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1.
Neural Regen Res ; 18(1): 170-175, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35799538

RESUMO

According to clinical statistics, the mortality of patients with early brainstem hemorrhage is high. In this study, we established rat models of brainstem hemorrhage by injecting type VII collagenase into the right basotegmental pontine and investigated the pathological changes of early brainstem hemorrhage using multi-sequence magnetic resonance imaging and histopathological methods. We found that brainstem hematoma gradually formed in the injured rats over the first 3 days and then reduced after 7 days. The edema that occurred was mainly of the vasogenic type. No complete myelin sheath structure was found around the focus of the brainstem hemorrhage. The integrity and continuity of nerve fibers gradually deteriorated over the first 7 days. Neuronal degeneration was mild in the first 3 days and then obviously aggravated on the 7th day. Inflammatory cytokines, interleukin-1ß, and tumor necrosis factor α appeared on the 1st day after intracerebral hemorrhage, reached peak levels on the 3rd day, and decreased from the 7th day. Our findings show the characteristics of the progression of early brainstem hemorrhage.

2.
BMC Pulm Med ; 22(1): 117, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361163

RESUMO

BACKGROUND: To investigate the value of endobronchial ultrasound (EBUS) and virtual bronchoscopic navigation (VBN) combined with rapid on-site evaluation (ROSE) in diagnosing peripheral pulmonary lesions (PPLs). METHODS: Between January 1st 2019 to September 1st 2021, EBUS and VBN examination were performed in expected consecutive patients with PPLs who were admitted to Zhangzhou Affiliated Hospital of Fujian Medical University (Fujian, China). Finally, based on the calculation of expected diagnostic yield of R-EBUS biopsy and drop out, 198 eligible patients were randomly divided into ROSE group (100 cases) and non-ROSE group (98 cases). The diagnostic yield of brushing and biopsy, the complications, the procedure time, the diagnosis time and expense during diagnosis were analyzed. RESULTS: In the ROSE group, the positive rate of EBUS brushing and biopsy were 68%, 84%, respectively. The average procedure time and diagnosis time were 18.6 ± 6.8 min, 3.84 ± 4.28 days, respectively, and the average expense was 643.44 ± 706.56 US.$ (4093.15 ± 4494.67 yuan ¥). In the controls, the positive rate of brushing and biopsy were 44%, 74%, respectively. The average procedure time and diagnosis time were 15.4 ± 5.7 min, 6.46 ± 3.66 days, respectively. And the average expense during diagnosis was 1009.27 ± 713.89 US.$ (6420.28 ± 4541.33 yuan ¥). There was significant difference in the positive rate of EBUS brushing and biopsy, diagnosis time and expense during diagnosis between both groups. And no significant difference was observed in the complications and the procedure time. Additionally, the impact of ROSE on diagnostic yield in right upper lobe and the size of lesion ≤ 2 cm in diameter was significant. CONCLUSION: In combination with ROSE, EBUS could significantly improve the positive rate of diagnosing PPLs, shorten diagnosis time and reduce expense during diagnosis. ROSE will be of great importance in the diagnosis of PPLs and medical resource.


Assuntos
Neoplasias Pulmonares , Broncoscopia/métodos , Endossonografia/métodos , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia
3.
Med Image Anal ; 81: 102560, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35932545

RESUMO

Bradykinesia is one of the core motor symptoms of Parkinson's disease (PD). Neurologists typically perform face-to-face bradykinesia assessment in PD patients according to the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). As this human-expert assessment lacks objectivity and consistency, an automated and objective assessment scheme for bradykinesia is critically needed. In this paper, we propose a tree-structure-guided graph convolutional network with contrastive learning scheme to solve the challenge of difficulty in fine-grained feature extraction and insufficient model stability, finally achieving the video-based automated assessment of Parkinsonian hand movements, which represent a vital MDS-UPDRS component for examining upper-limb bradykinesia. Specifically, a tri-directional skeleton tree scheme is proposed to achieve effective fine-grained modeling of spatial hand dependencies. In this scheme, hand skeletons are extracted from videos, and then the spatial structures of these skeletons are constructed through depth-first tree traversal. Afterwards, a tree max-pooling module is employed to establish remote exchange between outer and inner nodes, hierarchically gather the most salient motion features, and hence achieve fine-grained mining. Finally, a group-sparsity-induced momentum contrast is also developed to learn similar motion patterns under different interference through contrastive learning. This can promote stable learning of discriminative spatial-temporal features with invariant motion semantics. Comprehensive experiments on a large clinical video dataset reveal that our method achieves competitive results, and outperforms other sensor-based and RGB-depth methods. The proposed method leads to accurate assessment of PD bradykinesia through videos collected by low-cost consumer cameras of limited capabilities. Hence, our work provides a convenient tool for PD telemedicine applications with modest hardware requirements.

