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1.
Eur J Pharmacol ; : 175548, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36706801

RESUMO

Aging is a process accompanied by widespread degenerative changes which are a major cause of human disease and disability. One goal of aging research is to develop interventions or drugs that can extend organism lifespan and treat age-related diseases. Here, we report the identification of a broad spectrum anti-viral agent, ribavirin, as a potential pharmacological aging intervention. Ribavirin extended the lifespan and healthspan of Caenorhabditis elegans by inhibiting Target of Rapamycin (TOR) signaling and activating AMP-activated protein kinase (AMPK). Moreover, our data indicate that ribavirin activated AMPK by reducing the levels of adenosine triphosphate (ATP) and lysosomal v-ATPase-Ragulator-AXIN Complex. Thus, our studies successfully identify ribavirin as a potential anti-aging drug, and indicate that its anti-aging effect is mediated via AMPK-TOR signaling.

2.
Clin Neuropathol ; 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36708210

RESUMO

There are limited data regarding immune surveillance mechanisms in olfactory neuroblastoma. We investigated the expression of programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD4, and CD8 in olfactory neuroblastoma to identify potential therapeutic targets. Immunohistochemistry was used to detect PD-1 and CTLA-4 and measure the numbers of CD4+ and CD8+ T cells in 56 patients with olfactory neuroblastoma. The relationships between these molecules in tumor microenvironment, clinicopathological features, and survival were analyzed. The prevalence of PD-1 in Kadish C stage was 24.14%, significantly greater than in Kadish A and B stage. CD4+ T-cell and CD8+ T-cell levels correlated with higher Hyams histological grade and Kadish stage. In addition, PD-1 was related positively with CTLA-4, CD4+ T cells, and CD8+ T cells in olfactory neuroblastoma. Univariate survival analysis showed that higher PD-1 positivity, CD8+ T cells, and Hyams grade correlated with worse clinical outcome. Multivariate analysis showed that the expression of PD-1 was an independent parameter for poor prognosis. In conclusion, olfactory neuroblastoma with PD-1 expression had more aggressive clinicopathological features and worse prognosis. PD-1 may potentially predict the outcome of olfactory neuroblastoma patients.

3.
Microb Pathog ; 175: 105991, 2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36649780

RESUMO

Gut microbes and their metabolites are essential for maintaining host health and production. The intestinal microflora of pre-weaned calves gradually tends to mature with growth and development and has high plasticity, but few studies have explored the dynamic changes of intestinal microbiota and metabolites in pre-weaned beef calves. In this study, we tracked the dynamics of faecal microbiota in 13 new-born calves by 16S rRNA gene sequencing and analysed changes in faecal amino acid levels using metabolomics. Calves were divided into the relatively high average daily gain group (HA) and the relatively low average daily gain group (LA) for comparison. The results demonstrated that the alpha diversity of the faecal microbiota increased with calf growth and development. The abundance of Porphyromonadaceae bacterium DJF B175 increased in the HA group, while that of Lactobacillus reuteri decreased. The results of the LEfSe analysis showed that the microbiota of faeces of HA calves at eight weeks of age was enriched with P. bacterium DJF B175, while Escherichia coli and L. reuteri were enriched in the microbiota of faeces of LA calves. Besides, the total amino acid concentration decreased significantly in the eighth week compared with that in the first week (P < 0.05). Overall, even under the same management conditions, microorganisms and their metabolites interact to play different dynamic regulatory roles. Our results provide new insights into changes in the gut microbiota and metabolites of pre-weaned calves.

