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1.
Neurotherapeutics ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625864

RESUMO

This study aims to investigate the association between thymectomy and the risk of generalization in patients with ocular myasthenia gravis (MG). Data on patients with ocular MG from seven neurological centers in China were retrospectively reviewed. Ocular MG naïve to immunotherapy was categorized according to whether thymectomy was performed (thymectomized group vs. nonsurgical group). Patients in the thymectomized group all underwent surgery within 2 years since ocular symptom onset. The main outcome measure was the generalization. The follow-up period was defined from the date of ocular symptom onset to the date of generalization confirmation, immunotherapy initiation, or last follow-up (defined as 60 months). Of 519 eligible patients (mean [SD] age, 48.7 [15.2] years, 46.6% women), 31 (23.7%) of 131 generalized in the thymectomized group and 122 (31.4%) of 388 did in the nonsurgical group during a median follow-up of 19 months (IQR 8.0-50.0). Thymectomy was independently associated with reduced generalization risk (adjusted HR 0.41, 95% CI 0.25-0.66, P < 0.001). Multivariable stratified analysis also verified this association across the subgroups. Kaplan-Meier curves showed that the 5-year cumulative rate was significantly lower in the thymectomized group than in the nonsurgical group. To conclude, thymectomy may be considered effective in modifying the progression from ocular to generalized MG irrespective of thymoma.

2.
World J Surg Oncol ; 19(1): 260, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465365

RESUMO

OBJECTIVE: The study aimed to compare the Steroid 5 alpha-reductase 3 (SRD5A3) expression levels in breast cancer (BC) and normal tissues, to investigate the prognostic value of SRD5A3 mRNA expression in BC patients and to identify the SRD5A3-related signaling pathways using bioinformatics approaches. METHODS: We evaluated the expression levels of SRD5A3 and survival data in BC patients using different bioinformatic databases. Further, Cox regression analysis was conducted to predict the independent prognostic factors for BC. Moreover, the association of SRD5A3 with clinicopathological factors was measured through LinkedOmics database. And the potential role of SRD5A3 was determined by Gene Ontology and KEGG pathway enrichment analysis. Finally, protein network of SRD5A3 was constructed and genetic alterations were analyzed. RESULTS: Bioinformatic data indicated that both mRNA and protein expression levels of SRD5A3 were higher in BC group than those in the normal group (P < 0.05). Besides, BC patients with higher SRD5A3 mRNA expression levels had a lower overall survival (all P < 0.05). Cox regression analysis further demonstrated the independent prognostic value of SRD5A3 in BC (P = 0.015). SRD5A3 mRNA expression was significantly associated with N stage (P < 0.001), age (P < 0.05), and histologic subtype (P < 0.001) but had no significant relationship with other clinical characteristics (all P > 0.05). Moreover, the functional enrichment analysis revealed that the SRD5A3 was involved in metabolism-related pathways (all P < 0.05). CONCLUSIONS: SRD5A3 was highly expressed in BC tissues and high SRD5A3 expression was related to poorer prognosis. SRD5A3 serves as an oncogene and might function as a potential biomarker for prognosis and a therapeutic target for BC.


Assuntos
Neoplasias da Mama , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Biologia Computacional , Feminino , Ontologia Genética , Humanos , Proteínas de Membrana/genética , Prognóstico , RNA Mensageiro/genética
3.
Neurosci Lett ; 762: 136150, 2021 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-34352340

RESUMO

OBJECTIVE: Recently, a meta-analysis of genome-wide association studies (GWASs) has identified 38 novel independent loci associated with risk of Parkinson's disease (PD) in European populations. We sought to investigate whether these genetic susceptibility variants could be replicated in the Chinese Han population. METHODS: We genotyped 38 independent loci in 495 Chinese sporadic PD patients and 470 unrelated controls and performed allelic and genotypic association test using chi-square tests or Armitage test for trend. Polygenic risk score (PRS) models were built to evaluate the cumulative effects of the selected SNPs. RESULTS: We found that the rs11610045 of FBRSL1 (p = 0.02, OR = 0.63, allele model), rs76116224 of KCNS3 (p < 0.01, OR = 0.09, allele model), and the rs2248244 of DYRK1A (p = 0.02, OR = 1.35, allele model) were significantly associated with PD. The PRS model of cumulative effects of the SNPs associated with PD in our study had the area under the curve (AUC) of 0.61. CONCLUSIONS: Our study revealed that rs11610045 of FBRSL1, rs76116224 of KCNS3 and rs2248244 of DYRK1A showed an impact on the risk of PD, and the GWAS-derived PRS models we built had predictive value for PD risk in the Chinese population. Further studies are needed to explore the pathogenesis of these potentially risk-associated variants.