4.
JAMA Netw Open ; 5(8): e2225608, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35939301

RESUMO

Importance: Deep learning may be able to use patient magnetic resonance imaging (MRI) data to aid in brain tumor classification and diagnosis. Objective: To develop and clinically validate a deep learning system for automated identification and classification of 18 types of brain tumors from patient MRI data. Design, Setting, and Participants: This diagnostic study was conducted using MRI data collected between 2000 and 2019 from 37 871 patients. A deep learning system for segmentation and classification of 18 types of intracranial tumors based on T1- and T2-weighted images and T2 contrast MRI sequences was developed and tested. The diagnostic accuracy of the system was tested using 1 internal and 3 external independent data sets. The clinical value of the system was assessed by comparing the tumor diagnostic accuracy of neuroradiologists with vs without assistance of the proposed system using a separate internal test data set. Data were analyzed from March 2019 through February 2020. Main Outcomes and Measures: Changes in neuroradiologist clinical diagnostic accuracy in brain MRI scans with vs without the deep learning system were evaluated. Results: A deep learning system was trained among 37 871 patients (mean [SD] age, 41.6 [11.4] years; 18 519 women [48.9%]). It achieved a mean area under the receiver operating characteristic curve of 0.92 (95% CI, 0.84-0.99) on 1339 patients from 4 centers' data sets in diagnosis and classification of 18 types of tumors. Higher outcomes were found compared with neuroradiologists for accuracy and sensitivity and similar outcomes for specificity (for 300 patients in the Tiantan Hospital test data set: accuracy, 73.3% [95% CI, 67.7%-77.7%] vs 60.9% [95% CI, 46.8%-75.1%]; sensitivity, 88.9% [95% CI, 85.3%-92.4%] vs 53.4% [95% CI, 41.8%-64.9%]; and specificity, 96.3% [95% CI, 94.2%-98.4%] vs 97.9%; [95% CI, 97.3%-98.5%]). With the assistance of the deep learning system, the mean accuracy of neuroradiologists among 1166 patients increased by 12.0 percentage points, from 63.5% (95% CI, 60.7%-66.2%) without assistance to 75.5% (95% CI, 73.0%-77.9%) with assistance. Conclusions and Relevance: These findings suggest that deep learning system-based automated diagnosis may be associated with improved classification and diagnosis of intracranial tumors from MRI data among neuroradiologists.


Assuntos
Neoplasias Encefálicas , Aprendizado Profundo , Adulto , Encéfalo , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Curva ROC
5.
BMC Neurosci ; 23(1): 50, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35945502

