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1.
J Ethnopharmacol ; 282: 114636, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34520830

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal ink is used as a traditional topical medicine for treating inflammatory diseases via detoxification, relieving pain, hemostasis, and reducing swelling. However, the effect of medicinal ink on the inhibition of inflammatory responses and the underlying molecular mechanism remain unclear. AIM OF THE STUDY: The present study aimed to investigate the anti-inflammatory function of water extract of medical ink (WEMI) and elucidate its active mechanisms. MATERIALS AND METHODS: Cell viability was assessed using crystal violet staining assay. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected by ELISA. Nitric oxide (NO) production was measured by Griess assay. The activation of inflammatory signaling molecules stimulated by lipopolysaccharide (LPS) was evaluated by assessing levels of inducible nitric oxide synthase (iNOS), phosphorylated Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) using Western blot assay. RESULTS: Water extract of medical ink (WEMI) did not present cytotoxic effect on murine macrophage Raw264.7 cells. High dosage of WEMI slightly rescued LPS-suppressed cell viability of Raw264.7 cells. WEMI did not induce NO production or IL-6 secretion, though WEMI significantly induced secretion of TNF-α on Raw264.7 cells not stimulated with LPS. On the other hand, LPS effectively stimulated inflammation on Raw264.7 cells; however, WEMI dramatically reduced LPS-induced NO production. WEMI alleviated LPS-stimulated IL-6 secretion but did not affect the content of TNF-α. In addition, WEMI effectively reduced expression of iNOS by abolishing LPS-mediated phosphorylation of JAK2 and STAT3 but not TLR4-mediated NF-κB and MAPK molecules. CONCLUSIONS: Our findings suggest that WEMI targets of the JAK2/STAT3-mediated iNOS expression play a key role in alleviating LPS-induced inflammatory responses in RAW264.7 macrophages. Therefore, medicinal ink may be a potential topical agent for treating fasciitis or synovitis via regulating the immune system.

3.
Artigo em Chinês | MEDLINE | ID: mdl-34628815

RESUMO

Objective:To explore the pathological type, clinical features and their relationship with prognosis of chronic rhinosinusitis(CRS). Methods:A retrospective study of 135 patients with CRS who underwent surgical treatment in the Affiliated Jiangning Hospital of Nanjing Medical University from January 2017 to December 2018. Review the pathological slices retrospectively and divide the CRS into 4 types, eosinophilic type(eCRS), lymphocyte or(and) plasma cell type, neutrophil type and mixed type, the latter three are collectively referred to as "non-eosinophil type(non-eCRS)". Follow-up was conducted between January and February 2021 to analyze the distribution, clinical features, and differences in prognosis of the different endotypes. Results:①Among the 135 CRS patients, 42 cases(31.1%) were eCRS and 93 cases(68.9%) were non-eCRS(76 cases[56.3%] of lymphocyte or plasma cell type, 4 cases[3.0%] of neutrophil type and 13 cases[9.6%] of mixed type). The difference in composition ratio between the groups was statistically significant(n=135, P<0.001). ②The absolute value and percentage of preoperative peripheral blood eosinophils(EOS) in eCRS patients were higher than those of non-eCRS patients, and the difference was statistically significant(n=125, P(absolute value)=0.030, P(percentage)=0.033). The results of receiver operating characteristic curve showed that both absolute value and percentage have predictive value, and cut-off value was 0.325×109/L(absolute value) or 2.750%(percentage). There was no statistically significant difference in preoperative peripheral blood procalcitonin among the groups(n=69, P=0.647). ③The ratio(E/M value) of the bilateral ethmoid sinus scores and bilateral maxillary sinus scores of the preoperative paranasal sinus CT in eCRS patients was 2.03±1.23, while the non-eCRS patients was 1.47±0.96, and the difference was statistically significant(n=112, P=0.009). ④In total, 101 cases were effectively followed up, including 34 cases of eCRS(7 cases[20.6%] of control, 18 cases[52.9%] of partial control), 9 cases[26.5%] of non-control and 67 cases of non-eCRS(32 cases[47.8%] of control, 26 cases[38.8%] were partially controlled, 9 cases[13.4%] were not controlled), and the efficacy of the non-eCRS group was significantly better than that of the eCRS group(χ²=7.499, P=0.024). Conclusion:When the absolute value of EOS in the preoperative blood examination is greater than 0.325×109/L or the percentage is greater than 2.750%, eCRS can be predicted, but the accuracy is low. CT of patients with eCRS is mostly characterized by inflammation of the ethmoid sinus and usually E/M>2. The efficacy of eCRS group is worse than that of the non-eCRS group 2-4 years after surgery.