4.
Microb Pathog ; 158: 105118, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34339795

RESUMO

Porcine circovirus type 2 (PCV2) can cause various clinical diseases in pigs, resulting in huge losses for the pig farms all over the world. In order to develop a new strategy to control PCV2, it is essential to understand its mechanisms firstly, especially PCV2 interferes with the host's innate immunity. In the present study, lncRNA and mRNA expression profiles in porcine lymphnode response to PCV2 infection were deeply sequenced and analyzed. 3271 novel lncRNAs were identified in all. 1898 mRNAs and 282 lncRNAs showed differential expression between control and PCV2-infected groups. The bioinformatics analysis including lncRNA-mRNA co-expression network construction, as well as GO and KEGG pathway analysis focused on the DEGs was carried out. The results indicated that lncRNAs might participate in PCV2 infection-induced the pathogenesis of immunosuppression through regulating the host's immune responses, biological regulation, response to stimulus, cellular component organization or biogenesis and metabolism. And these differentially expressed lncRNAs might play important roles in response to PCV2 infection in the host's innate immune system. These findings provided a large-scale survey of dysregulated lncRNAs after PCV2 infection, especially the lncRNAs responded to host's innate immune within the lymphnode. This study will provide a novel insight into the lncRNAs' functions and the possible immunosuppressive mechanism induced by PCV2 infection. However, further research will be required to verify the characteristic function of the dysregulated lncRNAs.


Assuntos
Infecções por Circoviridae , Circovirus , RNA Longo não Codificante , Doenças dos Suínos , Animais , Infecções por Circoviridae/veterinária , Circovirus/genética , Biologia Computacional , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Suínos
5.
Artigo em Inglês | MEDLINE | ID: mdl-34415638

RESUMO

BACKGROUND: To investigate the effect of a modified mindfulness-based stress reduction (mMBSR) program on mental well-being and cognitive function of older adults. METHOD: Two hundred and fourty-six participants were randomly assigned to mMBSR (n = 120) group or waitlist control group which received mMBSR at 2-month (n = 123). Data collected at baseline, 2 and 4 months after recruitment. PRIMARY OUTCOME: mental well-being: Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS). SECONDARY OUTCOMES: Five Facet Mindfulness Questionnaire Short Form, Montreal Cognitive Assessment (MOCA), Verbal Fluency Test (VFT), international shopping list test, self-compassion scale, peace of mind scale, geriatric depression scale (GDS), and Pittsburgh sleep quality index (PSQI). In modified-intention-to-treat analysis, paired t-test for within group comparison, and ANCOVA to compare group differences at 2-months with adjustment of baseline values. RESULTS: Most participants were female (83.7%), living with others (67.0%), and married (50.7%). No significant difference of baseline characteristics except sleep quality. At 2 months, intervention group reported better mental well-being (0.9, 95%CI: 0.1-1.8, p = 0.025) and less depressive symptoms (-1.0; 95%CI: -1.7 to -0.3, p = 0.004). Within group at 2 months, intervention group had improvement in: mental well-being (SWEMWBS: 22.5-23.4, p = 0.011), cognitive function (MOCA: 24.6-25.8, p < 0.001; VFT: 38.7-42.1, p < 0.001), depressive symptoms (GDS: 4.1-3.1, p < 0.001), and sleep quality (PSQI: 8.3-6.7, p < 0.001). All these changes, except mental well-being, were sustained at 4 months. DISCUSSION: Attrition rate was 14% and mindfulness intervention was found to be feasible and acceptable in older adults. Major limitation of the study was the absence of an active control group to control for non-specific effect.