RESUMO

BACKGROUND: Evidences indicate that inflammasome compounds participate in amyotrophic lateral sclerosis (ALS), a fatal progressive motoneuron degenerative disease. Researchers have observed the expressions of nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) related inflammasome components in specific regions of the central nervous system in different ALS models, but the cellular spatiotemporal evolution of this canonical inflammasome pathway and pyroptosis during ALS progression are unclear. METHODS: The spinal cords of hSOD1G93A mice (ALS mice) and age-matched littermates (CON mice) were dissected at pre-symptomatic stage (60 d), early- symptomatic stage (95 d), symptomatic stage (108 d) and late-symptomatic stage (122 d) of the disease. By using Nissl staining, double immunofluorescence labelling, qRT-PCR or western blot, we detected morphology change and the expression, cellular location of GSDMD, NLRP3, caspase-1 and IL-1ß in the ventral horn of lumbar spinal cords over the course of disease. RESULTS: Neural morphology changes and GSDMD+/NeuN+ double positive cells were observed in ventral horn from ALS mice even at 60 d of age, even though there were no changes of GSDMD mRNA and protein expressions at this stage compared with CON mice. With disease progression, compared with age-matched CON mice, increased expressions of GSDMD, NLRP3, activated caspase-1 and IL-1ß were detected. Double immunofluorescence labeling revealed that NLRP3, caspase-1, IL-1ß positive signals mainly localized in ventral horn neurons at pre- and early-symptomatic stages. From symptomatic stage to late-symptomatic stage, robust positive signals were co-expressed in reactive astrocytes and microglia. CONCLUSIONS: Early activation of the canonical NLRP3 inflammasome induced pyroptosis in ventral horn neurons, which may participate in motor neuron degeneration and initiate neuroinflammatory processes during ALS progression.

6.
Brain Behav ; : e2725, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941828

RESUMO

BACKGROUND AND PURPOSE: Diabetes mellitus is a strong independent risk factor for stroke recurrence. However, the association between diabetes duration and the prognosis of stroke remains uncertain. We aimed to characterize whether an association exists between diabetes duration and stroke outcomes in patients with ischemic stroke or transient ischemic attack (TIA). METHODS: Between 2015 and 2018, 14,674 patients with ischemic stroke or TIA within 7 days and older than 18 years from the Third China National Stroke Registry (CNSR-III) were included in this analysis. Diabetes duration at baseline was collected by face-to-face interviews and further categorized into groups of without diabetes, diabetes < 4, 4 to <8 and ≥8 years. The association between diabetes duration and clinical outcomes, including stroke recurrence, poor function outcome (modified Rankin Scale score of 3-6), and all-cause mortality at the 1-year follow-up after stroke onset, was evaluated by a multivariable Cox proportional hazard regression model, competing risk model and logistic regression model with adjustment for demographic and clinical features. RESULTS: Among the 14,674 patients included, the average age was 62.0 years, and 68.5% were male. There were 1419 (9.7%) patients who had stroke recurrence, 1912 (13.0%) who had poor function outcome, and 478 (3.3%) who had all-cause mortality at the 1-year follow-up. After adjusting for potential covariates, a diabetes duration ≥8 years was associated with an increased risk of 1-year stroke recurrence (adjusted hazards ratio [HR], 1.31; 95% CI, 1.05-1.64; p = .02) in comparison to those without Diabetes mellitus. Using a competing risk regression model, a diabetes duration ≥8 years was a significant risk factor for stroke recurrence (HR, 1.31; 95% CI, 1.12-1.53). In contrast, there was no significant association between diabetes duration < 4, 4 to <8 years and clinical outcomes. CONCLUSIONS: Long-term diabetes duration (≥8 years), but not short-term diabetes duration, was associated with an increased risk of 1-year stroke recurrence in patients with ischemic stroke or TIA.

7.
ACS Omega ; 7(29): 24942-24950, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35910152

RESUMO

The abiotic reaction products of polycyclic aromatic hydrocarbons (PAHs) with hydroxyl radicals (•OH) and nitrate radicals (•NO3) are nitro-, oxygen-, and hydroxyl-containing PAHs (NPAHs, OPAHs, and OHPAHs). Four methods of the highest occupied molecular orbital (HOMO), Fukui function (FF), dual descriptor (DD), and population of π electrons (PP-π) are selected to predict the chemical reactivity of PAHs attacked by •OH and •NO3 in this study. The predicted •OH-initiated and •NO3-initiated transformation products are compared with the main PAH transformation products (PAH-TPs) observed in the laboratory. The results indicate that PP-π and DD approaches fail to predict the transformation products of fused PAHs containing five-membered rings. By predicting the PAH-TPs of 13-14 out of the 15 parent PAHs accurately, HOMO and FF methods were shown to be suitable for predicting the transformation products formed from the abiotic reactions of fused PAHs with •OH and •NO3.