Assuntos
Patologia Clínica , Rinite , Sinusite , Humanos , Prognóstico , Estudos Retrospectivos
4.
Alzheimers Dement ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34569707

RESUMO

INTRODUCTION: Tumor necrosis factor (TNF) inhibitors are widely used to treat rheumatoid arthritis (RA) and their potential to retard Alzheimer's disease (AD) progression has been reported. However, their long-term effects on the dementia/AD risk remain unknown. METHODS: A propensity scored matched retrospective cohort study was conducted among 40,207 patients with RA within the US Veterans Affairs health-care system from 2000 to 2020. RESULTS: A total of 2510 patients with RA prescribed TNF inhibitors were 1:2 matched to control patients. TNF inhibitor use was associated with reduced dementia risk (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.52-0.80), which was consistent as the study period increased from 5 to 20 years after RA diagnosis. TNF inhibitor use also showed a long-term effect in reducing the risk of AD (HR: 0.57, 95% CI: 0.39-0.83) during the 20 years of follow-up. CONCLUSION: TNF inhibitor use is associated with lower long-term risk of dementia/AD among US veterans with RA.

5.
Stem Cell Rev Rep ; 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34347272

RESUMO

Mesenchymal stem cells (MSCs) have become a promising tool for neurorestorative therapy of neurodegenerative diseases (NDDs), which are mainly characterized by the progressive and irreversible loss of neuronal structure and function in the central or peripheral nervous system. Recently, studies have reported that genetic manipulation mediated by noncoding RNAs (ncRNAs) can increase survival and neural regeneration of transplanted MSCs, offering a new strategy for clinical translation. In this review, we summarize the potential role and regulatory mechanism of two major types of ncRNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), during the neurogenesis of MSCs with gene expression profile analyses. We also overview the realization of MSC-based therapy mediated by ncRNAs in the treatment of spinal cord injury, stroke, Alzheimer's disease and peripheral nerve injury. It is expected that ncRNAs will become promising therapeutic targets for NDD on stem cells, while the underlying mechanisms require further exploration.

6.
Biomed Res Int ; 2021: 3445970, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34458365

RESUMO

Mounting evidence has recently shown that role of long noncoding RNA is critical in many human cancers. lncRNA GSTM3TV2 was first proven to play a vital role in pancreatic cancer. However, the mechanism of lncRNA GSTM3TV2 in hepatocellular carcinoma (HCC) is still uncovered. Here, we object to distinguish the expression of lncRNA GSTM3TV2 and reveal its mechanistic relationship with HCC. We observed that the expression of lncRNA GSTM3TV2 and FOSL2 were upregulated in HCC. Knockdown of lncRNA GSTM3TV2 significantly inhibited cell proliferation. Meanwhile, the migration and invasion of HCC cells were greatly decreased by the downregulated lncRNA GSTM3TV2. The luciferase reporter assays showed that lncRNA GSTM3TV2 could be directly bound to miR-597, and the level of miR-597 was also decreased in the tumor tissues. lncRNA GSTM3TV2 could stabilize FOSL2 expression, resulting in the oncogenic properties of lncRNA GSTM3TV2 in HCC. Our study indicated the oncogenic activities of lncRNA GSTM3TV2 and emphasized the role of the miR-597/FOSL2 signaling pathway.