6.
Brain Struct Funct ; 226(8): 2665-2673, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34373950

RESUMO

Increasing evidence suggests that genetic factors play a key role in the development of Parkinson's disease (PD). The variant rs11240572 in the PARK16 gene locus is strongly associated with PD. However, its effect on the pathogenesis of PD is yet to be clarified. The objective of the study was to explore the effect of the PARK16 rs11240572 variant on brain structure in PD patients. A total of 51 PD patients were enrolled in the study and genotyped for the rs11240572 variant. Clinical assessments and MRI scans were conducted across all participants. Voxel-based morphometry (VBM) was used to investigate gray matter volume (GMV) of the whole brain between these two groups. Correlation analysis was performed to identify the relationships between GMV and clinical features. There were 17 rs11240572-A variant carriers and 34 non-carriers, with no significant demographic differences between these two groups. Compared with non-carriers, rs11240572-A carriers showed increased GMV in the left caudate nucleus and putamen, but decreased GMV in the left superior temporal gyrus and supramarginal gyrus. In non-carriers, left basal ganglia GMV was positively correlated with UPDRS III (r = 0.365, p = 0.034) and bradykinesia (r = 0.352, p = 0.042), but negatively correlated with MMSE (r = - 0.344, p = 0.047), while in carriers negative correlation between basal ganglia GMV and MMSE was also observed (r = - 0.666, p = 0.004). Moreover, the GMV of left temporoparietal cortex was positively associated with cognitive function in both groups (carriers, r = 0.692, p = 0.002; non-carriers, r = 0.879, p < 0.001). When reducing the sample size of non-carriers to the level of the carrier sample, similar correlations were observed in both groups. Our study showed that the PARK16 rs11240572 variant affects the brain structure of patients with PD, especially in the basal ganglia and temporoparietal cortex. This indicated that this variant might play an important role in the pathogenesis of PD.

7.
J Parkinsons Dis ; 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34366373

RESUMO

BACKGROUND: The widely divergent responsiveness of Parkinson's disease (PD) patients to levodopa is an important clinical issue because of its relationship with quality of life and disease prognosis. Preliminary animal experiments have suggested that degeneration of the locus coeruleus (LC) attenuates the efficacy of levodopa treatment. OBJECTIVE: To explore the relationship between LC degeneration and levodopa responsiveness in PD patients in vivo. METHODS: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a good indicator of LC and substantia nigra (SN) degeneration, and levodopa challenge tests were conducted in 57 PD patients. Responsiveness to levodopa was evaluated by the rates of change of the Unified Parkinson's Disease Rating Scale Part III score and somatomotor network synchronization calculated from resting-state functional MRI before and after levodopa administration. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNRLC) and levodopa responsiveness. Multiple linear regression analysis was conducted to rule out the potential influence of SN degeneration on levodopa responsiveness. RESULTS: A significant positive correlation was found between CNRLC and the motor improvement after levodopa administration (R = 0.421, p = 0.004). CNRLC also correlated with improvement in somatomotor network synchronization (R = -0.323, p = 0.029). Furthermore, the relationship between CNRLC and levodopa responsiveness was independent of SN degeneration. CONCLUSION: LC degeneration might be an essential factor for levodopa resistance. LC evaluation using NM-MRI might be an alternative tool for predicting levodopa responsiveness and for helping to stratify patients into clinical trials aimed at improving the efficacy of levodopa.

8.
J Neurosci ; 41(37): 7727-7741, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34349001

RESUMO

Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway may play an important role in the regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G-protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER+ neurons in the RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER+ neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER+ neurons abrogated itch responses, indicating that GPER+ neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by the µ type opioid receptor (MOR) antagonism. Additionally, significant MOR phosphorylation in the RVM was detected in chronic itch models in wild-type but not in GPER-/- rats. Therefore, GPER not only identifies a population of medullary antipruritic neurons but may also determine the descending antipruritic tone through regulating µ opioid signaling.SIGNIFICANCE STATEMENT Therapeutic options for itch are limited because of an as yet incomplete understanding of the mechanisms of itch processing. Our data have provided novel insights into the cellular organization and molecular mechanisms of descending regulation of itch in normal and pathologic conditions. GPER+ neurons (largely GABAergic) in the RVM are antipruritic neurons under tonic opioidergic inhibition, activation of GPER promotes phosphorylation of MOR and disinhibition of the antipruritic GPER+ neurons from inhibitory opioidergic inputs, and failure to mobilize GPER+ neurons may result in the exacerbation of itch. Our data also illuminate on some of the outstanding questions in the field, such as the mechanisms underlying sex bias in itch, pain, and opioid analgesia and the paradoxical effects of morphine on pain and itch.

