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1.
Anesth Analg ; 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36322461

RESUMO

BACKGROUND: The aim of this study was to explore whether ice slush (IS) causing local hypothermia can effectively inhibit the oculocardiac reflex (OCR) during strabismus surgery. METHODS: This prospective, randomized, double-blind study included 58 patients with concomitant strabismus scheduled for lateral rectus (LR) recession under general anesthesia. Patients were randomly allocated to receive IS (IS group) or standard treatment (control group) with sterile saline at room temperature before surgery. OCR was defined as a sudden decrease in heart rate (HR) of >15% from baseline. If one incidence of the OCR was found in 1 patient in any stage (0/I/II/III), the patient was defined as an OCR responder, and the incidence of overall OCR was the incidence of OCR responders. The primary outcome was the incidence of overall OCR during all stages of the surgery, which was analyzed by the Z test and computed based on the absolute risk difference with 2-sided 95% confidence intervals (CIs) using the Newcombe method. RESULTS: The overall OCR occurred in 19 of 29 patients (62.5% [95% CI, 45.7-82.1]) in the IS group and 28 of 29 patients (96.6% [95% CI, 82.2-99.9]) in the control group (absolute risk difference, -31.0% [95% CI, -49.4 to -11.0]; Z test, P < .001), which demonstrated that the incidence of overall OCR in IS group was significantly lower than that in the control group. CONCLUSIONS: IS on the ocular surface causing local hypothermia is a promising and easily accessible method to reduce the overall OCR, which can improve the safety of strabismus surgery.

2.
Front Pharmacol ; 13: 1025618, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36330100

RESUMO

Background: Nano drug delivery system (NDDS) can significantly improve the delivery and efficacy of drugs against pancreatic cancer (PC) in many ways. The purpose of this study is to explore the related research fields of NDDS for PC from the perspective of bibliometrics. Methods: Articles and reviews on NDDS for PC published between 2003 and 2022 were obtained from the Web of Science Core Collection. CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel were comprehensively used for bibliometric and visual analysis. Results: A total of 1329 papers on NDDS for PC were included. The number of papers showed an upward trend over the past 20 years. The United States contributed the most papers, followed by China, and India. Also, the United States had the highest number of total citations and H-index. The institution with the most papers was Chinese Acad Sci, which was also the most important in international institutional cooperation. Professors Couvreur P and Kazuoka K made great achievements in this field. JOURNAL OF CONTROLLED RELEASE published the most papers and was cited the most. The topics related to the tumor microenvironment such as "tumor microenvironment", "tumor penetration", "hypoxia", "exosome", and "autophagy", PC treatment-related topics such as "immunotherapy", "combination therapy", "alternating magnetic field/magnetic hyperthermia", and "ultrasound", and gene therapy dominated by "siRNA" and "miRNA" were the research hotspots in the field of NDDS for PC. Conclusion: This study systematically uncovered a holistic picture of the performance of NDDS for PC-related literature over the past 20 years. We provided scholars to understand key information in this field with the perspective of bibliometrics, which we believe may greatly facilitate future research in this field.

3.
J Orthop Surg Res ; 17(1): 490, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384537

RESUMO

BACKGROUND: The quantity and quality of the paraspinal muscles are important factors that lead to spinal diseases. However, the role of paraspinal muscles in the pathogenesis of adjacent segment disease (ASD) after lumbar fusion surgery is rarely studied. The purpose of the research is to investigate the relationship between paraspinal muscles and ASD. METHODS: Thirty-three patients with ASD were included, and 33 controls without ASD were matched according to the basic demographic information. Cross-sectional images of the paraspinal muscles at each intervertebral disk level (L1-S1) before the first operation were analyzed, and the cross-sectional area (CSA) and degree of fat infiltration (FI) of the multifidus (MF) muscle and the erector spinae muscle were compared. RESULTS: There was no significant difference in demographic characteristics (P > 0.05) except for the bone mineral density (BMD) (P = 0.037) between the two groups. There were significant differences in the CSA and FI of the lower lumbar multifidus (P < 0.05). The CSA of the MF muscle at L3-L4, FI of the MF muscle at L4-L5 and L5-S1 and BMD were important risk factors for ASD. Among patients who received two-segment fusion for the first time, significant difference was observed in the degree of FI of the MF muscle in the lower lumbar segment (P < 0.05). CONCLUSIONS: The CSA, FI and BMD of the lower lumbar MF muscle were closely related to the occurrence of ASD. The CSA of the MF muscle at L3-L4, the degree of FI of the MF muscle at L4-L5 and L5-S1 and BMD were important risk factors for ASD. The number of fusion segments in the first operation has a certain impact on the above-mentioned conclusions.