Assuntos
Carcinoma Hepatocelular/metabolismo , Antígeno 2 Relacionado a Fos/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Feminino , Antígeno 2 Relacionado a Fos/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Transdução de Sinais , Regulação para Cima
7.
Front Immunol ; 12: 653711, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34354698

RESUMO

Background: Glioblastoma (GBM), one of the most aggressive tumors of the brain, has no effective or sufficient therapies. Identifying robust biomarkers for the response to immune checkpoint blockade (ICB) therapy, a promising treatment option for GBM patients, is urgently needed. Methods: We comprehensively evaluated lncRNA m6A modification patterns in m6A-sequencing (m6A-seq) data for GBM tissues and systematically investigated the immune and stromal regulators of these m6A-regulated lncRNAs. We used the single-sample gene-set enrichment analysis (ssGSEA) algorithm to investigate the difference in enriched tumor microenvironment (TME) infiltrating cells and the functional annotation of HSPA7 in individual GBM samples. Further, we validated that HSPA7 promoted the recruitment of macrophages into GBM TME in vitro, as well as in our GBM tissue section. We also explored its impact on the efficacy of ICB therapy using the patient-derived glioblastoma organoid (GBO) model. Results: Here, we depicted the first transcriptome-wide m6A methylation profile of lncRNAs in GBM, revealing highly distinct lncRNA m6A modification patterns compared to those in normal brain tissues. We identified the m6A-modified pseudogene HSPA7 as a novel prognostic risk factor in GBM patients, with crucial roles in immunophenotype determination, stromal activation, and carcinogenic pathway activation. We confirmed that HSPA7 promoted macrophage infiltration and SPP1 expression via upregulating the YAP1 and LOX expression of glioblastoma stem cells (GSCs) in vitro and in our clinical GBM tumor samples. We also confirmed that knockdown of HSPA7 might increase the efficiency of anti-PD1 therapy utilizing the GBO model, highlighting its potential as a novel target for immunotherapy. Conclusions: Our results indicated that HSPA7 could be a novel immunotherapy target for GBM patients.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Proteínas de Choque Térmico HSP70/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Glioblastoma/genética , Glioblastoma/imunologia , Glioblastoma/mortalidade , Proteínas de Choque Térmico HSP70/genética , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Estimativa de Kaplan-Meier , Osteopontina/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Proteína-Lisina 6-Oxidase/genética , RNA-Seq , Fatores de Transcrição/genética , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo
8.
Ear Hear ; 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34369415