4.
Plant Cell Environ ; 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36597190

RESUMO

ß-Glucosidase is validated as an elicitor for early immune responses in plants and it was detected in the salivary glands of Frankliniella occidentalis in previous research. Seven differentially expressed genes encoding ß-glucosidase were obtained by comparing the transcriptomes of F. occidentalis adults grown under two different CO2 concentrations (800 vs. 400 ppm), which might be associated with the differences in the interaction between F. occidentalis adults and its host plant, Phaseolus vulgaris under different CO2 levels. To verify this speculation, changes in defense responses based on the production and elimination of reactive oxygen species (ROS) in P. vulgaris leaves treated with three levels of ß-glucosidase activity under ambient CO2 (aCO2 ) and elevated CO2 (eCO2 ) were measured in this study. According to the results, significantly higher levels of ROS were noticed under eCO2 compared to aCO2 , which was caused by the increased ß-glucosidase activity in thrips due to increased cellulose content in P. vulgaris leaves under eCO2 . Together with the lower activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) in injured leaves under eCO2 , P. vulgaris leaves would be negatively affected on redox-based defense by eCO2 , thus facilitating thrips damage under climate change.

5.
Hematology ; 28(1): 2161194, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36607144

RESUMO

OBJECTIVE: SET domain containing protein 2 (SETD2) involves in the progression and development of chemotherapy resistance in acute myeloid leukemia (AML). Hence, this study aimed to investigate the relationship of SETD2 expression with disease risk, features, treatment response, and survival profile in AML. METHODS: One-hundred and sixty primary AML patients were retrospectively analyzed. Their bone marrow (BM) samples before and after induction therapy were retrieved for SETD2 detection by RT-qPCR. Moreover, SETD2 expression in BM samples of 20 disease controls (DCs) were also determined. RESULTS: SETD2 expression was downregulated in AML patients compared to DCs (P < 0.001). Higher SETD2 expression related to white blood cells ≤10 × 109/L despite not reaching statistical significance (P = 0.062). One-hundred and nineteen (74.4%) AML patients achieved complete response (CR), while the remaining 41 (25.6%) did not achieve that. Furthermore, increased SETD2 expression was associated with CR achievement (P = 0.015). Survival analyses displayed that SETD2 high (vs. low) was related to prolonged event-free survival (EFS) (P = 0.001) and overall survival (OS) (P = 0.021). Moreover, increased SETD2 quartile was correlated with favorable EFS (P = 0.004) and OS (P = 0.042). After adjustment using multivariate Cox's regression analysis, higher SETD2 quartile was independently related to prolonged EFS [hazard ratio (HR): 0.766, P = 0.013] and OS (HR: 0.669, P = 0.013). It was also noticed that SETD2 expression was elevated during the induction therapy (P < 0.001). CONCLUSION: Detection of SETD2 may assist in estimating treatment response and survival profile in AML patients.


Assuntos
Quimioterapia de Indução , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Histona-Lisina N-Metiltransferase
6.
Talanta ; 255: 124249, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36610257

RESUMO

It is extremely necessary to establish a rapid and high-throughput method to detect mycotoxins in food, because grains and cereals are greatly vulnerable to mycotoxins before and after harvest. In this study, we developed a portable aptasensor based on streptavidin magnetic microspheres (MMPs) and hybridization chain reaction (HCR) to simultaneously detect T-2 toxin and zearalenone (ZEN) in corn and oat flour. The MMPs compete with the aptamer for binding, which releases more H0 and triggers HCR with the H1 intermediate modified using 6-FAM and BHQ-1 and the unmodified H2. Subsequently, placing the HCR system corresponding to T-2 and ZEN in a constant-temperature fluorescence detector resulted in well-recovered fluorescence of the HCR products. T-2 and ZEN exhibited good fluorescence response in the dynamic range of 0.001-10 ng mL-1 and 0.01-100 ng mL-1 with detection limits of 0.1 pg mL-1 and 1.2 pg mL-1, respectively. In addition, this strategy achieved the selective detection of T-2 and ZEN in the spiked corn and oat flour samples. The results are also in good agreement with those obtained using commercial ELISA kits. This developed aptasensor with the characteristics of simple operation and portability has the application potential of establishing sensitive and portable field detection of various mycotoxins.