Assuntos
Densidade Óssea , Músculos Paraespinais , Humanos , Músculos Paraespinais/diagnóstico por imagem , Músculos Paraespinais/patologia , Estudos de Casos e Controles , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Imageamento por Ressonância Magnética , Fatores de Risco
4.
J Org Chem ; 87(22): 15061-15070, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36321917

RESUMO

A regio- and chemoselective sulfonylation of propargyl alcohols with sulfinamides in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) was developed. It provided straightforward and mild access to multi-substituted allenyl sulfones by using sulfinamides as the sulfonyl sources. This transformation was promoted by HFIP and did not require any catalysts or oxidants, which allowed for the successful conversion of various tertiary and secondary propargyl alcohols into allenyl sulfones in high yields.

5.
Bioinformatics ; 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36383169

RESUMO

MOTIVATION: Association testing on genome-wide association studies (GWAS) data is commonly performed under a single (mostly additive) genetic model framework. However, the underlying true genetic mechanisms are often unknown in practice for most complex traits. When the employed inheritance model deviates from the underlying model, statistical power may be reduced. To overcome this challenge, an integrative association test that directly infers the underlying genetic model from GWAS data has previously been proposed for single-SNP analysis. RESULTS: In this article, we propose a Cauchy combination Genetic Model-based association test (CauchyGM) under a generalized linear model framework for SNP-set level analysis. CauchyGM does not require prior knowledge on the underlying inheritance patterns of each SNP. It performs a score test which first estimates an individual p-value of each SNP in a SNP-set with both minor allele frequency (MAF) > 1% and three genotypes and further aggregates the rest SNPs using SKAT. CauchyGM then combines the correlated p-values across multiple SNPs and different genetic models within the set using Cauchy Combination Test. To further accommodate both sparse and dense signal patterns, we also propose an omnibus association test (CauchyGM-O) by combining CauchyGM with SKAT and burden test. Our extensive simulations show that both CauchyGM and CauchyGM-O maintain type I error well at the genome-wide significance level and provide substantial power improvement compared to existing methods. We apply our methods to a pharmacogenomic GWAS data from a large cardiovascular randomized clinical trial. Both CauchyGM and CauchyGM-O identify several novel genome-wide significant genes. AVAILABILITY AND IMPLEMENTATION: The R package CauchyGM is publicly available on github: https://github.com/ykim03517/CauchyGM. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

6.
World Neurosurg ; 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36436775

RESUMO

OBJECTIVE: To compare the preoperative and postoperative hand function and radiographic parameters in female patients with HD. METHODS: Consecutive female patients with HD undergoing anterior cervical discectomy and fusion were followed-up. The postoperative hand functional data were obtained from the last follow-up, while the postoperative radiographic data were obtained from the examinations in 3- or 6-month follow-up after surgical treatments. The preoperative and postoperative data of hand functional and radiographic assessments were collected and compared between them. Logistic regression analysis was used to clear potential risk factors for surgical treatment. RESULTS: In all, 15 female patients with HD were included in the follow-up study over 9 years. Significant differences were found in total scores (P<0.001) and all five dimensions, including function (P=0.003), activities of daily life (P=0.002), work (P=0.003), satisfaction (P=0.002), appearance (P=0.005), and HD-specific hand symptoms (P=0.001) in hand functional assessment. The comparison of C2-7 Cobb angle was statistically different (P=0.042) in radiographic assessments. The course of illness was of marginal significance (P=0.065) with curative effect of surgical treatment in logistic regression analysis. CONCLUSIONS: Anterior cervical discectomy and fusion was an effective way to treat female patients with HD, and the course of illness may be correlated with the efficacy of surgery. For some female patients with HD with a clear diagnosis, early surgical treatment is worthy of clinical consideration.