8.
Cell Mol Neurobiol ; 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35917044

RESUMO

Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS) mediated by aberrant auto-reactive immune responses. The current immune-modulatory therapies are unable to protect and repair immune-mediated neural tissue damage. One of the therapeutic targets in MS is the sphingosine-1-phosphate (S1P) pathway which signals via sphingosine-1-phosphate receptors 1-5 (S1P1-5). S1P receptors are expressed predominantly on immune and CNS cells. Considering the potential neuroprotective properties of S1P signaling, we utilized S1P1-GFP (Green fluorescent protein) reporter mice in the cuprizone-induced demyelination model to investigate in vivo S1P - S1P1 signaling in the CNS. We observed S1P1 signaling in a subset of neural stem cells in the subventricular zone (SVZ) during demyelination. During remyelination, S1P1 signaling is expressed in oligodendrocyte progenitor cells in the SVZ and mature oligodendrocytes in the medial corpus callosum (MCC). In the cuprizone model, we did not observe S1P1 signaling in neurons and astrocytes. We also observed ß-arrestin-dependent S1P1 signaling in lymphocytes during demyelination and CNS inflammation. Our findings reveal ß-arrestin-dependent S1P1 signaling in oligodendrocyte lineage cells implying a role of S1P1 signaling in remyelination.

9.
Genome Biol ; 23(1): 165, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915475

RESUMO

BACKGROUND: Due to post-cleavage residence of the Cas9-sgRNA complex at its target, Cas9-induced DNA double-strand breaks (DSBs) have to be exposed to engage DSB repair pathways. Target interaction of Cas9-sgRNA determines its target binding affinity and modulates its post-cleavage target residence duration and exposure of Cas9-induced DSBs. This exposure, via different mechanisms, may initiate variable DNA damage responses, influencing DSB repair pathway choices and contributing to mutational heterogeneity in genome editing. However, this regulation of DSB repair pathway choices is poorly understood. RESULTS: In repair of Cas9-induced DSBs, repair pathway choices vary widely at different target sites and classical nonhomologous end joining (c-NHEJ) is not even engaged at some sites. In mouse embryonic stem cells, weakening the target interaction of Cas9-sgRNA promotes bias towards c-NHEJ and increases target dissociation and reduces target residence of Cas9-sgRNAs in vitro. As an important strategy for enhancing homology-directed repair, inactivation of c-NHEJ aggravates off-target activities of Cas9-sgRNA due to its weak interaction with off-target sites. By dislodging Cas9-sgRNA from its cleaved targets, DNA replication alters DSB end configurations and suppresses c-NHEJ in favor of other repair pathways, whereas transcription has little effect on c-NHEJ engagement. Dissociation of Cas9-sgRNA from its cleaved target by DNA replication may generate three-ended DSBs, resulting in palindromic fusion of sister chromatids, a potential source for CRISPR/Cas9-induced on-target chromosomal rearrangements. CONCLUSIONS: Target residence of Cas9-sgRNA modulates DSB repair pathway choices likely through varying dissociation of Cas9-sgRNA from cleaved DNA, thus widening on-target and off-target mutational spectra in CRISPR/Cas9 genome editing.


Assuntos
Quebras de DNA de Cadeia Dupla , Edição de Genes , Animais , Sistemas CRISPR-Cas , DNA , Reparo do DNA por Junção de Extremidades , Reparo do DNA , Edição de Genes/métodos , Camundongos
10.
RSC Adv ; 12(31): 20227-20238, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35919611

RESUMO

Gas hydrate has great application potential in gas separation, energy storage, seawater desalination, etc. However, the intensity of mass and heat transfer is not enough to meet the needs of efficient hydrate synthesis. Nanoparticles, different from other liquid chemical additives, are considered as effective additives to promote hydrate formation due to their rich specific surface area and excellent thermal conductivity. This work summarizes the effect of the nanoparticles on the thermodynamics and kinetics of hydrate formation. And also, this work probes into the mechanism of the effect of the nanoparticles on the formation of hydrate as well as provides some suggestions for future research. It is found that it's difficult for nanoparticles to effectively promote the formation of the gas hydrate without the use of surfactants, because the adhesion characteristics of the nanoparticles make them easily agglomerate or even agglomerate in solution. In addition, at present, the research on the influence of nanoparticles on the formation and decomposition of natural gas hydrate is still very fragmented, and the micro mechanism of the influence is not clear, which requires more systematic and specific research in the future. At the same time, the development of nanoparticles that can promote the formation of natural gas hydrate should also become the focus of future research.