Assuntos
Aptâmeros de Nucleotídeos , Micotoxinas , Toxina T-2 , Zearalenona , Zearalenona/análise , Toxina T-2/análise , Contaminação de Alimentos/análise , Micotoxinas/análise , Aptâmeros de Nucleotídeos/genética , Zea mays/metabolismo , Limite de Detecção
7.
BMC Med Imaging ; 23(1): 14, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36698134

RESUMO

BACKGROUND: The aim was to compare the diffusion tensor imaging (DTI) indices derived from human hearts between 1.5 T and 3.0 T scanners. Additionally, the reproducibility of DTI indices was assessed between 1.5 T and 3.0 T scanners. METHODS: A total of 18 ex-vivo hearts were derived from patients who underwent heart transplantation. The DTI schemes were performed at 1.5 T and 3.0 T, respectively. Then, the same slices from each ex-vivo heart were selected for image analysis. The student's t-test or Wilcoxon-rank test was used to compare the statistical differences. The agreement of DTI indices was mainly reported as the interclass correlation coefficient (ICC). RESULTS: No significant differences (all P > 0.05) were found in the DTI indices between 1.5 T and 3.0 T scanners. Interestingly, the ICC of all DTI indices was relatively lower with a low b-value. The reproducibility of the helix angle (HA) was relatively lower when compared to the other DTI indices. CONCLUSION: The DTI indices of ex-vivo human hearts between 1.5 T and 3.0 T scanners had no significant differences. The consistency of DTI indices needed caution using a low b-value with different field strengths, and the relatively low reproducibility of HA should be considered.


Assuntos
Imagem de Tensor de Difusão , Coração , Humanos , Imagem de Tensor de Difusão/métodos , Reprodutibilidade dos Testes , Coração/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Interpretação de Imagem Assistida por Computador/métodos
8.
J Ophthalmol ; 2023: 3475468, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36700115

RESUMO

Purpose: To observe the decentration and tilt of implantable collamer lens (ICL) as well as possible visual effects postimplantation in primary iridociliary cysts. Methods: The present investigation was a retrospective cohort study. All 48 patients (91 eyes) who underwent ICL surgery at the Center of Refraction Surgery of Tianjin Medical University Eye Hospital between July 2018 and May 2020 were split into two groups based on the absence or presence of primary iridociliary cysts established by ultrasonic biological microscopy (UBM) examination. Intraocular pressure (IOP), corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), anterior chamber angle (ACA), anterior chamber volume (ACV), and anterior chamber depth (ACD) were recorded preoperatively and postoperatively at 1, 6, and 12 months. Additionally, we performed an analysis of the ICL vault, decentration, and tilt using a rotating Scheimpflug Oculus Pentacam camera system at 1, 6, and 12 months after surgery. Results: No serious complications were observed. Significant postoperative improvement (P < 0.05) of UDVA was established in the two studied groups; however, we did not observe statistically significant intergroup differences (P > 0.05) throughout the entire research period. In each group, the preoperative ACA, ACV, and ACD were statistically significantly reduced (P < 0.05), but no such decrease was established between their postoperative values (P > 0.05). We observed no statistical differences between both groups with regard to their values of IOP, ACA, ACV, ACD, ICL vault, ICL decentration, and tilt at 1, 6, and 12 months after surgery. Similarly, no statistically significant within-group correlation (P > 0.05) of the decentration of ICL and the tilt and the CDVA values was established. Conclusion: No postimplantation effect of ICL with a central hole on vision was established in myopia patients with primary iridociliary cysts, within certain limits of ICL decentration and tilt values.