RESUMO

OBJECTIVE: The association of occupational noise-induced hearing loss (NIHL) with noise energy was well documented, but the relationship between occupational noise and noise temporal structure is rarely reported. The objective of this study was to investigate the principal characteristics of the relationship between occupational NIHL and the temporal structure of noise. METHODS: Audiometric and shift-long noise exposure data were collected from 3102 Chinese manufacturing workers from six typical industries through a cross-sectional survey. In data analysis, A-weighted 8-h equivalent SPL (LAeq.8h), peak SPL, and cumulative noise exposure (CNE) were used as noise energy indicators, while kurtosis (ß) was used as the indicator of noise temporal structure. Two NIHL were defined: (1) high-frequency noise-induced hearing loss (HFNIHL) and (2) noise-induced permanent threshold shift at test frequencies of 3, 4, and 6 kHz (noise-induced permanent threshold shift [NIPTS346]). The noise characteristics of different types of work and the relationship between these characteristics and the prevalence of NIHL were analyzed. RESULTS: The noise waveform shape, with a specific noise kurtosis, was unique to each type of work. Approximately 27.92% of manufacturing workers suffered from HFNIHL, with a mean NIPTS346 of 24.16 ± 14.13 dB HL. The Spearman correlation analysis showed that the kurtosis value was significantly correlated with the difference of peak SPL minus its LAeq.8h across different types of work (p < 0.01). For a kurtosis-adjusted CNE, the linear regression equation between HFNIHL% and CNE for complex noise almost overlapped with Gaussian noise. Binary logistic regression analysis showed that LAeq.8h, kurtosis, and exposure duration were the key factors influencing HFNIHL% (p < 0.01). The notching extent in NIPTS at 4 kHz became deeper with the increase in LAeq.8h and kurtosis. HFNIHL% increased most rapidly during the first 10 years of exposure. HFNIHL% with ß ≥ 10 was significantly higher than that with ß < 10 (p < 0.05), and it increased with increasing kurtosis across different CNE or LAeq.8h levels. When LAeq.8h was 80 to 85 dB(A), the HFNIHL% at ß ≥ 100 was significantly higher than that at 10 ≤ ß < 100 or ß < 10 (p < 0.05 and p < 0.01, respectively). CONCLUSIONS: In the evaluation of hearing loss caused by complex noise, not only noise energy but also the temporal structure of noise must be considered. Kurtosis of noise is an indirect metric that is sensitive to the presence of impulsive components in complex noise exposure, and thus, it could be useful for quantifying the risk for NIHL. It is necessary to re-evaluate the safety of permissible exposure limit of 85 dB(A) as noise with a high kurtosis value can aggravate or accelerate early NIHL.

9.
ISME J ; 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413477

RESUMO

Natural populations of pathogens and their hosts are engaged in an arms race in which the pathogens diversify to escape host immunity while the hosts evolve novel immunity. This co-evolutionary process poses a fundamental challenge to the development of broadly effective vaccines and diagnostics against a diversifying pathogen. Based on surveys of natural allele frequencies and experimental immunization of mice, we show high antigenic specificities of natural variants of the outer surface protein C (OspC), a dominant antigen of a Lyme Disease-causing bacterium (Borrelia burgdorferi). To overcome the challenge of OspC antigenic diversity to clinical development of preventive measures, we implemented a number of evolution-informed strategies to broaden OspC antigenic reactivity. In particular, the centroid algorithm-a genetic algorithm to generate sequences that minimize amino-acid differences with natural variants-generated synthetic OspC analogs with the greatest promise as diagnostic and vaccine candidates against diverse Lyme pathogen strains co-existing in the Northeast United States. Mechanistically, we propose a model of maximum antigen diversification (MAD) mediated by amino-acid variations distributed across the hypervariable regions on the OspC molecule. Under the MAD hypothesis, evolutionary centroids display broad cross-reactivity by occupying the central void in the antigenic space excavated by diversifying natural variants. In contrast to vaccine designs based on concatenated epitopes, the evolutionary algorithms generate analogs of natural antigens and are automated. The novel centroid algorithm and the evolutionary antigen designs based on consensus and ancestral sequences have broad implications for combating diversifying pathogens driven by pathogen-host co-evolution.

10.
Front Immunol ; 12: 720907, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421925

RESUMO

Objective: To explore the outcomes of NMOSD attacks and investigate serum biomarkers for prognosis and severity. Method: Patients with NMOSD attacks were prospectively and observationally enrolled from January 2019 to December 2020 at four hospitals in Guangzhou, southern China. Data were collected at attack, discharge and 1/3/6 months after acute treatment. Serum cytokine/chemokine and neurofilament light chain (NfL) levels were examined at the onset stage. Results: One hundred patients with NMOSD attacks were included. The treatment comprised intravenous methylprednisolone pulse therapy alone (IVMP, 71%), IVMP combined with apheresis (8%), IVMP combined with intravenous immunoglobulin (18%) and other therapies (3%). EDSS scores decreased significantly from a medium of 4 (interquartile range 3.0-5.5) at attack to 3.5 (3.0-4.5) at discharge, 3.5 (2.0-4.0) at the 1-month visit and 3.0 (2.0-4.0) at the 3-month visit (p<0.01 in all comparisons). The remission rate was 38.0% at discharge and 63.3% at the 1-month visit. Notably, relapse occurred in 12.2% of 74 patients by the 6-month follow-up. Higher levels of T helper cell 2 (Th2)-related cytokines, including interleukin (IL)-4, IL-10, IL-13, and IL-1 receptor antagonist, predicted remission at the 1-month visit (OR=9.33, p=0.04). Serum NfL levels correlated positively with onset EDSS scores in acute-phase NMOSD (p<0.001, R2 = 0.487). Conclusions: Outcomes of NMOSD attacks were generally moderate. A high level of serum Th2-related cytokines predicted remission at the 1-month visit, and serum NfL may serve as a biomarker of disease severity at attack. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04101058, identifier NCT04101058.