7.
Toxicol Sci ; 2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36308466

RESUMO

Lead (Pb) -induced microglial activation and neuroinflammation has been considered as one of the main pathological events of Pb neurotoxicity. The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. However, the relationship between chronic Pb exposure and neurogenic NLRP3 inflammasome is unclear. Therefore, the aim of this study was to characterize the role of NLRP3 inflammasome activation during the chronic Pb exposure using in vitro and in vivo models. Our results showed that chronic Pb exposure induce learning and memory impairment in mice, mainly related to the activation of microglia and NLRP3 inflammasome. This phenomenon was reversed in mice by treating with the NLRP3 inhibitor MCC950 and using NLRP3-/- mice. In addition, Pb caused the activation of NLRP3 inflammasome, the production of mitochondrial ROS (mtROS) and mitochondrial Ca2+ overload in BV2 cells. Amelioration of mtROS abolished Pb-induced NLRP3 inflammasome activation. Moreover, after regulation of Ca2+ redistribution, mtROS and NLRP3 inflammasome activation was restored. In conclusion, NLRP3 inflammasome activation in microglia plays a vital role in Pb neurotoxicity, by a novel mechanism of enhancing mtROS production and Ca2+ redistribution.

8.
Toxicol Appl Pharmacol ; 455: 116266, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36209798

RESUMO

We have previously reported that preconception exposure to iAs may contribute to the development of diabetes in mouse offspring by altering gene expressions in paternal sperm. However, the individual contributions of iAs and its methylated metabolites, monomethylated arsenic (MAs) and dimethylated arsenic (DMAs), to changes in the sperm transcriptome could not be determined because all three As species are present in sperm after in vivo iAs exposure. The goal of the present study was to assess As species-specific effects using an ex vivo model. We exposed freshly isolated mouse sperm to either 0.1 or 1 µM arsenite (iAsIII) or the methylated trivalent arsenicals, MAsIII and DMAsIII, and used RNA-sequencing to identify differentially expressed genes, enriched pathways, and associated protein networks. For all arsenicals tested, the exposures to 0.1 µM concentrations had greater effects on gene expression than 1 µM exposures. Transcription factor AP-1 and B cell receptor complexes were the most significantly enriched pathways in sperm exposed to 0.1 µM iAsIII. The Mre11 complex and Antigen processing were top pathways targeted by exposure to 0.1 µM MAsIII and DMAsIII, respectively. While there was no overlap between gene transcripts altered by ex vivo exposures in the present study and those altered by in vivo exposure in our prior work, several pathways were shared, including PI3K-Akt signaling, Focal adhesion, and Extracellular matrix receptor interaction pathways. Notably, the protein networks associated with these pathways included those with known roles in diabetes. This study is the first to assess the As species-specific effects on sperm transcriptome, linking these effects to the diabetogenic effects of iAs exposure.


Assuntos
Arsênio , Arsenicais , Arsenitos , Diabetes Mellitus , Camundongos , Masculino , Animais , Arsenitos/toxicidade , Arsenitos/metabolismo , Arsênio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Transcrição AP-1/metabolismo , Metilação , Sêmen/metabolismo , Arsenicais/farmacologia , Diabetes Mellitus/metabolismo , Espermatozoides/metabolismo , RNA/metabolismo , Transcrição Genética , Receptores de Antígenos de Linfócitos B/metabolismo
9.
Int Immunopharmacol ; 113(Pt A): 109333, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36306558

RESUMO

Epithelial barrier dysfunction is involved in the pathogenesis of asthma. Previous studies show that SUMOylation can regulate epithelial junction molecule localization. However, the role of SUMOylation in epithelial barrier dysfunction in asthma remains unclear. This study found that inhibition of SUMOylation attenuates house dust mite (HDM)-induced epithelial barrier dysfunction. The SUMOylation levels of junction molecules were determined by co-immunoprecipitation (CO-IP) and proximity ligation assay (PLA). HDM treatment significantly enhanced SUMOylation levels of ß-catenin, while no effect was seen on ZO-1, Occludin, and E-cadherin SUMOylation levels. Inhibition of ß-catenin SUMOylation through 2-D08 treatment or SUMOylation modification site mutant (K233A) promoted its membrane localization and repressed Wnt/ß-catenin signaling. Further, we identified that CBX4, an E3 ligase, mediated SUMOylation of ß-catenin. Knockdown of CBX4 promoted ß-catenin membrane localization and improved epithelial barrier function. In vivo analysis showed that AAV6-shCBX4-mediated knockdown of CBX4 attenuated HDM-induced allergic airway inflammation and epithelial barrier dysfunction. The findings showed that inhibiting ß-catenin SUMOylation by targeting CBX4 mitigated HDM-induced epithelial barrier dysfunction in asthma.