9.
Plant Cell Environ ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449086

RESUMO

Herbivore-induced plant volatiles prime neighbouring plants to respond more strongly to subsequent attacks. However, the key volatiles that trigger this state and their priming mechanisms remain largely unknown. The tea geometrid Ectropis obliqua is one of the most devastating leaf-feeding pests of tea plants. Here, plant-plant communication experiments demonstrated that volatiles emitted from tea plants infested by E. obliqua larvae triggered neighbouring plants to release volatiles that repel E. obliqua adult, especially mated females. Volatile analyses revealed that the quantity of eight volatiles increased dramatically when plants were exposed to volatiles emitted by infested tea plants, including (Z)-3-hexenol, linalool, α-farnesene, ß-Ocimene and (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT). The results of behavioural bioassays demonstrated that ß-Ocimene strongly repelled mated E. obliqua females. Individual volatile compound exposure experiments revealed that (Z)-3-hexenol, linalool, α-farnesene and DMNT triggered the emission of ß-Ocimene from tea plants. Chemical inhibition experiments demonstrated that the emission of ß-Ocimene induced by (Z)-3-hexenol, linalool, α-farnesene and DMNT were dependent on Ca2+ and JA signalling. These findings help us to understand how E. obliqua moths respond to volatiles emitted from tea plants and provide new insight into volatile-mediated plant-plant interactions. They have potential significance for the development of novel insect and pest control strategies in crops.

10.
Methods Mol Biol ; 2358: 73-82, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34270046

RESUMO

The transmembrane receptor kinase family is the largest protein kinase family in Arabidopsis. Many members of this family play critical roles in plant signaling pathways. However, many of these kinases have yet uncharacterized functions and very little is known about the direct substrates of these kinases. We have developed the "ShortPhos" method, an efficient and simple mass spectrometry (MS)-based phosphoproteomics protocol to perform comparative phosphopeptide profiling of knockout mutants of receptor-like kinases. Through this method, we are able to better understand the functional roles of plant kinases in the context of their signaling networks.

11.
Dalton Trans ; 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34223568

RESUMO

Luminescent ß-diketone-based lanthanide complexes have been well explored as chemical sensor materials for biomedicine applications. Herein, three mononuclear Eu3+ complexes based on bis-ß-diketone ligands (L1, L2 and L3) that can reduce luminescence quenching caused by water were developed. The ligands feature two ß-diketone units covalently bound at the 1,8-position of the derivatized anthracene (modified with tetracyanoethylene, TCNE). X-ray crystallographic analysis reveals that their self-assemblies with Ln3+ ions in a 2 : 1 stoichiometric ratio form mononuclear anion complexes, [EuL2]-, in which two ligands coordinate to the metal center in a mutually orthogonal manner. This kind of arrangement together with the bulge of TCNE from the anthracene plane well protected the complexes from the quenching effects of water molecules in the second coordination. The photophysical measurements showed that the complexes not only had high luminescence quantum yields (QYs, up to 50-67%) but also presented excellent water-quenching resistant capability.