11.
Food Funct ; 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35924970

RESUMO

Nurses often experience adverse health effects associated with increasing levels of work-related stress. Stress may induce systemic effects through the HPA axis, glucocorticoid responses, and inflammatory cascades. Psychobiotics may help alleviate stress through associations of the microbiota, anti-inflammation factors, and the gut-brain axis. We aimed to investigate whether interventions with a psychobiotic, heat-killed (HK)-PS23 cells, may help improve perceived stress, anxiety, and related biological markers among highly stressed clinical nurses. This double-blind, randomized, placebo-controlled study included seventy clinical nurses from a medical center in Northern Taiwan who scored 27 or higher on the 10-item version of the Perceived Stress Scale (PSS), and participants were randomized into either taking HK-PS23 or a placebo for 8 weeks. Baseline and endpoint results of the PSS, Job Stress Scale, State and Trait Anxiety Index (STAI), emotional questionnaires, gastrointestinal severity questionnaires, Trails Marking Tests, blood biological markers, and sleep data were analyzed. While both groups demonstrated improvements in most measures over time, only the blood cortisol measure demonstrated significant group differences after the 8-week trial. Further analyses of the subgroup with higher anxiety (nurses with STAI ≥ 103) revealed that anxiety states had improved significantly in the HK-PS23 group but not in the placebo group. In summary, this placebo-controlled trial found significant reduction in the level of blood cortisol after 8 weeks of HK-PS23 use. The distinctive anxiolytic effects of HK-PS23 may be beneficial in improving perceived anxiety and stress hormone levels in female nurses under pressure. Clinical trial registration: https://clinicaltrials.gov/, identifier: NCT04452253-sub-project 1.

12.
J Neurol ; 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35925397

RESUMO

AIM: We aimed to develop a score and validate it in a prospective cohort to identify the patients with ESUS at high risk for stroke recurrence. METHODS: We assessed the stroke recurrence in ESUS patients of the Third China National Stroke Registry. We performed multivariable logistic regression analysis to identify predictors of stroke recurrence in the derivation cohort. Based on the coefficient of each covariate of the fitted multivariable model, we generated an integer-based point scoring system. We validated the score in the validation cohort assessing its discrimination and calibration. RESULTS: 2415 patients were included: 1611 in the derivation and 804 in the validation sample. We developed a scoring system (0-15 points) by assigning 2 points for hypertension, 3 points for diabetes mellitus, 4 points for multiple stage infarction, 2 points for watershed involved infarction, 1 points for left atrial diameter index (per increasing 2.5 mm/m2) and 3 points for without statin at discharge. The rate of stroke recurrence was 5.9% per year (95% CI 4.2-7.6%) in patients with low risk(a score of 0-5), 9.4% (7.3-11.5%) in patients with intermediate risk (6-10), and 26.8% (16.5-37.1%) in patients with high risk (11-15). The AUC (area under curve of receiver operator characteristic curve) of the score in the derivation cohort and validation cohort was, respectively, 0.60 (0.55-0.65) and 0.63 (0.56-0.70). The score was well calibrated both in the derivation cohort (p = 0.36) and validation cohort (p = 0.26) with the Hosmer-Lemeshow test. CONCLUSION: The developed score can improve risk stratification after ESUS in secondary care settings.