Assuntos
Asma , beta Catenina , Animais , Humanos , beta Catenina/metabolismo , Sumoilação , Linhagem Celular , Pyroglyphidae , Asma/patologia , Dermatophagoides pteronyssinus/metabolismo , Ligases/genética , Proteínas do Grupo Polycomb
10.
Clin Infect Dis ; 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36065768

RESUMO

BACKGROUND: Lingering symptoms have been reported by survivors of Ebola Virus Disease (EVD). There are few data describing the persistence and severity of these symptoms over time. METHODS: Symptoms of headache, fatigue, joint pain, muscle pain, hearing loss, visual loss, numbness of hands or feet were longitudinally assessed among participants in the Liberian Ebola Survivors Cohort study. Generalized linear mixed effects models, adjusted for sex and age, were used to calculate the odds of reporting a symptom and it being rated as highly interfering with life. RESULTS: From June 2015 to June 2016, 326 survivors were enrolled a median of 389 days (range 51-614) from acute EVD. At baseline 75.2% reported at least one symptom; 85.8% were highly interfering with life. Over a median follow-up of 5.9 years, reporting of any symptom declined (odds ratio for each 90 days of follow-up = 0.96, 95% CI: 0.95,0.97; p < 0.0001) with all symptoms declining except for numbness of hands or feet. Rating of any symptom as highly interfering decreased over time. Among 311 with 5 years of follow-up, 52% (n = 161) reported a symptom and 29% (n = 47) of these as highly interfering with their lives. CONCLUSION: Major post-EVD symptoms are common early during convalescence and decline over time along with severity. However, even 5 years after acute infection, a majority continue to have symptoms and, for many, these continue to greatly impact their lives. These findings call for investigations to identify the mechanisms of post-EVD sequelae and therapeutic interventions to benefit the thousands of effected EVD survivors.

11.
J Cell Mol Med ; 26(19): 4974-4985, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36128650

RESUMO

Orai family are a calcium channel of cell membrane extracellular Ca2+ influx which participates in tissue fibrosis. But the roles of Orai3 have less attention on the mechanism of regulating lung fibrosis. In this study, we found that Orai3 expression was increased significantly in BLM-induced lung fibrosis. The knockdown of Orai3 decreased TGF-ß1-induced fibroblast proliferation, ECM production, activation of NFAT1 and Calpain/ERK signal pathway and glycolysis levels. Orai3 interacting with Orai1 was increased in BLM-induced lung fibrosis and TGF-ß1-induced fibroblast, while the Stim1 interacting with Orai1 and SOCE activity was suppressed, leading in a high and stable extracellular Ca2+ influx. Furthermore, the over-expression of Orai3 did not enhance Orai3 interacting with Orai1 under TGF-ß1 free fibroblast. And then, the deeper mechanism of TGF-ß1-induced increased SEPTIN4 promoted Orai3 interacting with Orai1. Our results indicated that Orai3 could be one of the therapy targets for PF in which remodels Orai channel, suppresses SOCE activity and activated fibroblast to alleviate fibrosis progress.


Assuntos
Fibrose Pulmonar , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Calpaína/metabolismo , Fibroblastos/metabolismo , Humanos , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Fibrose Pulmonar/genética , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-36081760

RESUMO

For more than a decade, genetically engineered autologous T-cells have been successfully employed as immunotherapy drugs for patients with incurable blood cancers. The active components in some of these game-changing medicines are autologous T-cells that express viral vector-delivered chimeric antigen receptors (CARs), which specifically target proteins that are preferentially expressed on cancer cells. Some of these therapeutic CAR expressing T-cells (CAR-Ts) are engineered via transduction with γ-retroviral vectors (γ-RVVs) produced in a stable producer cell line that was derived from murine PG13 packaging cells (ATCC CRL-10686). Earlier studies reported on the copackaging of murine virus-like 30S RNA (VL30) genomes with γ-retroviral vectors generated in murine stable packaging cells. In an earlier study, VL30 mRNA was found to enhance the metastatic potential of human melanoma cells. These findings raise biosafety concerns regarding the possibility that therapeutic CAR-Ts have been inadvertently contaminated with potentially oncogenic VL30 retrotransposons. In this study, we demonstrated the presence of infectious VL30 particles in PG13 cell-conditioned media and observed the ability of these particles to deliver transcriptionally active VL30 genomes to human cells. Notably, VL30 genomes packaged by HIV-1-based vector particles transduced naïve human cells in culture. Furthermore, we detected the transfer and expression of VL30 genomes in clinical-grade CAR-T cells generated by transduction with PG13 cell-derived γ-retroviral vectors. Our findings raise biosafety concerns regarding the use of murine packaging cell lines in ongoing clinical applications.

