miR7-3HG correlated with M1 macrophages and NIFK-AS1, EMX2OS and VAC14-AS1 correlated with memory B cells (|r| > 0.3, P < 0.001). Conclusion: We constructed a novel ferroptosis-related signature model including mRNAs, miRNAs and lncRNAs, and characterized its association with immune infiltration in AD. The model provides novel ideas for the pathologic mechanism elucidation and targeted therapy development of AD.

9.
Front Cell Neurosci ; 17: 1080344, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36814866

RESUMO

Intracerebral hemorrhage (ICH) is a serious cerebrovascular disease with high rates of morbidity, mortality, and disability. Optimal treatment of ICH is a major clinical challenge, as the underlying mechanisms remain unclear. Ferroptosis, a newly identified form of non-apoptotic programmed cell death, is characterized by the iron-induced accumulation of lipid reactive oxygen species (ROS), leading to intracellular oxidative stress. Lipid ROS causes damage to nucleic acids, proteins, and cell membranes, eventually resulting in ferroptosis. In the past 10 years, ferroptosis has resulted in plenty of discoveries and breakthroughs in cancer, neurodegeneration, and other diseases. Some studies have also reported that ferroptosis does occur after ICH in vitro and in vivo and contribute to neuronal death. However, the studies on ferroptosis following ICH are still in the preliminary stage. In this review, we will summarize the current evidence on the mechanism underlying ferroptosis after ICH. And review the traditional modes of neuronal death to identify the crosstalk with ferroptosis in ICH, including apoptosis, necroptosis, and autophagy. Additionally, we also aim to explore the promising therapeutic application of ferroptosis in cell death-based ICH.

10.
Front Aging Neurosci ; 15: 1070854, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36761180

RESUMO

Objective: This study aimed to identify the potential urine biomarkers of vascular dementia (VD) and unravel the disease-associated mechanisms by applying Liquid chromatography tandem-mass spectrometry (LC-MS/MS). Methods: LC-MS/MS proteomic analysis was applied to urine samples from 3 groups, including 14 patients with VD, 9 patients with AD, and 21 normal controls (NC). By searching the MS data by Proteome Discoverer software, analyzing the protein abundances qualitatively and quantitatively, comparing between groups, combining bioinformatics analysis using Gene Ontology (GO) and pathway crosstalk analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG), and literature searching, the differentially expressed proteins (DEPs) of VD can be comprehensively determined at last and were further quantified by receiver operating characteristic (ROC) curve methods. Results: The proteomic findings showed quantitative changes in patients with VD compared to patients with NC and AD groups; among 4,699 identified urine proteins, 939 and 1,147 proteins displayed quantitative changes unique to VD vs. NC and AD, respectively, including 484 overlapped common DEPs. Then, 10 unique proteins named in KEGG database (including PLOD3, SDCBP, SRC, GPRC5B, TSG101/STP22/VPS23, THY1/CD90, PLCD, CDH16, NARS/asnS, AGRN) were confirmed by a ROC curve method. Conclusion: Our results suggested that urine proteins enable detection of VD from AD and VC, which may provide an opportunity for intervention.

11.
Microbiol Immunol ; 67(3): 142-153, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36537561

RESUMO

This research aimed to investigate the role of the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-129-5p (miR-129-5p)/paired box gene 6 (PAX6) axis in sepsis-induced acute lung injury (ALI). MLE-12 cells and C57BL/6 mice were induced by LPS to establish lung injury in in vitro and in vivo models. Cell viability and apoptosis were measured by cell counting kit-8 assay and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining, respectively. Levels of inflammatory cytokines in cell supernatants and bronchoalveolar lavage fluid (BALF) were detected by ELISA. Lung injury was evaluated by lung wet weight-to-dry weight ratio and hematoxylin-eosin staining. MALAT1, PAX6, and zinc finger E-box-binding homeobox 2 (ZEB2) expression was elevated and miR-129-5p expression was reduced in the serum of patients with sepsis-induced ALI, LPS-induced MLE-12 cells, and lung tissues of ALI mice. MALAT1 interference delayed the LPS-induced cell proliferation decrease, apoptosis increase, and inflammatory factor increase. miR-129-5p inhibition could reverse the delaying effect of MALAT1 interference on LPS-induced lung cell injury. PAX6 overexpression (oe) reversed the inhibitory effect of miR-129-5p oe on LPS-induced lung cell injury. Downregulating MALAT1 reduced pulmonary edema, inflammatory cytokine levels, lung injury, and apoptosis in ALI mice. Moreover, miR-129-5p suppression or PAX6 oe reversed the delaying effect of MALAT1 interference on sepsis-induced ALI. MALAT1 aggravates sepsis-induced ALI via the miR-129-5p/PAX6/ZEB2 axis.