13.
Neurology ; 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918168

RESUMO

BACKGROUND AND OBJECTIVES: To explore regional discrepancy of the adherence to guideline-recommended stroke interventions, with respect to the stroke belt division (north vs. south), the economic development division (east vs. middle vs. west), and potential interaction. METHODS: We conducted a retrospective observational study using data from the Chinese Stroke Center Alliance (CSCA) from August 2015 to August 2019. The primary outcome was hospital personnel adherence to eleven individual guideline-recommended treatments. The co-primary outcomes included two summary measures: a composite score (range, 0 [nonadherence] to 1[perfect adherence]), and an all-or-none binary outcome for adherence to evidence-based stroke. Regional disparities were assessed according to the stroke belt division and the economic development division respectively, as well as the interaction between these two divisions. Multivariate regression models with generalized estimating equations were used to analyze the outcomes. RESULTS: This study included 838,229 patients with acute ischemic stroke (AIS) from 1,473 hospitals. The overall quality of care in the non-belt regions (southern China) was higher than the stroke-belt regions (northern China), as reflected by a higher composite score (0.77vs 0.75; adjusted OR: 1.03 [95% CI, 1.02-1.04]; P < 0.001) and a higher all-or-none measure (25.5% vs 22.0%; 1.32 [1.17-1.49], P < 0.001). Patients in the East and the Central had higher odds of using intravenous tissue-type plasminogen activator (East: 1.81 [95% CI, 1.51-2.18], P < 0.001; Central: 1.57 [95% CI, 1.26-1.95], P < 0.001), early antithrombotics (East: 1.77 [1.49-2.11], P < 0.001; Central: 1.37 [1.12-1.66], P < 0.001), lipid-lowering medications (East: 1.29 [1.08-1.53], P < 0.001), and DVT prophylaxis (East: 1.28 [1.08-1.50], P = 0.003) compared to those in the West. Patients in the non-belt regions had higher odds of getting dysphagia screening (1.82 [1.55-2.13], P < 0.001) and rehabilitation assessment (which though varied among different economic development levels). Reflected by significant interaction effects, for patients in the East, those in the non-belt regions had greater odds of receiving anticoagulation (1.62 [1.34-1.96]; P < 0.001) but lower odds of receiving antihtrombotics (0.63 [0.52-0.77]; P < 0.001) and antidiabetic medication (0.87 [0.77-0.99]; P= 0.03); for patients in the West, those in the non-belt regions were less likely to receive antihypertensive (0.64 [0.46-0.88]; P = 0.004) and antidiabetic (0.66 [0.54-0.81]; P < 0.001) medications. DISCUSSION: Stroke care performance measures differed across regions, along the stroke-belt division, and the economic development division. The overall quality of care in the non-stroke-belt regions was higher than the stroke-belt regions. The two divisions had interaction effects on several individual measures.

14.
Acta Pharmacol Sin ; 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918412

RESUMO

Rheumatoid arthritis (RA) is characterized by synovial inflammation, synoviocyte expansion and damage to cartilage and bone. We recently reported that peroxisome proliferator-activated receptor (PPAR)-γ inhibited the proliferation and activation of fibroblast-like synoviocytes (FLS), and was downregulated in RA synovial. In this study we investigated the role of PPAR-γ in RA and the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced in rats; from D15, AIA rats were orally administered pioglitazone (30 mg·kg-1·d-1) or rosiglitazone (4 mg·kg-1·d-1) for 14 days. Collagen-induced arthritis (CIA) was induced in wild-type and Ppar-γ+/- mice. We showed that the expression of PPAR-γ was significantly reduced, whereas that of TNF-α was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-γ expression (Ppar-γ+/-) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-γ antagonist) or si-PPAR-γ promoted the activation and inflammation of TNF-α-induced FLS in vitro. On the contrary, administration of PPAR-γ agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-γ into the ankle of AIA rat in vivo induced overexpression of PPAR-γ, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-γ into the ankle also reversed the ankle inflammation in Ppar-γ+/- CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-γ overexpression was closely related to p53 signaling pathway in TNF-α-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-γ in RA FLS. Taken together, PPAR-γ alleviates the inflammatory response of TNF-α-induced FLS by binding p53 in RA.