11.
Oxid Med Cell Longev ; 2021: 7654143, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34422209

RESUMO

Age-related macular degeneration (AMD) is a major cause of severe and irreversible vision loss with limited effective therapies. Diminished autophagy and increased oxidative damage caused by ROS in the retinal pigment epithelium (RPE) have been implicated in the pathogenesis of AMD, and strategies aimed at enhancing autophagy are likely to protect these cells from oxidative damage. We have previously shown that berberine (BBR), an isoquinoline alkaloid isolated from Chinese herbs, was able to protect human RPE cells from H2O2-induced oxidative damage through AMPK activation. However, the precise mechanisms behind this protective effect remain unclear. Given the essential role of AMPK in autophagy activation, we postulated that BBR may confer protection against H2O2-induced oxidative damage by stimulating AMPK-dependent autophagy. Our results showed that BBR was able to induce autophagy in D407 cells, whereas autophagy inhibitor PIKIII or silencing of LC3B blocked the protective effect of BBR. Further analysis showed that BBR activated the AMPK/mTOR/ULK1 signaling pathways and that both pharmacological and genetic inhibitions of the AMPK pathway abolished the autophagy-stimulating effect of BBR. Similar results were obtained in primary cultured human RPE cells. Taken together, these results demonstrate that BBR is able to stimulate autophagy in D407 cells via the activation of AMPK pathway and that its protective effect against H2O2-induced oxidative damage relies on its autophagy-modulatory effect. Our findings also provide evidence to support the potential application of BBR in preventing and treating AMD.

12.
J Neurochem ; 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34418095

RESUMO

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease of the central nervous system. Gasdermin D (GSDMD) is associated with autoimmune disorders and neuroinflammatory disorders, but its role in anti-NMDAR encephalitis is unclear. In this study, we measured serum levels of GSDMD in 42 patients with anti-NMDAR encephalitis and 25 healthy controls. Of the 42 patients, 17 had follow-up evaluation of GSDMD levels and modified Rankin scale (mRS) scores at 3 months. Association of GSDMD with anti-NMDAR encephalitis and its clinical parameters were evaluated. Serum GSDMD levels were significantly higher in patients with anti-NMDAR encephalitis than in healthy controls (p = 0.002, padjusted  = 0.009), especially in males (p = 0.001, padjusted  = 0.022). This was also evident in patients with severe impairment (mRS >3 vs mRS ≤3; p < 0.001). Serum GSDMD was associated with mRS before and after adjustment for age and gender (r = 0.440 and 0.430, p = 0.004 and 0.006, respectively) as well as serum CH50 (r = -0.419 and -0.426, p = 0.011 and 0.012, respectively). Furthermore, 3-month follow-up evaluation revealed that after treatment, anti-NMDAR encephalitis patients had significantly decreased serum GSDMD levels (p = 0.007) and significantly decreased mRS scores (p = 0.002) compared with before treatment. Furthermore, the changes in mRS scores were negatively associated with changes in GSDMD levels, although the associations were not significant (r = -0.222, p = 0.393). Our findings show that serum GSDMD levels are elevated in anti-NMDAR encephalitis and are associated with disease prognosis.