Assuntos
Lesão Pulmonar Aguda , MicroRNAs , RNA Longo não Codificante , Sepse , Animais , Camundongos , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Apoptose , Citocinas , Lipopolissacarídeos/efeitos adversos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Fator de Transcrição PAX6 , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , Sepse/complicações , Sepse/genética
12.
Front Neurol ; 13: 929290, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36034298

RESUMO

As a common indication of nervous system diseases, neuroinflammation has attracted more and more attention, especially in the process of a variety of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Two types of non-coding RNAs (ncRNAs) are widely involved in the process of neuroinflammation in neurodegenerative diseases, namely long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). However, no research has systematically summarized that lncRNAs and miRNAs regulate neurodegenerative diseases through neuroinflammatory mechanisms. In this study, we summarize four main mechanisms of lncRNAs and miRNAs involved in neuroinflammation in neurodegenerative diseases, including the imbalance between proinflammatory and neuroprotective cells in microglia and astrocytes, NLRP3 inflammasome, oxidative stress, and mitochondrial dysfunction, and inflammatory mediators. We hope to clarify the regulatory mechanism of lncRNAs and miRNAs in neurodegenerative diseases and provide new insights into the etiological treatment of neurodegenerative diseases from the perspective of neuroinflammation.

13.
Blood Purif ; 51(12): 972-989, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35649340

RESUMO

BACKGROUND: Limited previous studies had proved that oXiris-continuous veno-venous hemofiltration (CVVH) could decrease endotoxins and inflammatory factors, thereby improving circulation's stability. However, conclusive data are lacking regarding the comparison between oXiris membrane (with the function of removing endotoxins and decreasing inflammatory factors) and AN69 filters (with the only function of decreasing inflammatory) on the mortality of patients with septic shock. The potential mechanisms of oXiris that might influence the mortality of septic shock patients remain unexplored. METHODS: This is a single-center, retrospective cohort study. The experimental group (30 patients with septic shock) was treated with oXiris-CVVH, and the control group (46 patients with septic shock) was treated with AN69 filter-CVVH. We employed the inverse probability of treatment-weighting method (IPTW), doubly robust estimation, and mediating effect analysis to analyze those clinical outcomes, with a special focus on the results of 28-day mortality, 72-h lactate, the need for norepinephrine (NE) in the next 72 h. RESULTS: A total of 76 patients with septic shock who received blood purification therapies were enrolled. After IPTW, differences in patient characteristics have been minimized. The 28-day mortality in the control group is higher than in the treatment group (73.3% vs. 47.3%, p < 0.001; median survival time: 10 vs. ≥28 days, log-rank p = 0.0366). And the 25% decrease and the 50% decrease in demand for NE in the next 72 h are different between the treatment and control groups (median time of 25% decrease in demand: 24 vs. >72 h, log-rank p = 0.0126; median time of 50% decrease in demand: 24 vs. >72 h, log-rank p = 0.0322). The 72-h lactic acid level and white blood cell (WBC) counts in the oXiris group are lower than in the control group. The 72-h lactate fully mediated the effects of oXiris on 28-day mortality after confounds adjustment. CONCLUSIONS: For septic shock patients, the use of oXiris-CVVH was associated with lower mortality and appeared to reduce lactate, NE dosage, PCT, and WBC counts, as compared to AN69-CVVH.


Assuntos
Terapia de Substituição Renal Contínua , Hemofiltração , Choque Séptico , Humanos , Hemofiltração/métodos , Estudos Retrospectivos , Endotoxinas , Norepinefrina , Ácido Láctico , Probabilidade
14.
Neurochem Res ; 47(8): 2396-2404, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35622215

RESUMO

Temporal lobe epilepsy (TLE) is a complex neurological disease, and its occurrence and development are closely related to the autophagy signaling pathway. However, the mechanism by which electroacupuncture (EA) affects the regulation of autophagy has not been fully elucidated. TLE gene chip dataset GSE27166 and data from rats without epilepsy (n = 6) and rats with epilepsy (n = 6) were downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) in the TLE and control groups were identified with the online tool GEO2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to analyse the functional and pathway enrichment of genes in the most important modules. A rat model of TLE induced by lithium-pilocarpine treatment was established. EA treatment at DU20 and DU14 in TLE rats was performed for 2 weeks. Neuronal regeneration was determined using immunofluorescence staining. The protein levels of AKT/mTOR signaling pathway and autophagy markers were detected through western blotting and immunohistochemistry. This study identified 1837 DEGs, including 798 upregulated genes and 1039 downregulated genes. GO enrichment and KEGG analyses were performed on DEGs and revealed functional enrichment mainly in the mTOR signaling pathway and autophagy-animal. Furthermore, the number of mature neurons was significantly increased upon coexpressing BrdU/NeuN in TLE rats treated with EA. Western blotting and immunohistochemistry results showed significantly decreased levels of the phosphorylated-AKT and p-mTOR in the hippocampal CA3 and DG regions of TLE rats with EA treatment. And increased p-ULK1/ULK1, LC3-II/LC3-I and p62 levels in TLE rats with EA stimulation. Therefore, this study suggested that EA promoted autophagy in hippocampal neurons during the onset of epilepsy by regulating the AKT/mTOR signaling pathway to treat epilepsy.