16.
Phytomedicine ; 105: 154366, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35933900

RESUMO

BACKGROUND: AMP-activated protein kinase (AMPK) is an effective target for treating diabetes. However, successful drug development is delayed due to issues including toxicity. Plant-derived natural product AMPK activators have emerged as a new way to treat diabetes due to its potential low safety risks. Here, we studied the effect of hernandezine (HER), a natural product derived from Thalictrum, in activating AMPK and treating T2D in mouse models. METHOD: We tested HER in various cells and tissues, including primary hepatocytes, skeletal myotubes cell lines, as well as major metabolic tissues from diabetic (db/db) and diet-induced obesity (DIO) model mice. The effect of HER on glucose uptake via AMPK in vitro and in vivo was confirmed utilizing cell transfection and adenovirus interference analysis. Tissue staining assessed the effect of HER on adipogenesis. Real-time quantitative polymerase chain reaction (real-time PCR) was applied to verify the effect of HER on transcription factors. Western blot analysis was used to determine the activation of phosphorylated AMPK and ACC pathways. RESULTS: Biochemically, we found that HER prevented pAMPK from dephosphorylation to prolong its activity, disproving previous direct activation model and providing a new model to explain HER-mediated AMPK activation. HER could be orally delivered to animals and has a 3-fold long half-life in vivo as compared to metformin. Importantly, long-term oral HER treatment potently reduced body weight and blood glucose in both type 2 diabetes mullitus (T2DM) mouse models by increasing glucose disposal and reducing lipogenesis, and appeared not to induce cardiac hypertrophy. CONCLUSION: Natural product HER indirectly activates AMPK by suppressing its dephosphorylation. Oral HER effectively alleviated hyperglycemia and reduced body weight in T2D mouse models, appeared to have a low risk of causing cardiac hypertrophy, and might be a potential therapeutic option for T2DM.

17.
Rheumatol Ther ; 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35932360

RESUMO

INTRODUCTION: Ankylosing spondylitis (AS) is a chronic progressive inflammatory disease of the spine and its affiliated tissues. AS mainly affects the axial bone, sacroiliac joint, hip joint, spinal facet, and adjacent ligaments. We used machine learning (ML) methods to construct diagnostic models based on blood routine examination, liver function test, and kidney function test of patients with AS. This method will help clinicians enhance diagnostic efficiency and allow patients to receive systematic treatment as soon as possible. METHODS: We consecutively screened 348 patients with AS through complete blood routine examination, liver function test, and kidney function test at the First Affiliated Hospital of Guangxi Medical University according to the modified New York criteria (diagnostic criteria for AS). By using random sampling, the patients were randomly divided into training and validation cohorts. The training cohort included 258 patients with AS and 247 patients without AS, and the validation cohort included 90 patients with AS and 113 patients without AS. We used three ML methods (LASSO, random forest, and support vector machine recursive feature elimination) to screen feature variables and then took the intersection to obtain the prediction model. In addition, we used the prediction model on the validation cohort. RESULTS: Seven factors-erythrocyte sedimentation rate (ESR), red blood cell count (RBC), mean platelet volume (MPV), albumin (ALB), aspartate aminotransferase (AST), and creatinine (Cr)-were selected to construct a nomogram diagnostic model through ML. In the training cohort, the C value and area under the curve (AUC) value of this nomogram was 0.878 and 0.8779462, respectively. The C value and AUC value of the nomogram in the validation cohort was 0.823 and 0.8232055, respectively. Calibration curves in the training and validation cohorts showed satisfactory agreement between nomogram predictions and actual probabilities. The decision curve analysis showed that the nonadherence nomogram was clinically useful when intervention was decided at the nonadherence possibility threshold of 1%. CONCLUSION: Our ML model can satisfactorily predict patients with AS. This nomogram can help orthopedic surgeons devise more personalized and rational clinical strategies.


AS is a chronic progressive inflammatory disease of the spine and its affiliated tissues. AS starts gradually, and its early symptoms are mild. Some hospitals lack HLA-B27 and related imaging instruments to assist in the diagnosis of AS. There are relatively few studies on liver function and kidney function of patients with AS. We used ML methods to construct diagnostic models. Our model can satisfactorily predict patients with AS. This diagnostic model can help orthopedic surgeons devise more personalized and rational clinical strategies.