9.
Lancet Haematol ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36702138

RESUMO

BACKGROUND: Relapse remains high in patients with myelodysplastic syndrome-refractory anaemia with excess blasts (RAEB) or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate whether granulocyte-colony stimulating factor (G-CSF) and decitabine plus busulfan-cyclophosphamide conditioning reduced relapse compared with busulfan-cyclophosphamide in this population. METHODS: We did an open-label, randomised, phase 3 trial at six hospitals in China. Eligible patients (aged 14-65 years) had myelodysplastic syndrome-RAEB or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2 and HSCT comorbidity index of 0-2. Patients were randomly assigned (1:1) to receive G-CSF, decitabine, and busulfan-cyclophosphamide conditioning or busulfan-cyclophosphamide conditioning. Randomisation was done with permuted blocks (block size four) with no stratification and was implemented through an interactive web-based response system, which was independent of study site staff and investigators. G-CSF, decitabine, and busulfan-cyclophosphamide conditioning comprised G-CSF 5 µg/kg daily subcutaneously (days -17 to -10), decitabine 20 mg/m2 daily intravenously (days -14 to -10), busulfan 3·2 mg/kg daily intravenously (days -7 to -4), and cyclophosphamide 60 mg/kg daily intravenously (days -3 and -2). Busulfan-cyclophosphamide conditioning comprised the same dose and duration of busulfan and cyclophosphamide. The primary endpoint was 2 year cumulative incidence of relapse. All efficacy and safety endpoints were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02744742; the trial is complete. FINDINGS: Between April 18, 2016, and Sept 30, 2019, 297 patients were screened for eligibility, 202 of whom were randomly assigned to G-CSF, decitabine, and busulfan-cyclophosphamide (n=101) or busulfan-cyclophosphamide (n=101) conditioning. 123 (61%) participants were male and 79 (31%) were female. Median follow-up was 32·4 months (IQR 10·0-43·0). The 2-year cumulative incidence of relapse was 10·9% (95% CI 5·8-17·9) in the G-CSF, decitabine, and busulfan-cyclophosphamide group and 24·8% (16·8-33·5) in the busulfan-cyclophosphamide group (hazard ratio 0·39 [95% CI 0·19-0·79]; p=0·011). Within 100 days after transplantation, the most common grade 3-4 adverse events in the G-CSF, decitabine, and busulfan-cyclophosphamide group and the busulfan-cyclophosphamide group were infections (34 [34%] and 32 [32%]), acute graft-versus-host disease (30 [30%] and 30 [30%]), and gastrointestinal toxicity (28 [28%] and 29 [29%]). 11 (11%) patients in the G-CSF, decitabine, and busulfan-cyclophosphamide group and 13 (13%) in the busulfan-cyclophosphamide group died of adverse events. There were no treatment related deaths. INTERPRETATION: Our results suggest that G-CSF, decitabine, and busulfan-cyclophosphamide conditioning is a better choice than busulfan-cyclophosphamide conditioning for patients with myelodysplastic syndrome-RAEB or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic HSCT. This conditioning could be a suitable therapuetic option for this patient population. FUNDING: None. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

10.
Virus Genes ; 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36701048

RESUMO

Escherichia coli is a common conditional pathogen, for which antibiotic therapy is considered an effective treatment. The imprudent use of antibiotics has led to the increase of multiple-antibiotic-resistant E. coli species. With the incidence of antibiotic resistance reaching a crisis point, it is imperative to find alternative treatments for multidrug-resistant infections. Using phage for pathogen control is a promising treatment option to combat bacterial resistance. In this study, a novel virulent Podoviridae phage Kayfunavirus TM1 infecting Escherichia coli was isolated from pig farm sewage in Guangxi, China. The one-step growth curve with the optimal multiplicity of infection of 0.01 revealed a latent period of 10 min and a burst size of 50 plaque-forming units per cell. The stability test reveals that it is stable from 4 to 60 °C and pH from 3 to 11. The double-stranded DNA genome of phage Kayfunavirus TM1 is composed of 39,948 base pairs with a GC content of 50.03%.