12.
Parasit Vectors ; 14(1): 368, 2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34274015

RESUMO

BACKGROUND: Borrelia miyamotoi is a newly described relapsing fever spirochete transmitted by ixodid tick species. Little is known about the prevalence of B. miyamotoi infections in humans and ticks in Inner Mongolia, China. Therefore, we investigated the prevalence of B. miyamotoi in Ixodes persulcatus ticks, and we aimed to isolateB. miyamotoi from I. persulcatus from four regions of Greater Khingan, Inner Mongolia, China. METHODS: From May to June each year during the period 2016-2019, host-seeking adult I. persulcatus ticks were collected from vegetation. Genomic DNA was prepared from half of each tick body for PCR template, and the remaining half was used to cultivate B. miyamotoi in BSK-M medium. We employed quantitative real-time PCR (qPCR) to detect Borrelia DNA in the ticks and to calculate the prevalence of B. miyamotoi and infections with other borreliae. For characterization of the isolated B. miyamotoi, we performed draft genome sequencing and multilocus sequencing analysis (MLSA). RESULTS: A total of 2656 adult I. persulcatus ticks were collected. The overall prevalence of relapsing fever (RF) borreliae in ticks was 5.0% (134/2656) and that of Lyme disease (LD) borreliae was 43.8% (1164/2656). Co-infection with RF and LD borreliae was observed in 63 ticks (2.4%). Ticks that were positive for RF borreliae by qPCR were subjected to glycerophosphodiester diester phosphodiesterase gene (glpQ) PCR amplification and sequencing, through which we identified the RF borrelia specimens as B. miyamotoi. Furthermore, the B. miyamotoi strain Hetao-1 was isolated from I. persulcatus, and a draft genome sequence was obtained from the isolate. Sequencing determined the strain Hetao-1 genome to be approximately 906.1 kbp in length (28.9% average GC content), and MLSA identified the strain as ST633, which has previously been reported in Japan and Mongolia. CONCLUSION: We detected B. miyamotoi from I. persulcatus ticks collected in Inner Mongolia, and successfully isolated a B. miyamotoi strain. To our knowledge, this is the first study to culture a B. miyamotoi isolate from China. The data on the prevalence of B. miyamotoi and other borreliae in I. persulcatus ticks will be fundamental for future epidemiological studies of B. miyamotoi disease in Inner Mongolia.

13.
Oxid Med Cell Longev ; 2021: 9981480, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34257825

RESUMO

Background: Inflammatory bowel disease (IBD) is a result of a complex interplay, making development of a specific treatment a challenging task. Corticosterone was considered a risk factor of stress relative enteritis. Our previous studies found that melatonin exerts an improvement effect in sleep deprivation (SD)- induced corticosterone overproduction and colitis. A present study further explored the mechanism whereby melatonin prevented corticosterone-mediated SD-induced colitis. Methods: A 72-hour SD mouse model with or without melatonin supplementation and fecal microbiota transplantation (FMT) to investigate the core role of corticosterone in melatonin-mediated gut microbiota improving SD-induced colitis. Further, corticosterone-treated mice were assessed to the effect of melatonin on corticosterone-mediated gut microbiota dysbiosis-induced colitis. Meanwhile, an in vitro test studied modulatory mechanism of metabolite melatonin. Results: SD caused an excessive corticosterone, gut microbiota disorder and colitis phenotype. Similarly, corticosterone-supplemented mice also exhibited gut microbiota dysbiosis and colitis, and the FMT from SD-mice to normal mice could restore the SD-like colitis, but no change in the corticosterone level, which suggested that corticosterone-mediated intestinal microbiota imbalance plays a central role in SD-induced colitis. Further, we demonstrated melatonin-mediated MT2 weakened GR feedback, suppressed oxidative stress, restored the intestinal microbiota and its metabolites homeostasis, and inactivated the STAT3/AP-1/NF-κB pathway-induced inflammatory response in vivo and in vitro. Conclusions: We revealed that excessive corticosterone is a core risk factor for SD-induced colitis and provided a better understanding of the effects of melatonin, expected to be a personalized targeted therapy drug, on corticosterone-mediated gut microbiota inducing colitis.