13.
Phys Rev Lett ; 127(6): 064501, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34420350

RESUMO

We study acoustic streaming in liquids driven by a nondissipative acoustic body force created by light-induced temperature gradients. This thermoacoustic streaming produces a velocity amplitude nearly 100 times higher than the boundary-driven Rayleigh streaming and the Rayleigh-Bénard convection at a temperature gradient of 10 K/mm in the channel. The Rayleigh streaming is altered by the acoustic body force at a temperature gradient of only 0.5 K/mm. The thermoacoustic streaming allows for modular flow control and enhanced heat transfer at the microscale. Our study provides the groundwork for studying microscale acoustic streaming coupled with temperature fields.

14.
J Neurol Sci ; 428: 117568, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34247015

RESUMO

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of protein A immunoadsorption (IA) for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis resistant to intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIG). METHODS: We prospectively evaluated patients with refractory anti-NMDAR encephalitis, treated with protein A IA. Demographic data, clinical characteristics, modified Rankin Score (mRS), and anti-NMDAR antibodies were documented before and after IA and at follow-up. Clinical improvement was defined as a decrease of mRS ≥1. Adverse events were recorded throughout the study. RESULTS: Ten patients with mRS ≥3 were enrolled and treated with protein A IA; treatment was performed for an average of 5.2 times per patient. Among the nine patients with positive serum anti-NMDAR, the titer decreased in seven patients, of which two became negative. The cerebrospinal fluid (CSF) anti-NMDAR titer decreased in all patients, and one became negative. Anti-NMDAR levels were tested in two patients at follow-up and found to have declined continuously. All patients exhibited clinical improvement with a mRS decline ≥1 after IA treatment (median mRS: 5.0 [range, 3.0-5.0] vs. 4.0 [range, 2.0-4.0], p = 0.014), and the median mRS decreased to 1.0 (range, 0-3.0) at follow-up. After IA, all patients exhibited accelerated recovery. No adverse events were observed during IA treatment. CONCLUSION: Protein A IA may be effective for treating IVMP/IVIG-resistant anti-NMDAR encephalitis and well tolerated. It is necessary to initiate larger-scale prospective controlled studies to validate the efficacy and safety of protein A IA in anti-NMDAR encephalitis.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Encefalite Antirreceptor de N-Metil-D-Aspartato/terapia , Anticorpos , Humanos , Imunoglobulinas Intravenosas , Estudos Prospectivos , Proteína Estafilocócica A
15.
Neurology ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266923

RESUMO

OBJECTIVE: Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer's disease (AD) risk only in apoliprotein E4 genotype (APOE ε4) allele carriers. The objective of this study was to examine the interactive effects of plasma CRP and apoliprotein E (APOE) genotype on cognition and AD biomarkers. METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study was analyzed, including APOE genotype; plasma CRP concentrations; diagnostic status (i.e., MCI and dementia due to AD); Mini-Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) Dementia Staging Instrument; cerebral spinal fluid (CSF) concentrations of amyloid-ß peptide (Aß42), total tau (t-Tau) and phosphorylated tau (p-Tau); and amyloid (AV45) PET imaging. Multivariable regression analyses tested the associations between plasma CRP and APOE on cognitive and biomarker outcomes. RESULTS: Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had one, and 70 (12.4%) had two APOE ε4 alleles. Only among participants who had two APOE ε4 alleles, elevated CRP was associated with lower MMSE at baseline [ß (95%CI): -0.52 ( -1.01, -0.12)] and 12-month follow-up [ß (95%CI): -1.09 (-1.88, -0.17)] after adjusting for sex, age and education. The interaction of two APOE ε4 alleles and elevated plasma CRP was associated with increased CSF levels of t-Tau (ß = +11.21, SE = 3.37, p < 0.001) and p-Tau (ß = +2.74, SE = 1.14, p < 0.01). Among those who had no APOE ε4 allele, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at 12-month follow-up. CONCLUSIONS: CRP released during peripheral inflammation could be a mediator in APOE ε4 related AD neurodegeneration and serve as a drug target for AD.