13.
Front Med (Lausanne) ; 9: 933799, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36117977

RESUMO

Since the outbreak of SARS-CoV-2/COVID-19 in Wuhan, China in 2019, it has rapidly spread to the world, and the number of infections has gradually increased. The hospitalization rate of patients has also gradually increased, which poses a huge challenge to hospitals and medical staff for patients with SARS-CoV-2 requiring surgical treatment. Therefore, avoiding cross-infection in the operating room is an important protective work. The operating room is an important department of the hospital, scientific and reasonable management is particularly important. Therefore, we have put forward corresponding suggestions and strategies for preoperative preparation and evaluation of patients, intraoperative management, postoperative terminal management, and protection of medical staff, and hope that these measures can better prevent and control the infection of SARS-CoV-2 in the operating room.

14.
Transl Oncol ; 26: 101502, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36137350

RESUMO

Heat shock protein 90 (Hsp90) has been an important therapeutic target for cancer therapy for decades. Unexpectedly, the monotherapy of N-terminal Hsp90 inhibitor STA9090 related clinical trials halted in phase III, and metastases were reported in animal models with the treatment of N-terminal Hsp90 inhibitors. Vacuolar protein sorting-associated protein 35 (VPS35) plays a vital role in endosome-derived EV (extracellular vesicle) traffic in neurodegeneration diseases, but no vps35 related EV were reported in tumors till now. Since tumor derived EVs contributes to metastasis and VPS35 is recently found to be involved in the invasion and metastasis of hepatocellular carcinoma (HCC), whether N-terminal Hsp90 inhibitor STA9090 induced EVs generation and the role of VPS35 in it were explored in this study. We found that N-terminal Hsp90 inhibitor STA9090 upregulated Bclaf1 and VPS35 levels, increased the secretion of EVs, and STA9090-induced-EVs promoted the invasion of HepG2 cells. As the clinical data suggested that the increased Bclaf1 and VPS35 levels correlated with increased metastasis and poorer prognosis in HCC, we focused on the Bclaf1-VPS35-EVs axis to further explore the mechanism of VPS35-related metastasis. The results demonstrated that Bclaf1 facilitated the transcription of VPS35 via bZIP domain, and knockdown of Bclaf1 or VPS35 alleviated pro-metastatic capability of STA9090-induced-EVs. All the results revealed the role of Bclaf1-VPS35-EVs axis on metastasis of HCC, and VPS35 knockdown decreased Hsp90 Inhibitor STA9090 induced extracellular vesicle release and metastasis, which provided a new combination therapeutic strategy to inhibit the metastasis of HCC caused by N-terminal Hsp90 inhibitor induced extracellular vesicles.