14.
Parkinsonism Relat Disord ; 88: 82-89, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34147950

RESUMO

OBJECTIVES: To explore the microstructural alterations in subcortical nuclei in Parkinson's disease (PD) at different stages with diffusion kurtosis imaging (DKI) and tensor imaging and to test the performance of diffusion metrics in identifying PD. METHODS: 108 PD patients (64 patients in early-stage PD group (EPD) and 44 patients in moderate-late-stage PD group (MLPD)) and 64 healthy controls (HC) were included. Tensor and kurtosis metrics in the subcortical nuclei were compared. Partial correlation was used to correlate the diffusion metrics and Unified Parkinson's Disease Rating Scale part-III (UPDRS-III) score. Logistic regression and receiver operating characteristic analysis were applied to test the diagnostic performance of the diffusion metrics. RESULTS: Compared with HC, both EPD and MLPD patients showed higher fractional anisotropy and axial diffusivity, lower mean kurtosis (MK) and axial kurtosis in substantia nigra, lower MK and radial kurtosis (RK) in globus pallidus (GP) and thalamus (all p < 0.05). Compared with EPD, MLPD patients showed lower MK and RK in GP and thalamus (all p < 0.05). MK and RK in GP and thalamus were negatively correlated with UPDRS-III score (all p < 0.01). The logistic regression model combining kurtosis and tensor metrics showed the best performance in diagnosing PD, EPD, and MLPD (areas under curve were 0.817, 0.769, and 0.914, respectively). CONCLUSIONS: PD has progressive microstructural alterations in the subcortical nuclei. DKI is sensitive to detect microstructural alterations in GP and thalamus during PD progression. Combining kurtosis and tensor metrics can achieve a good performance in diagnosing PD.

15.
Int Immunopharmacol ; 96: 107779, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34162146

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is an inflammatory response relative chronic disease in the intestinal tract. Our previous study demonstrated melatonin exerts an improvement effect on stress related IBD. The present study was further performed to clarify the mechanism of melatonin in dextran sodium sulfate (DSS)-induced colitis in mice. METHODS: We successfully established a DSS-induced colitis mouse model and hydrogen peroxide (H2O2)-treated intestinal epithelial cells (IECs) with or without melatonin supplementation to explore the improvement of melatonin in the DSS-induced colitis. RESULTS: Melatonin supplementation normalized the colitis, oxidative stress, mitochondria dysfunction, apoptosis and inflammation response, including the increase of intestinal permeability, histological score and the level of IL-1ß, TNF-α, iNOS, NLRP3, MDA, Bax, Caspase3, Cytochrome C and Caspase9, as well as the reduction of body weight, colon length, Card9, IFN-γ, IL-10, T-AOC, Calpain1, Mfn2, VDAC1, RORα and SIRT1 proteins in DSS-treated mice. However, the improvement effects of melatonin were blocked by MT2 antagonist 4P-PDOT, PI3K antagonist LY294002, AKT antagonist GSK690693 and Nrf2 antagonist ML385, while mimicked by P65 antagonist PDTC in H2O2-IECs. CONCLUSION: Melatonin-mediated MT2 activated PI3K/AKT/Nrf2/RORα/SIRT1 pathway and suppressed NF-κB pathway, ultimately improved DSS-induced colitis, which provides evidence for melatonin as an efficient therapy against oxidative stress associated IBD.

16.
BMC Neurol ; 21(1): 187, 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33964895

RESUMO

BACKGROUND: To date, the genetic contribution to Parkinson's disease (PD) remains unclear. Mutations in the collagen type VI alpha 3 (COL6A3) gene were recently identified as a cause of isolated dystonia. Since PD and dystonia are closely related disorders with shared clinical and genetic characteristics, we explored the association between COL6A3 and PD in a Chinese cohort. METHODS: We performed genetic screening of COL6A3 in a Chinese cohort of 173 patients with sporadic PD and 200 healthy controls. We identified variants that are likely to have pathogenic effects based on: 1) a minor allele frequency of < 0.01; and 2) the variant being recognized as deleterious by at least 15 different in silico predicting tools. Finally, we tested the aggregate burden of COL6A3 on PD via SKAT-O analysis. RESULTS: First, we found compound heterozygous COL6A3 gene mutations in one early-onset PD patients. Then, we explored whether COL6A3 variants contributed to increased risk of developing PD in a Chinese population. We detected 21 rare non-synonymous variants. Pathogenicity predictions identified 7 novel non-synonymous variants as likely to be pathogenic. SKAT-O analysis further revealed that an aggregate burden of variants in COL6A3 contributes to PD (p = 0.038). CONCLUSION: An increased aggregate burden of the COL6A3 gene was detected in patients with PD.