16.
ACS Appl Mater Interfaces ; 13(31): 37680-37692, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34313427

RESUMO

It remains a conundrum to reconcile the contradiction between effective tumor retention and deep intratumor infiltration for nanotherapeutics due to the sophisticated drug delivery journey. Herein, we reported an acid-sensitive supramolecular nanoassemblies (DCD SNs) based on the multivalent host-gest inclusions of two polymer conjugates for conquering diverse physiological blockages and amplifying therapeutic efficacy. The multiple inclusions of repetitive units on the hydrophilic polymer backbone reinforced the binding affinity and induced robust self-assembly, ameliorating instability of the self-assemblies and facilitating to prolong the drug retention time. By virtue of the acid-sensitive Schiff base linkages, the supramolecular nanoassembly could respond to the unique tumor microenvironment (TME), dissociate, and transform into smaller particles (∼30 nm), thereby efficiently traversing the complicated extracellular matrix and irregular blood vessels to achieve deep intratumor infiltration. The acid-sensitive DCD SNs can absorb a large number of protons in the acidic lysosomal environment, causing the proton sponge effect, which was conducive to their escape from endolysosomes and accelerated lysosomal disruption, so that the active chemotherapeutic doxorubicin (DOX) could enter the nucleus well and exert severe DNA damage to induce apoptosis. This versatile supramolecular nanoplatform is anticipated to be a promising candidate to overcome the limitations of insufficient stability within the circulation and weak intratumor penetration.

17.
Artigo em Inglês | MEDLINE | ID: mdl-34281127

RESUMO

A survey was administered to 385 noise-exposed workers from an auto parts factory and 1268 non-noise-exposed health department employees in China. Individual 8 h A-weighted equivalent sound levels (LAeq,8h), earplug personal attenuation ratings (PARs), and pure-tone audiometric tests were performed. The average LAeq,8h of noise-exposed workers was 87 dB (A) with a mean PAR of 7 dB. The prevalence of high-frequency hearing loss was 65% for noise-exposed workers and 33% for the non-noise-exposed employees. The use of earplugs had no observable effect on the prevalence of high-frequency hearing loss of the study participants (OR 0.964, 95% CI 0.925-1.005, p = 0.085). No significant relationship between the effectiveness offered by earplug use and high-frequency hearing thresholds at 3, 4, and 6 kHz was found (t = -1.54, p = 0.125). The mandatory requirement of earplug use without individualized training on how to wear HPDs correctly had no detectable effect on the prevention of hearing loss at the auto parts factory. The hearing conservation program at the surveyed factory was not effective. Periodic hearing tests, earplug fit testing, expanding the offer of different types of hearing protection, and employee education about the importance of protecting their hearing were recommended to the occupational health and safety program.


Assuntos
Perda Auditiva Provocada por Ruído , Ruído Ocupacional , Saúde do Trabalhador , China/epidemiologia , Dispositivos de Proteção das Orelhas , Perda Auditiva Provocada por Ruído/epidemiologia , Perda Auditiva Provocada por Ruído/prevenção & controle , Humanos , Ruído Ocupacional/efeitos adversos , Ruído Ocupacional/prevenção & controle
18.
Mol Ther ; 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34217892