11.
Leuk Lymphoma ; : 1-12, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36657437

RESUMO

THZ1, a CDK7 inhibitor, has potent antitumor effects in several cancers; however, its role in Acute myeloid leukemia (AML) is unclear. We explored the effects and potential mechanisms of THZ1, alone and in combination with azacitidine (AZA), in AML cells and xenograft models. THZ1 decreased cell viability, induced apoptosis in a dose and time-dependent manner, induced G0/G1 cell cycle arrest, decreased phosphorylated CDK1 and CDK2 expression, and inhibited RNA Pol II phosphorylation at multiple serine sites. The combination of AZA and THZ1 exhibited synergistic antileukemic effects in AML cell lines and primary cells with MCL1 and c-MYC downregulation. Moreover, the combination therapy significantly decreased tumor burden and prolonged animal survival in xenograft mice models. Our data demonstrate that CDK7 inhibition induces the apoptosis of AML cells and exerts a synergistic antileukemia effect with AZA in vitro and in vivo, which supports future exploration of this combination in clinical studies.

13.
Drug Des Devel Ther ; 17: 39-53, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36660250

RESUMO

Background: Acne is a highly prevalent skin disease, and inflammation plays an important role. Compound Huangbai Liquid (CHL) is a classical traditional Chinese medicine (TCM) with remarkable clinical therapeutic effects on acne. However, a holistic network pharmacological approach to explain the mechanism of CHL in the treatment of acne has not been explored. Methods: In this study, active components and action targets of Compound Huangbai Liquid were assessed via BATMAN-TCM. The target genes related to acne were extracted from GeneCards, DisGeNet and OMIM databases. Venn diagrams to predict potential targets for the treatment of acne. Protein-Protein interaction (PPI) analysis was proceeded through String database to obtain the core protein, and the protein interaction network was constructed by Cytoscape 3.9.1. Gene Ontology (Go) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on Metascape platforms and bioinformatics.com.cn. TCM-compound-target-disease network and disease-target pathway network were constructed using Cytoscape to give the visual result. Finally, the results were further verified by establishing the mouse acne animal model. Results: This approach identified 165 active compounds, 1117 gene targets, 156 acne-related targets, and 34 potential target proteins for the treatment of acne with CHL. The biological processes were primarily related to cellular response to lipid, response to lipopolysaccharide, and regulation of secretion. The CHL was significantly associated with ten pathways including the Chagas disease and pathways in cancer. Animal experiments showed that CHL could significantly alleviate the levels of inflammatory factors and TLR4/NF-κB/p38 MAPK signaling pathway in acne. Conclusion: This study revealed the multiple active components, multiple targets, and multiple pathways of CHL in the treatment of acne, which provided a new perspective for the study of the mechanism of traditional Chinese medicine in the treatment of acne.


Assuntos
Acne Vulgar , Medicamentos de Ervas Chinesas , Animais , Camundongos , Farmacologia em Rede , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Acne Vulgar/tratamento farmacológico , Modelos Animais de Doenças , Simulação de Acoplamento Molecular
14.
Foods ; 12(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36673428

RESUMO

Bifidobacterium animalis A12 was used for the development of fermented sausage. The growth activity, tolerance, and enzyme activity of B. animalis A12 and its contribution to the texture and flavour of fermented sausages were evaluated. Additionally, the sensory texture, flavour components, and amino acid nutrients during the fermentation process were assessed. B. animalis had high tolerance to NaCl and nitrite, and B. animalis A12 had protease and lipase activities. The pH value of sausage fermented with B. animalis A12 was lower than that of sausage fermented without any fermentation strain. Hexanal, heptanal, decanal, cis-2-decanal, and 4-methoxy-benzaldehyde are the unique aldehydes flavour components of fermented sausages in the A12 group. The highest content of volatile flavour substances and amino acids, and the color and texture characteristics of fermented sausage in the experimental group at 18 h were better than those at other times. These results suggest that B. animalis A12 has the potential to be used as a starter culture for im-proving flavour and texture in fermented sausage.