Assuntos
Colágeno Tipo VI/genética , Doença de Parkinson/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem
17.
J Magn Reson Imaging ; 54(4): 1098-1106, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33949744

RESUMO

BACKGROUND: Excessive iron accumulation is one of the main pathogeneses of Parkinson's disease (PD). Ceruloplasmin plays an important role in keeping the iron homoeostasis. PURPOSE: To explore the association between serum ceruloplasmin depletion and subcortical iron distribution in PD. STUDY TYPE: Prospective. POPULATION: One hundred and twenty-one normal controls, 34 PD patients with low serum ceruloplasmin (PD-LC), and 28 patients with normal serum ceruloplasmin (PD-NC). SEQUENCE: Enhanced susceptibility-weighted angiography (ESWAN) on a 3 T scanner. ASSESSMENT: Quantitative susceptibility mapping was employed to quantify the regional iron content by using a semi-automatic method. Serum ceruloplasmin concentration was measured from peripheral blood sample. Clinical assessments were conducted by a neurologist. STATISTICAL TESTS: General linear model was used to compare the intergroup difference of region iron distribution among groups, and the statistics was adjusted by Bonferroni method (P < 0.01). Partial correlation analysis was used to detect the association between regional iron distribution and serum ceruloplasmin concentration (P < 0.05). RESULTS: Compared with normal controls, significant iron accumulation in substantia nigra, putamen, and red nucleus was observed in PD-LC, while the only region showing significant iron accumulation was SN in PD-NC. Between PD-NC and PD-LC, the iron accumulation in putamen remained significantly different, which had a negative correlation with serum ceruloplasmin in whole PD patients (r = -0.338, P = 0.008). DATA CONCLUSION: Nigral iron accumulation characterizes PD patients without significant association with serum ceruloplasmin. Differentially, when PD patients appear with reduced serum ceruloplasmin, more widespread iron accumulation would be expected with additionally involving putamen and red nucleus. All these findings provide insightful evidence for the abnormal iron metabolism behind the ceruloplasmin depletion in PD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: 2.


Assuntos
Ceruloplasmina , Doença de Parkinson , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ceruloplasmina/metabolismo , Humanos , Ferro/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Estudos Prospectivos , Substância Negra
18.
J Biol Chem ; 296: 100622, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33811861

RESUMO

Fasting induces lipid accumulation in the liver, while the mechanisms by which fasting dysregulates liver fatty acid oxidation are not clear. Fatty acid ω-oxidation is induced in the fasting state, and administration of dicarboxylic acids to fasting animals decreases plasma ketone bodies. We hypothesized that endogenous dicarboxylic acids might play a role in controlling mitochondrial ß-oxidation in fasting animals. A peroxisome proliferator-activated receptor-alpha agonist and an inhibitor for peroxisomal ß-oxidation were administered to the fasting rats to investigate the role of dicarboxylic acids in liver fatty acid oxidation and lipid homeostasis. We observed that excessive ß-oxidation of endogenous dicarboxylic acids by peroxisomes generated considerable levels of succinate in the liver. Excessive succinate oxidation subsequently increased the mitochondrial NADH/NAD+ ratio and led to an accumulation of 3-OH-CoA and 2-enoyl-CoA intermediates in the liver. This further induced feedback suppression of mitochondrial ß-oxidation and promoted hepatic lipid deposition and steatosis. Specific inhibition of peroxisomal ß-oxidation attenuated fasting-induced lipid deposition in the liver by reducing succinate production and enhancing mitochondrial fatty acid oxidation. We conclude that suppression of mitochondrial ß-oxidation by oxidation of dicarboxylic acids serves as a mechanism for fasting-induced hepatic lipid accumulation and identifies cross talk between peroxisomal and mitochondrial fatty acid oxidation.


Assuntos
Ácidos Dicarboxílicos/química , Jejum , Corpos Cetônicos/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Mitocôndrias/metabolismo , Peroxissomos/metabolismo , Animais , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley
19.
Artigo em Inglês | MEDLINE | ID: mdl-33845750