18.
Expert Opin Drug Saf ; : 1-6, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35924402

RESUMO

BACKGROUND: Epidermal Growth Factor Receptor/ Anaplastic Lymphoma Kinase Tyrosine kinase inhibitors (EGFR/ALK TKIs) may provoke fatal interstitial pneumonitis (IP). The study was conducted to characterize the main characteristics of EGFR/ALK TKI-induced IP and identify factors associated with death. RESEARCH DESIGN AND METHODS: A disproportionality analysis was conducted using Vigibase, the World Health Organization pharmacovigilance database. Clinical features of patients with EGFR/ALK-TKI-related IP were compared between the fatal and non-fatal groups. RESULTS: A total of 3355 EGFR/ALK-TKI-IP events were identified, over half of them from Asia (57.47%) and mostly the aged (63.21%). Osimertinib appeared the strongest IP association. The median time to onset (TTO) was 40 (interquartile range [IQR] 16-84) days. There were significant differences between the fatal and non-fatal groups in terms of reporting year and TKI regimens (P < 0.05). The fatality rate of erlotinib-induced IP was the highest (35.54%). CONCLUSION: Our study showed that EGFR/ALK TKIs were associated with IP that had a high fatality rate and tended to occur earlier in fatal cases. It is necessary to raise awareness of IP surveillance when EGFR/ALK TKIs were administered.

19.
Cancer Lett ; : 215851, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35926819

RESUMO

DNA damage repair plays a vital role in maintaining the genomic integrity of cells and has been exploited therapeutically in the treatment of cancer. We have previously demonstrated that the upregulation of CXorf67 in posterior fossa type A ependymoma sensitizes tumor cells to PARP inhibitors by suppressing the PALB2-BRCA2 protein-protein interaction (PPI). Here, we performed structure-based virtual screening of ∼2 million small molecular entities followed by NanoBiT-based screening, and determined that pentagalloylglucose (PGG) disrupts the PALB2-BRCA2 PPI. Structure-based molecular docking and in vitro binding affinity assays revealed that PGG occupies a well-defined binding groove in the tips of the fourth and fifth blades of the PALB2 WD40 domain. PGG reduces BRCA2 recruitment to DNA damage sites and inhibits the formation of RAD51 foci, suppressing homologous recombination repair. PGG also inhibits proliferation and survival in several cancer cell lines, including breast cancer and medulloblastoma cells, and suppresses the in vivo growth of tumor xenografts. Thus, PGG is a specific inhibitor of the PALB2-BRCA2 PPI, which has potential value in cancer treatment to sensitize tumors to PARP inhibitors and radiotherapy.

20.
Parasit Vectors ; 15(1): 279, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927758

RESUMO

BACKGROUND: Toxocara canis is a cosmopolitan parasite with a significant adverse impact on the health of humans and animals. The spleen is a major immune organ that plays essential roles in protecting the host against various infections. However, its role in T. canis infection has not received much attention. METHODS: We performed sequencing-based transcriptome profiling of long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression in the spleen of Beagle puppies at 24 h post-infection (hpi), 96 hpi and 36 days post-infection (dpi). Deep sequencing of RNAs isolated from the spleen of six puppies (three infected and three control) at each time point after infection was conducted. RESULTS: Our analysis revealed 614 differentially expressed (DE) lncRNAs and 262 DEmRNAs at 24 hpi; 726 DElncRNAs and 878 DEmRNAs at 96 hpi; and 686 DElncRNAs and 504 DEmRNAs at 36 dpi. Of those, 35 DElncRNA transcripts and 11 DEmRNAs were detected at all three time points post-infection. Many DE genes were enriched in immune response, such as ifit1, ifit2 and rorc. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that some genes (e.g. prkx and tnfrsf11a) were involved in the T cell receptor signaling pathway, calcium signaling pathway, Ras signaling pathway and NF-κB signaling pathway. CONCLUSIONS: The findings of this study show marked alterations in the expression profiles of spleen lncRNAs and mRNAs, with possible implications in the pathophysiology of toxocariasis.


Assuntos
RNA Longo não Codificante , Toxocara canis , Animais , Cães , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Baço/metabolismo , Toxocara canis/genética , Toxocara canis/metabolismo
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