15.
New Phytol ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36683527

RESUMO

CYCLIN-DEPENDENT KINASE 8 (CDK8), a component of the kinase module of the Mediator complex in Arabidopsis, is involved in many processes, including flowering, plant defense, drought, and energy stress responses. Here, we investigated cdk8 mutants and CDK8-overexpressing lines to evaluate whether CDK8 also plays a role in regulating lipid synthesis, an energy demanding anabolism. Quantitative lipid analysis demonstrated significant reductions in lipid synthesis rates and lipid accumulation in developing siliques and seedlings of cdk8, and conversely, elevated lipid contents in wild type seed overexpressing CDK8. Transactivation assays show that CDK8 is necessary for maximal transactivation of the master seed oil activator WRINKLED1(WRI1) by the seed maturation transcription factor ABSCISIC ACID INSENSITIVE3 (ABI3), supporting a direct regulatory role of CDK8 in oil synthesis. Thermophoretic studies show GEMINIVIRUS REP INTERACTING KINASE1 (GRIK1), an activating kinase of KIN10 (a catalytic subunit of SUCROSE NON-FERMENTING1-RELATED KINASE1), physically interacts with CDK8, resulting in its phosphorylation and degradation in the presence of KIN10. This work defines a mechanism whereby, once activated, KIN10 downregulates WRI1 expression and suppresses lipid synthesis via promoting the degradation of CDK8. The KIN10-CDK8 dependent regulation of lipid synthesis described herein is additional to our previously reported KIN10-dependent phosphorylation and degradation of WRI1.

16.
Lab Chip ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36688448

RESUMO

Angiogenesis, the formation of new blood vessels from existing vessels, has been associated with more than 70 diseases. Although numerous studies have established angiogenesis models, only a few indicators can be used to analyze angiogenic structures. In the present study, we developed an image-processing pipeline based on deep learning to analyze and quantify angiogenesis. We utilized several image-processing algorithms to quantify angiogenesis, including a deep learning-based cell nuclear segmentation algorithm and image skeletonization. This method could quantify and measure changes in blood vessels in response to biochemical gradients using 16 indicators, including length, width, number, and nuclear distribution. Moreover, this procedure is highly efficient for the three-dimensional quantitative analysis of angiogenesis and can be applied to diverse angiogenesis investigations.

17.
Heliyon ; 9(1): e12757, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36685395

RESUMO

Plant invasive success is attributed to invaders' ecological advantages over their native neighbors. However, increasing evidence suggests that these advantages are expected to attenuate over time because of natural enemy accumulation, ecological evolution of native species and autotoxicity. We determined how an invasive Ageratina adenophora could remain its competitive advantages over time by avoiding its autotoxicity. Our results highlighted that the autotoxicity of A. adenophora in its invaded soil was reduced by some microbes. Moreover, an autotoxic allelochemical, 2-coumaric acid glucoside, detected in the invaded soil, demonstrated distinctly autotoxic effects on its seed germination and seedling growth. However, the autotoxic effects were greatly alleviated by a bacterium Bacillus cereus, accumulated by A. adenophora. Furthermore, the allelochemical could be almost completely degraded by B. cereus within 96 h. Accordingly, we speculate that A. adenophora could aggregate B. cereus to release its autotoxicity maintaining its competitive advantages over time.

18.
Brain Behav ; : e2886, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624932

RESUMO

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) mutation is a common genetic risk factor of Parkinson's disease (PD). Presynaptic dysfunction is an early pathogenic event associated with dopamine (DA) dysregulation in striatum of the brain. DA uptake activity of DA uptake transporter (DAT) affects synaptic plasticity and motor and non-motor behavior. Synaptogyrin-3 (SYNGR3) is part of the synaptogyrin family, especially abundant in brain. Previous in vitro studies demonstrated interaction between SYNGR3 and DAT. Reduced SYNGR3 expression was observed in human PD brains with unclear reasons. METHODS: Here, we further explored whether inducing SYNGR3 expression can influence (i) cellular DA uptake using differentiated human SH-SY5Y neuronal cells, (ii) striatal synaptosomal DA uptake in a mutant LRRK2R1441G  knockin mouse model of PD, and (iii) innate rodent behavior using the marble burying test. RESULTS: Young LRRK2 mutant mice exhibited significantly lower SYNGR3 levels in striatum compared to age-matched wild-type (WT) controls, resembling level in aged WT mice. SYNGR3 is spatially co-localized with DAT at striatal presynaptic terminals, visualized by immuno-gold transmission electron microscopy and immunohistochemistry. Their protein-protein interaction was confirmed by co-immunoprecipitation. Transient overexpression of SYNGR3 in differentiated SH-SY5Y cells increased cellular DA uptake activity without affecting total DAT levels. Inducing SYNGR3 overexpression by adeno-associated virus-7 (AAV7) injection in vivo into striatum increased ex vivo synaptosomal DA uptake in LRRK2 mutant mice and improved their innate marble burying behavior. CONCLUSION: Brain SYNGR3 expression may be an important determinant to striatal DA homeostasis and synaptic function. Our preliminary behavioral test showed improved innate behavior after SYNGR3 overexpression in LRRK2 mutant mice, advocating further studies to determine the influence of SYNGR3 in the pathophysiology of DA neurons in PD.