15.
BMC Musculoskelet Disord ; 23(1): 848, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071416

RESUMO

BACKGROUND: This study aimed to compare the biomechanical differences between anterior cervical discectomy and fusion (ACDF) with multiple-level separate plates and conventional long plates by using finite element analysis. METHODS: The following four finite element models were created to simulate various fixations: (1) C4-6 ACDF with multiple plates, (2) C4-6 ACDF with a single plate, (3) C3-6 ACDF with multiple plates, and (4) C3-6 ACDF with a single plate. The maximum Von-mises stress of the cage and fixation, compressive force of the adjacent intervertebral discs and range of motion (ROM) of different segments in the four models were calculated and analyzed. RESULTS: For C4-6 ACDF, the maximum Von-mises stress of the cage and fixation was lower in the multiple plate fixation model in all motion states. Similarly, for the C3-6 ACDF models, the peak stress of the C3-4 and C5-6 cages was lower with multiple plates fixation in all motions but the stress of the C4-5 cage in the multiple plates model was slightly higher in flexion, bending and rotation. Besides, applying multiple plates in C3-6 ACDF models resulted in a decreased maximum stress of the fixation under different motions except for bending. In both the C4-6 ACDF and C3-6 ACDF models, the ROM values of the adjacent motion segments were lower in the multiple plates models in extension, bending and rotation. In the C4-6 ACDF models, the peak stress on the adjacent intervertebral discs in the multiple plates models was slightly smaller. In C3-6 ACDF models, the maximum stress on the adjacent intervertebral discs was larger in the single-plate model under flexion, bending and rotation movements. CONCLUSION: Multiple plates fixation has a positive effect on increasing stiffness and maintaining the ROM of adjacent segments, indicating lower risk of construct failure and adjacent segment degeneration. Further studies are required to confirm its efficacy in clinical practice.


Assuntos
Vértebras Cervicais , Fusão Vertebral , Fenômenos Biomecânicos , Vértebras Cervicais/cirurgia , Discotomia/métodos , Análise de Elementos Finitos , Humanos , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos
16.
Stem Cell Rev Rep ; 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35962175

RESUMO

Stem cell senescence and depletion are major causes of aging and aging-related diseases. The NAD (Nicotinamide adenine dinucleotide) - SIRT1 (Silent Information Regulator 1) - PARP1 (Poly (ADP-ribose) polymerase-1) axis has gained interest owing to its significant role in regulating stem cell senescence and organismal aging. A recent study from our lab showed that pre-B-cell leukemia transcription factor1 (PBX1) overexpression attenuates hair follicle-derived mesenchymal stem cells (HF-MSCs) senescence and apoptosis by regulating ROS-mediated DNA damage via PARP1 downregulation; thus, suggesting that PARP1 downregulation is a common manifestation of the roles of both PBX1 and SIRT1 in HF-MSCs senescence attenuation, and implying a potential link between PBX1 and SIRT1. To this end, HF-MSCs overexpressing PBX1, overexpressing both PBX1 and PARP1, downregulating SIRT1, and overexpressing PBX1 as well as downregulating SIRT1 were generated, and senescence, apoptosis, DNA damage, and repair biomarkers were analyzed. Our results showed that (1) PBX1 overexpression alleviated HF-MSCs senescence and apoptosis accompanied by SIRT1 upregulation, PARP1 downregulation, and increased intracellular NAD and ATP levels. (2) SIRT1 knockdown enhanced cellular senescence and apoptosis, accompanied by increased ROS accumulation, DNA damage aggravation, and decreased intracellular NAD and ATP levels. (3) PBX1 overexpression rescued HF-MSCs senescence and apoptosis induced by SIRT1 knockdown. (4) PBX1 rescued PARP1 overexpression-mediated ATP and NAD depletion, accompanied by increased SIRT1 expression. Collectively, our results revealed that a positive interaction feedback loop exists between PBX1 and SIRT1. To the best of our knowledge we are the first to report that there is a PBX1-SIRT1-PARP1 axis that plays a critical role in alleviating HF-MSCs senescence and apoptosis. We provide a new perspective on the mechanisms underlying stem cell senescence as well as age-related disease prevention and treatment.

17.
Front Neurol ; 13: 969484, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36034284

RESUMO

Purpose: Hirayama disease (HD) has been largely believed to affect only distal muscles. However, the proximal upper extremities have been affected in some cases, which can be confused with motor neuron diseases. Methods: Baseline data, deep tendon reflex, Hoffmann sign, cervical curvature, sagittal Cobb angle, atrophied spinal cord, high signal intensity, loss of attachment, and affected muscles and segments on electromyography (EMG) were retrospectively obtained and compared between patients with HD with proximal involvement and patients with simple distal HD in one center from September 2007 to April 2022. Results: In this study, fifteen patients with proximal HD and 30 patients with simple distal HD were included. The proximal group had a larger proportion of patients with decreased biceps reflex, decreased triceps reflex, brisk or hyperactive knee reflex, positive Hoffmann sign, and cervical kyphosis. The curvatures of the upper part of the cervical spine (C2-4) were lost to a greater degree in the proximal group. More affected segments were observed on magnetic resonance imaging (MRI) and electromyography in the proximal group. Conclusion: The injured segments were longer and the upper curvature of the cervical spine was poorer in patients with HD with proximal involvement. These findings indicated that proximal involvement may indicate more serious HD.