Assuntos
Eletroacupuntura , Epilepsia do Lobo Temporal , Animais , Autofagia , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/terapia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo
15.
J Hum Genet ; 67(2): 103-106, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34462534

RESUMO

Congenital disorders of glycosylation (CDGs) are inherited metabolic diseases affecting protein and lipid glycosylation. DDOST-CDG is a rare, newly identified type of CDGs, with only one case reported so far. In this study, we report a Chinese patient with a homozygous pathogenic variant in DDOST (c.1187G>A) and who presented with feeding difficulty, lactose intolerance, facial dysmorphism, failure to thrive, strabismus, high myopia, astigmatism, hypotonia, developmental delay and situs inversus totalis. Serum transferrin isoelectrofocusing demonstrated defective glycosylation in our patient. This finding further identifies DDOST as a genetic cause of CDGs and expands the clinical phenotype of DDOST-CDG.


Assuntos
Anormalidades Múltiplas/genética , Defeitos Congênitos da Glicosilação/genética , Predisposição Genética para Doença/genética , Hexosiltransferases/genética , Proteínas de Membrana/genética , Mutação , Anormalidades Múltiplas/patologia , Sequência de Bases , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/patologia , Saúde da Família , Humanos , Intolerância à Lactose/patologia , Masculino , Linhagem , Análise de Sequência de DNA/métodos , Situs Inversus/patologia
16.
Cell Mol Neurobiol ; 42(6): 1623-1643, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33595806

RESUMO

The Shank family proteins are enriched at the postsynaptic density (PSD) of excitatory glutamatergic synapses. They serve as synaptic scaffolding proteins and appear to play a critical role in the formation, maintenance and functioning of synapse. Increasing evidence from genetic association and animal model studies indicates a connection of SHANK genes defects with the development of neuropsychiatric disorders. In this review, we first update the current understanding of the SHANK family genes and their encoded protein products. We then denote the literature relating their alterations to the risk of neuropsychiatric diseases. We further review evidence from animal models that provided molecular insights into the biological as well as pathogenic roles of Shank proteins in synapses, and the potential relationship to the development of abnormal neurobehavioral phenotypes.


Assuntos
Proteínas do Tecido Nervoso , Sinapses , Animais , Modelos Animais de Doenças , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Sinapses/metabolismo
17.
Front Immunol ; 12: 702244, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484198

RESUMO

Primary intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality throughout the world. ICH is a multifactorial disease that emerges from interactions among multiple genetic and environmental factors. DNA methylation plays an important role in the etiology of complex traits and diseases. We used the Illumina Infinium Human Methylation 850k BeadChip to detect changes in DNA methylation in peripheral blood samples from patients with ICH and healthy controls to explore DNA methylation patterns in ICH. Here, we compared genomic DNA methylation patterns in whole blood from ICH patients (n = 30) and controls (n = 34). The ICH and control groups showed significantly different DNA methylation patterns at 1530 sites (p-value < 5.92E-08), with 1377 hypermethylated sites and 153 hypomethylated sites in ICH patients compared to the methylation status in healthy controls. A total of 371 hypermethylated sites and 35 hypomethylated sites were in promoters, while 738 hypermethylated sites and 67 hypomethylated sites were in coding regions. Furthermore, the differentially methylated genes between ICH patients and controls were largely related to inflammatory pathways. Abnormalities in the DNA methylation pattern identified in the peripheral blood of ICH patients may play an important role in the development of ICH and warranted further investigation.


Assuntos
Biomarcadores/sangue , Hemorragia Cerebral/sangue , Hemorragia Cerebral/genética , Metilação de DNA/genética , Adulto , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
18.
Front Endocrinol (Lausanne) ; 12: 665309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276557