RESUMO

Glioma is a heterogeneous cellular environment in which immune cells play critical roles in tumor progression. Myeloid-derived suppressor cells (MDSCs) contribute to the formation of the immunosuppressive microenvironment of glioma; however, how glioma cells interact with MDSCs and how this interaction affects the function of other immune cells are unclear. Glioma cells can systemically communicate with immune cells via the secretion of exosomes, which contain microRNAs (miRNAs). Leveraging miRNA sequencing of exosomes, we identified enrichment of miR-1246 in glioma-derived exosomes and exosomes isolated from the cerebrospinal fluid (CSF) of glioma patients. We demonstrated that miR-1246 drives the differentiation and activation of MDSCs in a dual specificity phosphatase 3 (DUSP3)/extracellular signal­regulated kinase (ERK)-dependent manner. In addition, postoperative CSF exosomal miR-1246 expression was found to be associated with the glioma recurrence rate. Hypoxia, a well-recognized feature of the glioblastoma microenvironment, increased miR-1246 levels in glioma-derived exosomes by enhancing miR-1246 transcription and selective packaging via upregulation of POU class 5 homeobox 1 (POU5F1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Importantly, we identified a mechanism of 2-methoxyestradiol, a microtubule inhibitor currently undergoing clinical trials for glioblastoma. 2-Methoxyestradiol suppresses MDSC activation by inhibiting hypoxia-driven exosomal miR-1246 expression in glioma cells and PD-L1 expression in MDSCs.

19.
Neuroimmunomodulation ; 28(3): 187-192, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34237754

RESUMO

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is a recently defined autoimmune inflammatory disease of the central nervous system in which GFAP IgG is present in the cerebrospinal fluid (CSF). Its primary clinical manifestation is meningoencephalitis, and it usually responds well to corticosteroids. Herein, we report a case of a patient with GFAP-A with initial symptoms of psychological and cognitive impairment, which did not respond to high-dose methylprednisolone therapy but was successfully treated with protein A immunoadsorption (PAIA) therapy. METHODS: GFAP IgG was detected by indirect immunofluorescence assay. The patient's data were analyzed retrospectively. RESULTS: A 48-year-old man presented with anxiety, depression, cognitive decline, tremor, gait disturbance, and fecal and urine incontinence. Autoimmune GFAP-A was diagnosed based on the following: (1) T2-weighted and fluid-attenuated inversion recovery MRI findings of hypersensitive lesions in the subcortical and deep white matter of the brain, with multiple longitudinally extensive lesions in the cervical and chest regions of the spinal cord, and (2) high levels of GFAP IgG in the CSF. Clinical symptoms and abnormalities detected on neuroimaging worsened after administration of high-dose intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIG) but improved significantly after PAIA therapy. CONCLUSION: Psychological impairment can be the first sign of autoimmune GFAP-A. PAIA might be an effective treatment for patients with GFAP-A who respond poorly to conventional IVMP and IVIG therapy.

20.
J Neurol ; 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34283286

RESUMO

INTRODUCTION: Brain metastases (BM) remains the most cumbersome disease burden in patients with lung cancer. This study aimed to investigate whether serum brain injury biomarkers can indicate BM, to further establish related diagnostic models, or to predict prognosis of BM. MATERIALS AND METHODS: This was a prospective study of patients diagnosed with lung cancer with BM (BM group), with lung cancer without BM (NBM group), and healthy participants (control group). Serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were detected at baseline. We identified and integrated the risk factors of BM to establish diagnostic models. RESULTS: A total of 158 patients were included (n = 37, 57, and 64 in the BM, NBM, and control groups, respectively). Serum biomarker levels were significantly higher in the NBM group than in the control group. Higher serum NfL and GFAP concentrations were associated with BM (odds ratios, 3.06 and 1.79, respectively). NfL (area under curve [AUC] = 0.77, p < 0.001) and GFAP (AUC = 0.64, p = 0.02) had diagnostic value for BM. The final diagnostic model included NfL level, age, Karnofsky Performance Status. The model had an AUC value of 0.83 (95% confidence interval [CI] 0.75-0.92). High NfL concentration was correlated with poor overall survival of patients with BM (hazard ratio, 3.31; 95% CI 1.22-9.04; p = 0.019). CONCLUSION: Serum NfL and GFAP could be potential diagnostic biomarkers for BM in patients with lung cancer. We established a model that can provide individual diagnoses of BM. Higher NfL level may be associated with poor prognosis of patients with BM.

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