18.
Brain Res Bull ; 187: 199-209, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35850190

RESUMO

Different studies have confirmed P2X7 receptor-mediated inflammatory mediators play a key role in the development of pain. P2X7 receptor activation can induce the development of pain by mediating the release of inflammatory mediators. In view of the fact that P2X7 receptor is expressed in the nervous system and immune system, it is closely related to the stability and maintenance of the nervous system function. ATP activates P2X7 receptor, opens non-selective cation channels, activates multiple intracellular signaling, releases multiple inflammatory cytokines, and induces pain. At present, the role of P2X7 receptor in inflammatory response and pain has been widely recognized and affirmed. Therefore, in this paper, we discussed the pathological mechanism of P2X7 receptor-mediated inflammation and pain, focused on the internal relationship between P2X7 receptor and pain. Moreover, we also described the effects of some antagonists on pain relief by inhibiting the activities of P2X7 receptor. Thus, targeting to inhibit activation of P2X7 receptor is expected to become another potential target for the relief of pain.


Assuntos
Inflamação , Receptores Purinérgicos P2X7 , Trifosfato de Adenosina , Citocinas/metabolismo , Humanos , Mediadores da Inflamação , Dor , Antagonistas do Receptor Purinérgico P2X/farmacologia
19.
Biometrics ; 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35833513

RESUMO

Cancer (treatment) vaccines that are made of neoantigens, or peptides unique to tumor cells due to somatic mutations, have emerged as a promising method to reinvigorate the immune response against cancer. A key step to prioritizing neoantigens for cancer vaccines is computationally predicting which neoantigens are presented on the cell surface by a human leukocyte antigen (HLA). We propose to address this challenge by training a neural network using mass spectrometry (MS) data composed of peptides presented by at least one of several HLAs of a subject. We embed the neural network within a mixture model and train the neural network by maximizing the likelihood of the mixture model. After evaluating our method using data sets where the peptide presentation status was known, we applied it to analyze somatic mutations of 60 melanoma patients and identified a group of neoantigens more immunogenic in tumor cells than in normal cells. Moreover, neoantigen burden estimated by our method was significantly associated with a measurement of the immune system activity, suggesting these neoantigens could induce an immune response.

20.
Oxid Med Cell Longev ; 2022: 8279269, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35903712

RESUMO

Hair follicles (HFs) maintain homeostasis through the hair cycles; therefore, disrupting the hair cycle may lead to hair loss. Our previous study showed that apoptosis-inducing factor (AIF) nuclear translocation and poly [ADP-ribose] polymerase 1 (PARP1) upregulation induced apoptosis in mouse hair follicles during the hair cycle transition from anagen to catagen. However, the mechanism underlying this phenomenon remains unclear. In this study, we found that intrinsic ROS levels increased during the hair follicle cycle transition from anagen to catagen, followed by abrupt DNA breaks and activation of homologous recombinant and nonhomologous end joining DNA repair, along with the enhancement of apoptosis. Mice in different stages of the hair cycle were sacrificed, and the dorsal skins were collected. The results of western blot and histological staining indicated that AIF-PARP1 plays a key role in HF apoptosis, but their role in the regulation of the HF cycle is not clear. Mice were treated with inhibitors from anagen to catagen: treatment with BMN 673, a PARP1 inhibitor, increased DNA breaks and activated the cytochrome c/caspase-3-mediated apoptotic pathway, accelerating HF regression. Ac-DEVD-CHO (Ac), a caspase-3 inhibitor, attenuated HF degeneration by upregulating PARP1 expression, suggesting a seesaw relationship between cytochrome c-caspase-3- and AIF-PARP1-mediated apoptosis, wherein PARP1 may be the fulcrum. In addition, macrophages were involved in regulating the hair cycle, and the rate of M1 macrophages around HFs increased during catagen, while more M2 macrophages were found during anagen and telogen. Our results indicate that intrinsic ROS drive HF cycle progression through DNA damage and repair, followed by apoptosis. Intrinsic ROS drive hair follicle cycle progression by modulating DNA damage and repair, and consecutively, hair follicle apoptosis and macrophage polarization work together to promote the hair follicle cycle.

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