19.
Phys Med Biol ; 68(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36595239

RESUMO

Cardiac diffusion tensor imaging (DTI) is a noninvasive method for measuring the microstructure of the myocardium. However, its long scan time significantly hinders its wide application. In this study, we developed a deep learning framework to obtain high-quality DTI parameter maps from six diffusion-weighted images (DWIs) by combining deep-learning-based image generation and tensor fitting, and named the new framework FG-Net. In contrast to frameworks explored in previous deep-learning-based fast DTI studies, FG-Net generates inter-directional DWIs from six input DWIs to supplement the loss information and improve estimation accuracy for DTI parameters. FG-Net was evaluated using two datasets ofex vivohuman hearts. The results showed that FG-Net can generate fractional anisotropy, mean diffusivity maps, and helix angle maps from only six raw DWIs, with a quantification error of less than 5%. FG-Net outperformed conventional tensor fitting and black-box network fitting in both qualitative and quantitative metrics. We also demonstrated that the proposed FG-Net can achieve highly accurate fractional anisotropy and helix angle maps in DWIs with differentb-values.


Assuntos
Imagem de Tensor de Difusão , Processamento de Imagem Assistida por Computador , Imagem de Tensor de Difusão/métodos , Processamento de Imagem Assistida por Computador/métodos , Imagem de Difusão por Ressonância Magnética/métodos , Redes Neurais de Computação , Coração/diagnóstico por imagem , Anisotropia
20.
Elife ; 122023 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-36622753

RESUMO

Chondrosarcomas are primary cancers of cartilaginous tissue and capable of alteration to highly aggressive, metastatic, and treatment-refractory states, leading to a poor prognosis with a five-year survival rate at 11 months for dedifferentiated subtype. At present, the surgical resection of chondrosarcoma is the only effective treatment, and no other treatment options including targeted therapies, conventional chemotherapies, or immunotherapies are available for these patients. Here, we identify a signal pathway way involving EZH2/SULF1/cMET axis that contributes to malignancy of chondrosarcoma and provides a potential therapeutic option for the disease. A non-biased chromatin immunoprecipitation sequence, cDNA microarray analysis, and validation of chondrosarcoma cell lines identified sulfatase 1 (SULF1) as the top EZH2-targeted gene to regulate chondrosarcoma progression. Overexpressed EZH2 resulted in downregulation of SULF1 in chondrosarcoma cell lines, which in turn activated cMET pathway. Pharmaceutical inhibition of cMET or genetically silenced cMET pathway significantly retards the chondrosarcoma growth and extends mice survival. The regulation of EZH2/SULF1/cMET axis were further validated in patient samples with chondrosarcoma. The results not only established a signal pathway promoting malignancy of chondrosarcoma but also provided a therapeutic potential for further development of effective target therapy to treat chondrosarcoma.


Assuntos
Neoplasias Ósseas , Condrossarcoma , Proteína Potenciadora do Homólogo 2 de Zeste , Sulfotransferases , Animais , Camundongos , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Cartilagem/patologia , Condrossarcoma/genética , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Sulfotransferases/genética , Humanos , Proteína Potenciadora do Homólogo 2 de Zeste/genética
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