RESUMO

BACKGROUND: Cancer stem cells could influence tumor recurrence and metastasis. OBJECTIVE: To develop a new effective treatment modality targeting breast cancer stem cells (BCSCs), and to explore the role of Apatinib in BCSCs. METHODS: BCSCs were isolated from MDA-MB-231 cells by immune magnetic beads method. BCSCs were treated with Apatinib, lentiviral plasmids (lncRNA ROR) and iCRT-3 (Wnt pathway inhibitors). Viability, colony numbers, sphere numbers, apoptosis, migration, invasion of BCSCs were detected by MTT, colony formation, tumor sphere, flow cytometry, wound-healing, transwell assays, respectively. The expressions of markers (ABCG2, CD44, CD90, and CD24), epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, N-cadherin, Vimentin, MMP-2, MMP-9), and Wnt/ß-catenin pathway-related proteins (Wnt3a, Wnt5a, ß-catenin) in breast cancer stem cells were determined by performing Western blot and qRT-PCR analysis. RESULTS: Apatinib decreased the viability and colony numbers of BCSCs in a concentration-dependent manner, and it also reduced sphere numbers, suppressed migration, invasion and lncRNA ROR expression, and induced apoptosis of BCSCs. However, these results were partially reversed by lncRNA ROR overexpression. Apatinib suppressed stem property, EMT process and Wnt/ß-catenin pathway in BCSCs, which was partially reversed by lncRNA ROR overexpression. Moreover, lncRNA ROR overexpression increased the colony and sphere numbers, and promoted the cell viability, apoptosis inhibition, migration and invasion of BCSCs, but these effects were partially reversed by iCRT-3. LncRNA ROR overexpression increased the stem property, EMT process and Wnt/ß-catenin pathway, which were partially counteracted by iCRT-3. CONCLUSION: Apatinib inhibited stem property and malignant biological behaviors of BCSCs by blocking Wnt/ß-catenin signal pathway through down-regulating lncRNA ROR.

20.
mSphere ; 6(2)2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731468

RESUMO

Bacteria of different shapes have adopted distinct mechanisms to faithfully coordinate morphogenesis and segregate their chromosomes prior to cell division. Despite recent focuses and advances, the mechanism of cell division in ovococci remains largely unknown. Streptococcus suis, a major zoonotic pathogen that causes problems in human health and in the global swine industry, is an elongated and ellipsoid bacterium that undergoes successive parallel splitting perpendicular to its long axis. Studies on cell cycle processes in this bacterium are limited. Here, we report that MsmK (multiple sugar metabolism protein K), an ATPase that contributes to the transport of multiple carbohydrates, has a novel role as a cell division protein in S. suis MsmK can display ATPase and GTPase activities, interact with FtsZ via the N terminus of MsmK, and promote the bundling of FtsZ protofilaments in a GTP-dependent manner in vitro Deletion of the C-terminal region or the Walker A or B motif affects the affinity between MsmK and FtsZ and decreases the ability of MsmK to promote FtsZ protofilament bundling. MsmK can form a complex with FtsZ in vivo, and its absence is not lethal but results in long chains and short, occasionally anuclear daughter cells. Superresolution microscopy revealed that the lack of MsmK in cells leads to normal septal peptidoglycan walls in mother cells but disturbed cell elongation and peripheral peptidoglycan synthesis. In summary, MsmK is a novel cell division protein that maintains cell shape and is involved in the synthesis of the peripheral cell wall.IMPORTANCE Bacterial cell division is a highly ordered process regulated in time and space and is a potential target for the development of antimicrobial drugs. Bacteria of distinct shapes depend on different cell division mechanisms, but the mechanisms used by ovococci remain largely unknown. Here, we focused on the zoonotic pathogen Streptococcus suis and identified a novel cell division protein named MsmK, which acts as an ATPase of the ATP-binding cassette-type carbohydrate transport system. MsmK has GTPase and ATPase activities. In vitro protein assays showed that MsmK interacts with FtsZ and promotes FtsZ protofilament bundling that relies on GTP. Superresolution microscopy revealed that MsmK maintains cell shape and is involved in peripheral peptidoglycan synthesis. Knowledge of the multiple functions of MsmK may broaden our understanding of known cell division processes. Further studies in this area will elucidate how bacteria can faithfully and continually multiply in a constantly changing environment.


Assuntos
Proteínas de Bactérias/metabolismo , Divisão Celular/genética , Proteínas do Citoesqueleto/metabolismo , Streptococcus suis/genética , Streptococcus suis/metabolismo , Adenosina Trifosfatases/genética , Proteínas de Bactérias/genética , Transporte Biológico , Metabolismo dos Carboidratos , Parede Celular/metabolismo , Proteínas do Citoesqueleto/genética , Fosforilação , Streptococcus suis/química
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