RESUMO

Diabetes in the elderly increases cognitive impairment, but the underlying mechanisms are still far from fully understood. A non-targeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) was performed to screen out the serum biomarkers of diabetic mild cognitive impairment (DMMCI) in rats. Total 48 SD rats were divided into three groups, Normal control (NC) group, high-fat diet (HFD) fed group and type 2 diabetes mellitus (T2DM) group. The T2DM rat model was induced by intraperitoneal administration of streptozotocin (STZ, 35 mg/kg) after 6 weeks of high-fat diet (HFD) feeding. Then each group was further divided into 4-week and 8-week subgroups, which were calculated from the time point of T2DM rat model establishment. The novel object recognition test (NORT) and the Morris water maze (MWM) method were used to evaluate the cognitive deficits in all groups. Compared to the NC-8w and HFD-8w groups, both NOR and MWM tests indicated significant cognitive dysfunction in the T2DM-8w group, which could be used as an animal model of DMMCI. Serum was ultimately collected from the inferior vena cava after laparotomy. Metabolic profiling analysis was conducted using ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) technology. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to verify the stability of the model. According to variable importance in the project (VIP > 1) and the p-value of t-test (P < 0.05) obtained by the OPLS-DA model, the metabolites with significant differences were screened out as potential biomarkers. In total, we identified 94 differentially expressed (44 up-regulated and 50 down-regulated) endogenous metabolites. The 10 top up-regulated and 10 top down-regulated potential biomarkers were screened according to the FDR significance. These biomarkers by pathway topology analysis were primarily involved in the metabolism of sphingolipid (SP) metabolism, tryptophan (Trp) metabolism, Glycerophospholipid (GP) metabolism, etc. Besides, SP metabolism, Trp metabolism and GP metabolism mainly belonging to the lipid metabolism showed marked perturbations over DMMCI and may contribute to the development of disease. Taken collectively, our results revealed that T2DM could cause cognitive impairment by affecting a variety of metabolic pathways especially lipid metabolism. Besides, serum PE, PC, L-Trp, and S1P may be used as the most critical biomarkers for the early diagnosis of DMMCI.


Assuntos
Biomarcadores/sangue , Cromatografia Líquida/métodos , Disfunção Cognitiva/diagnóstico , Diabetes Mellitus Experimental/complicações , Metaboloma , Espectrometria de Massas em Tandem/métodos , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Masculino , Análise de Componente Principal , Ratos , Ratos Sprague-Dawley
19.
Exp Ther Med ; 21(5): 504, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33791013

RESUMO

The present study was performed to investigate the clinical manifestations and pathogenic variants in three large families with autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) and/or benign familial infantile epilepsy (BFIE) in China. Detailed clinical data and family history were collected. Genomic DNA was isolated from the peripheral blood samples of all available members. The genetic diagnosis was made by whole-exome sequencing on the three probands and the candidate variants were verified by PCR-Sanger sequencing. The pathogenicity of variants was predicted by bioinformatics analyses and classified according to the American College of Medical Genetics criteria. A total of three causative heterozygous variants were identified in the proline-rich transmembrane protein 2 (PRRT2) gene by DNA sequencing: A novel c.324_334del(p.Val109Argfs*21) deletion variant in Family A, as well as the previously known c.510_513del(p.Ser172Argfs*3) deletion variant in Family B and c.649dupC(p.Arg217Profs*8) duplication variant in Family C. The three variants of PRRT2 co-segregated with the phenotype and genotype in the family members. The present results deepen the current understanding of PKD/BFIE and extend the genotypic-phenotypic spectrum of PKD/BFIE.

20.
Front Aging Neurosci ; 13: 619945, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33597859

RESUMO

Objective: This study aimed to identify potential diagnostic biomarkers of diabetic vascular dementia (DVD) and unravel the underlying mechanisms using mass spectrometry (MS). Methods: Label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic analysis was applied to urine samples from four groups, including 14 patients with vascular dementia (VD), 22 patients with type 2 diabetes mellitus (T2DM), 12 patients with DVD, and 21 normal controls (NCs). Searching the MS data by Proteome Discoverer software (ThermoFisher Scientific; Waltham, MA, USA), protein abundances were analyzed qualitatively and quantitatively and compared between these groups. Combining bioinformatics analysis using Gene Ontology (GO), pathway crosstalk analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) network analysis using STRING, and literature searching, the differentially expressed proteins (DEPs) of DVD can be comprehensively judged and were further quantified by receiver operating characteristic (ROC) curve methods. Results: The proteomic findings showed quantitative changes in patients with DVD compared to patients with NC, T2DM, and VD groups; among 4,744 identified urine proteins, 1,222, 1,152, and 1,180 proteins displayed quantitative changes unique to DVD vs. NC, T2DM, and VD, respectively, including 481 overlapped common DEPs. Then, nine unique proteins [including HP, SERPIND, ATP5PB, VNN2, ALDH3A1, U2AF2, C6, A0A5C2GRG5 (no name), and A0A5C2FZ29 (no name)] and two composite markers (CM) (A0A5C2GRG5+U2AF2 and U2AF2+C6) were confirmed by a ROC curve method. Conclusion: This study provided an insight into the potential pathogenesis of DVD and elucidated a method for early detection.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA