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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120228, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34388430

RESUMO

Lysosome is one of the important organelles in intracellular transport. It plays a significant role in the physiological process. The lysosomal microenvironment affects the functions of lysosome. When the original acidic environment of lysozyme is destroyed or the fluid viscosity increases gradually, various diseases are easily induced. However, most fluorescent probes can only locate in cells. The fewer probes of subcellular organelles were found and their functions are often single. So, it is of great importance to design multifunctional fluorescent probes with the capable of localizing in lysosome. In this study, a novel lysosome probe, 4-(4-Pyren-1-yl-but-3-enyl)-morpholine (PIM), was synthesized using pyrene as a fluorescent group and morpholine as a target group. The introduction of morpholine group made PIM localize in lysosome with high selectivity. The fluorescence will be enhanced with the increased viscosity because of restricting the rotation of CC bond and CN in PIM, and the detecting linear range is from 4.05 cP to 393.48 cP, which qualified the requirement of the viscosity monitoring in body. Meanwhile, the fluorescence intensity of PIM declines with the decrease of pH because the Schiff base of PIM is hydrolyzed, which was affirmed by 1H NMR, LC-MS and fluorescence spectra. Moreover, cell imaging and MTT experiments confirmed that PIM as a novel bifunctional probe can be used to detect pH and endogenous viscosity in lysosome.


Assuntos
Corantes Fluorescentes , Lisossomos , Fluorescência , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Pirenos , Viscosidade
2.
Int J Hyg Environ Health ; 239: 113875, 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34757279

RESUMO

The potential effect of long-term exposure to ambient air pollutants on low-grade systematic inflammation has seldom been evaluated taking indoor air pollution and self-protection behaviors on smog days into account. A total of 24,346 participants at baseline were included to conduct a cross-sectional study. The annual (2016) average pollutant concentrations were assessed by air monitoring stations for PM2.5, PM10, SO2, NO2, O3 and CO. Associations between annual ambient air pollution and low-grade systematic inflammation (hsCRP>3 mg/L) were estimated by generalized linear mixed models. Stratification analysis was also performed based on demographic characteristics, health-related behaviors and disease status. Annual ambient NO2 and O3 were all associated with low-grade systematic inflammation in single-pollutant models after adjusting for age, sex, blood lipids, blood pressure, lifestyle risk factors, cooking fuel, heating fuel and habits during smog days (NO2 per 10 µg/m3: OR = 1.057, P = 0.018; O3 per 10 µg/m3: OR = 0.953, P = 0.012). The 2-year and 3-year ozone concentrations were consistently associated with lower systematic inflammation (2-year O3 per 10 µg/m3: OR = 0.959, P = 0.004; 3-year O3 per 10 µg/m3: OR = 0.961, P = 0.014). In two-pollutant models, the estimated effects of annual NO2 and O3 on low-grade systematic inflammation remained stable. The effect size of annual pollutants on inflammation increased in participants without air-purifier usage (NO2 per 10 µg/m3: OR = 1.079, P = 0.009; O3 per 10 µg/m3: OR = 0.925, P = 0.001), while the association was null in the air-purifier usage group. Thus, long-term exposure to ambient NO2 and O3 was associated with low-grade systemic inflammation, and the results were generally stable after sensitivity analysis. The usage of air purifiers on smog days can modify the association between gaseous pollutants and systematic inflammation.

3.
J Pharm Anal ; 11(5): 628-637, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34765276

RESUMO

Berberine (BBR) is an isoquinoline alkaloid extracted from Coptis chinensis that improves diabetes, hyperlipidemia and inflammation. Due to the low oral bioavailability of BBR, its mechanism of action is closely related to the gut microbiota. This study focused on the CYP51 enzyme of intestinal bacteria to elucidate a new mechanism of BBR transformation by demethylation in the gut microbiota through multiple analytical techniques. First, the docking of BBR and CYP51 was performed; then, the pharmacokinetics of BBR was determined in ICR mice in vivo, and the metabolism of BBR in the liver, kidney, gut microbiota and single bacterial strains was examined in vitro. Moreover, 16S rRNA analysis of ICR mouse feces indicated the relationship between BBR and the gut microbiota. Finally, recombinant E. coli containing cyp51 gene was constructed and the CYP51 enzyme lysate was induced to express. The metabolic characteristics of BBR were analyzed in the CYP51 enzyme lysate system. The results showed that CYP51 in the gut microbiota could bind stably with BBR, and the addition of voriconazole (a specific inhibitor of CYP51) slowed down the metabolism of BBR, which prevented the production of the demethylated metabolites thalifendine and berberrubine. This study demonstrated that CYP51 promoted the demethylation of BBR and enhanced its intestinal absorption, providing a new method for studying the metabolic transformation mechanism of isoquinoline alkaloids in vivo.

4.
Opt Express ; 29(21): 33197-33209, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34809136

RESUMO

We theoretically and experimentally investigate the laser-detected magnetic resonance spectra dressed by a radio-frequency magnetic field in Fg = 4 of D1 line of cesium atoms. The analytical expression of the transmission spectrum for magnetic resonance dressed by a radio-frequency magnetic field is derived and has substantial agreement with the transmission spectra observed in the experiment. The theoretical prediction of the ratio of the amplitudes of the two sidebands with the detuning is basically consistent with the experimental data, which confirms the validity of the analytical expression. The separation between the two sidebands under resonance shows a highly linear proportion to the amplitude of the dressing field, which may provide a useful scheme for the measurement of radio-frequency magnetic field and magnetic imaging.

5.
Obes Facts ; 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34839297

RESUMO

INTRODUCTION: The prevalence of hyperuricemia is increasing world widely; the understanding of population attributable faction of modifiable risk factors is important for disease prevention. Given the sparse evidence on how modifiable risk factors influence hyperuricemia in mainland China, we aim to explore the effect of excess weight and alcohol consumption and the population attributable fractions of hyperuricemia based on a national survey in mainland China. METHODS: Using data from China National Health Survey which included 31746 Han Chinese aged 20-80 from ten provinces, we estimated the prevalence and modifiable risk factors (overweight/obesity and alcohol consumption)of hyperuricemia. Hyperuricemia was defined as serum uric acid > 417 µmol/L in men and > 340 µmol/L in women. Restricted cubic spline models were used to demonstrate the linear and non-linear association between exposures and hyperuricemia. The adjusted population attributable risk (PAR) was calculated to understand the relative importance of each modifiable risk factor. RESULTS: The prevalence of hyperuricemia was 25.1% in men and 15.9% in women. The population fraction of hyperuricemia cases that could be avoided by weight loss was 20.6% (19.2% to 22.0%) in men and 18.1% (17.1% to 19.0%) in women. The PAR of alcohol consumption was 12.8% (8.5% to 17.1%) in men. Participants from southwest China had the highest hyperuricemia prevalence (47.9% in men and 29.9% in women), but with lower PAR of modifiable risk factors, especially in men (16.7%). Subjects in North China had lower hyperuricemia prevalence but higher PAR of modifiable risk factors. 44.8% male hyperuricemia cases in Inner Mongolia (26.9% of hyperuricemia prevalence) and 37.7% cases in men from Heilongjiang (34.4% of hyperuricemia prevalence) were attributable to overweight/obesity and alcohol consumption. CONCLUSION: There are significant sex and geographic difference on population attributable risk of hyperuricemia due to modifiable risk factors. More tailored prevention strategies are needed to prevent hyperuricemia through weight loss and the reduction of alcohol consumption.

6.
Bioresour Technol ; : 126423, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34838964

RESUMO

The Acinetobacter indicus strain ZJB20129 isolated from an urban sewage treatment plant demonstrated the heterotrophic nitrification-aerobic denitrification (HN-AD) ability. Stain ZJB20129 could remove 98.73% of ammonium-N, 97.26% of nitrite-N and 96.55% of nitrate-N, and the maximum removal rate was 3.66, 4.62 and 5.21 mg/L/h, respectively. Ammonium was preferentially used during simultaneous nitrification and denitrification. Strain ZJB20129 exhibited highest ammonium removal capability when carbon source was sodium succinate, C/N ratio was 15, pH was 8.0, and temperature was 35 ℃. Key enzymes involved in HN-AD including hydroxylamine oxidase, periplasmic nitrate reductase and nitrite reductase as well as their encoding genes were detected, and the metabolic pathway of HN-AD was subsequently predicted. Our results suggested that Acinetobacter indicus ZJB20129 displayed superior nitrogen removal performance on actual wastewater and thus made it have a good application prospect in wastewater biological treatment.

7.
Adv Mater ; : e2106380, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34750869

RESUMO

The two-dimensional Dion-Jacobson (DJ) perovskite solar cells generally show mediocre device performances as restrained by their defective film quality. The rigid diammonium organic interlayer spacers are intolerant to lattice mismatches, which induces defects and distortions and ultimately deteriorates the optoelectronic properties. Herein, we introduce a secondary interlayer spacer into the formamidinium (FA) based low-dimensional perovskite and substantially improve the film quality. The flexible monovalent spacer cations effectively alleviate lattice distortions and reduce crystal defects, providing perovskite films with desirable microscopic morphology, preferable crystal orientation, reduced defect states and improved charge transport capability. As a result, the optimized perovskite solar cell (PSC) based on the (PDA0.9 PA0.2 )(FA)3 Pb4 I13 (PDA = propane-1,3-diammonium, PA = propylammonium) film exhibits the exceptional power conversion efficiency of 16.0%, the highest reported value in its class. In addition, the device demonstrates the enhanced thermal stability, retaining 90% of its initial efficiency after aging at 85°C for 800 h. This article is protected by copyright. All rights reserved.

8.
Mol Cell Biol ; : MCB0046721, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34723652

RESUMO

A subset of hospitalized COVID-19 patients, particularly the aged and those with co-morbidities, develop the most severe form of the disease, characterized by Acute Respiratory Disease Syndrome (ARDS), coincident with experiencing a "cytokine storm." Here, we demonstrate that cytokines which activate the NF-kappaB pathway can induce Activin A. Patients with elevated Activin A, Activin B, and FLRG at hospital admission were associated with the most severe outcomes of COVID-19, including the requirement for mechanical ventilation, and all-cause mortality. A prior study showed that Activin A could decrease viral load, which indicated there might be a risk to giving COVID-19 patients an inhibitor of Activin. To evaluate this, the role for Activin A was examined in a hamster model of SARS-CoV2 infection, via blockade of Activin A signaling. The hamster model demonstrated that use of an anti-ActivinA antibody did not worsen the disease and there was no evidence for increase in lung viral load and pathology. The study indicates blockade of Activin signaling may be beneficial in treating COVID-19 patients experiencing ARDS.

9.
Front Cardiovasc Med ; 8: 756098, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34796214

RESUMO

Neointima formation is a serious complication caused by mechanical trauma to the vessel. (R)-4,6-dimethoxy-3-(4-methoxy phenyl)-2,3-dihydro-1H-indanone [(R)-TML 104] is a synthesized analog of the natural product resveratrol sesquiterpenes (±)-isopaucifloral F. The present study aimed to investigate the effects and underlying mechanisms of (R)-TML104 on neointima formation. Our results showed that (R)-TML104 prevented neointima formation based on a carotid artery injury model in mice. Furthermore, (R)-TML104 inhibited platelet-derived growth factor-BB (PDGF-BB)-induced vascular smooth muscle cells (VSMC) phenotypic transformation, evidenced by increased α-smooth muscle actin, reduced VSMC proliferation, and migration. Simultaneously, (R)-TML104 upregulated sirtuin-1 (SIRT1) expression in VSMC. We further uncovered that SIRT1 expression is critical for the inhibitory effects of (R)-TML104 on PDGF-BB-induced VSMC phenotypic transformation in vitro and injury-induced neointima formation in vivo. Finally, (R)-TML104-upregulated SIRT1 inhibited PDGF-BB-induced VSMC phenotypic transformation by downregulating nicotinamide adenine dinucleotide phosphate oxidase 4 expression via decreasing nuclear factor-κB acetylation. Taken together, these results revealed that (R)-TML104 upregulates SIRT1 expression and ameliorates neointima formation. Therefore, the application of (R)-TML104 may constitute an effective strategy to ameliorate neointima formation.

10.
Allergy Asthma Immunol Res ; 13(6): 863-881, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34734505

RESUMO

PURPOSE: The pathogenic mechanisms of antrochoanal polyps (ACPs) remain largely unknown. This study aimed to characterize inflammatory patterns and tissue remodeling features in ACPs. METHODS: Inflammatory cell infiltration and tissue edema severity as well as fibrin deposition in ACPs and bilateral eosinophilic and noneosinophilic nasal polyps (NPs) were studied with immunohistochemical and immunofluorescence staining. Cytokine levels in sinonasal tissues were detected with the Bio-Plex assay. The expression of coagulation and fibrinolytic markers was measured using reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assays. RESULTS: Compared to control tissues and bilateral eosinophilic and noneosinophilic NPs, ACPs had higher levels of neutrophil infiltration and expression of myeloperoxidase (MPO), interleukin (IL)-8 and interferon (IFN)-γ. In total, 94.4% of ACPs demonstrated an eosinophil cationic protein/MPO ratio of < 1, compared to 79.0% of noneosinophilic and 26% of eosinophilic NPs. Principle component and multiple correspondence analyses revealed a neutrophilic and type 1 inflammation pattern in ACPs. Compared to control tissues, edema scores and fibrin deposition were increased, whereas d-dimer and tissue plasminogen activator (tPA) levels were decreased in ACPs and bilateral NPs, with more prominent changes in ACPs even than in eosinophilic NPs. The tPA levels were negatively correlated with IFN-γ, IL-8, and MPO levels in ACPs. Neutrophils were the major cellular source of IFN-γ in ACPs, and the number of IFN-γ+ neutrophils was elevated in ACPs than in control tissues and bilateral eosinophilic and noneosinophilic NPs. CONCLUSIONS: ACPs are characterized by the neutrophilic and type 1 inflammation endotype. Neutrophil-derived IFN-γ is associated with reduced tPA production in ACPs.

11.
Int J Biol Macromol ; 192: 590-599, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34648801

RESUMO

The present study aimed at assuring whether homogeneous cultivated Dendrobium huoshanense stem polysaccharide (cDHPS) could inhibit gastric cancer in vivo, and whether its anti-gastric cancer activity could be affected by its molecular weight and O-acetyl group. Three different fractions (cDHPS-I, cDHPS-II and cDHPS-III) with decreased molecular weights and one fraction (cDHPS-IV) without O-acetyl group were prepared from cDHPS. Their structures were identified systematically. The backbone of cDHPS-I-III was the same as that of cDHPS, while their relative molecular weights displayed a decreasing order as follows: cDHPS > cDHPS-I > cDHPS-II > cDHPS-III. The backbone of cDHPS-IV was similar to those of cDHPS and cDHPS-I-III, but with the absence of O-acetyl groups. Animal experiments exhibited that cDHPS and cDHPS-I-IV could significantly inhibit tumor growth, induce tumor cell apoptosis, suppress tumor angiogenesis and enhance T cell immune response of murine forestomach carcinoma (MFC) tumor-bearing mice. Moreover, all the above effects of cDHPS and cDHPS-I-IV on MFC tumor-bearing mice exhibited a decreasing order as follows: cDHPS > cDHPS-I > cDHPS-II > cDHPS-III > cDHPS-IV. The results suggest that cDHPS could inhibit gastric cancer in vivo, and its anti-gastric cancer activity was closely linked with its molecular weight and O-acetyl group.

12.
Fitoterapia ; 156: 105068, 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34715153

RESUMO

Three labdane-type [multisins A-C (1-3)], two guaiane-type [multisins D (4) and E (5)], and one eudesmane-type [multisin F (6)] previously undescribed terpenoids, together with 14 mono- (7-20) and seven dimeric- (21-27) known terpenoids, were isolated from the 90% MeOH extract of the whole plant of Chloranthus multistachys. Their structures and absolute configurations were determined by extensive spectroscopic methods and electronic circular dichroism (ECD) calculations. Compounds 4 and 5 are rare trinor-sesquiterpenes with a de-isopropyl guaiane skeleton, whereas compound 6 is a rearranged dinor-eudesmene featuring an uncommon octahydro-1H-indene ring system. Among the isolates, the dimeric lindenane sesquiterpenoid shizukaol C (25) exhibited the most potent (IC50 = 8.04 µM) anti-neuroinflammatory activity by inhibiting the nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated murine BV-2 microglial cells.

13.
Front Endocrinol (Lausanne) ; 12: 693669, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603197

RESUMO

Background: Solitary intracranial hypothalamic mass occurs rarely. The etiological diagnosis of solitary hypothalamus lesion is challenging and often unachievable. Although previous studies indicated that lesions affecting the hypothalamus often cause significant metabolic disorders, few reports about the metabolic disturbances of patients with solitary hypothalamic mass have been reported. Method: Twenty-five patients with solitary hypothalamus lesions who had been evaluated and treated in Huashan Hospital from January 2010 to December 2020 were retrospectively enrolled. The clinical manifestations, radiological features, endocrine and metabolic disorders, and pathology were analyzed. Results: The male to female ratio was 5/20. The median age of onset was 22 (19, 35) years old. The most common initial symptom was polydipsia/polyuria (19/25, 76.0%) and amenorrhea (9/20, 45.0%). A high prevalence of hypopituitarism of different axes was found, with almost all no less than 80%. Central hypogonadism (21/22, 95.5%) and central diabetes insipidus (19/21, 90.5%) were the top two pituitary dysfunctions. Conclusive diagnoses were achieved by intracranial surgical biopsy/resection or stereotactic biopsy in 16 cases and by examining extracranial lesions in 3 cases. The pathological results were various, and the most common diagnoses were Langerhans cell histiocytosis (7/19) and hypothalamitis (5/19). The mean timespan from onset to diagnosis in the 19 cases was 34 ± 26 months. Metabolic evaluations revealed remarkable metabolic disorders, including hyperlipidemia (13/16, 81.3%), hyperglycemia (10/16, 62.5%), hyperuricemia (12/20, 60%), overweight/obesity (13/20, 65.0%), and hepatic adipose infiltration (10/13, 76.6%). Conclusion: Either surgical or stereotactic biopsy will be a reliable and relatively safe procedure to help to confirm the pathological diagnosis of solitary hypothalamic mass. Metabolic disorders were severe in patients with solitary hypothalamic mass. The management of such cases should cover both the treatment of the primary disease, as well as the endocrine and metabolic disorders.

14.
Vet Microbiol ; 263: 109245, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34649011

RESUMO

African swine fever (ASF) is a highly lethal contagious disease of swine caused by African swine fever virus (ASFV). Cleaning and disinfection remain one of the most effective tools to prevent the ASFV spread in pig holdings. This study evaluated the inactivation effect of a highly complexed iodine (HPCI) disinfectant against ASFV. A commercially available povidone-iodine (PVP-I) was used as reference for comparison. The results showed that 5% HPCI and 5% PVP-I did not exhibit cytotoxicity in primary porcine alveolar macrophages, and 107.0 and 105.0 TCID50/mL ASFV were completely inactivated by 5% and 0.25% HPCI, respectively, in 5 min via either immersion or spray disinfection. However, 5% PVP-I required at least 15 min to completely inactivate 107.0 TCID50/mL ASFV, whereas 0.25% PVP-I failed to completely inactivate 105.0 TCID50/mL ASFV. This study demonstrated that HPCI could rapidly and efficiently inactivate ASFV, representing an effective disinfectant for ASF control.

15.
Front Oncol ; 11: 682928, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34604028

RESUMO

The purpose was aimed to establish a simple computational model to predict tumor prognosis by combining neutrophil to lymphocyte Ratio (NLR) and biomarkers of oncological characteristics in patients undergoing vascular reconstructive radical resection of PDAC. The enrolled patients was divided into high or low NLR group with the cutoff value determined by the receiver operator characteristic (ROC) curve. Different vascular anastomoses were selected according to the Chaoyang classification of PDAC. Survival rates were calculated using the Kaplan-Meier and evaluated with the log-rank test. Cox risk regression model was used to analyze the independent risk factors for prognostic survival. The optimal cut-off value of NRL was correlated with the differentiation, tumor size, TNM stage and distant metastasis of advanced PDAC. A curative resection with vascular reconstructive of advanced PDAC according to Chaoyang classification can obviously improve the survival benefits. Cox proportional hazards demonstrated higher evaluated NLR, incisal margin R1 and lymphatic metastasis were the independent risk predictor for prognosis with the HR > 2, meanwhile, age beyond 55, TNM stage of III-IV or Tumor size > 4cm were also the obvious independent risk predictor for prognosis with the HR ≤ 2. The advanced PADC patients marked of RS group (3 < RS ≤ 6) showed no more than 24 months of survival time according to RS model based on the six independent risk predictors. Vascular reconstruction in radical resection of advanced PDAC improved survival, higher elevated NLR (>2.90) was a negative predictor of DFS and OS in those patients accompanying portal system invasion.

16.
Technol Cancer Res Treat ; 20: 15330338211045820, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34605709

RESUMO

Background: This presented study was aimed to evaluate the diagnostic and prognostic value of PD-L1+Neutrophils (PD-L1+NEUT) and neutrophil to lymphocyte ratio (NLR) based on our previous experience of Foxp3+Treg in transplantation. Methods: the NLR cutoff value of 1.79 was used to include 136 cases from the 204 patients with hepatocellular carcinoma (HCC) confirmed by clinical pathology, which were divided into highly-moderately and poorly differentiated HCC groups. The expressions of PD-L1+NEUT and Foxp3+Treg in peripheral blood and cancer tissue were detected with flow cytometry, meanwhile, PD-L1 and Foxp3 expressed in carcinoma and para-carcinoma tissues were marked by immunohistochemistry. Survival rates, including overall survival and disease-free survival, were calculated by the Kaplan-Meier curve and evaluated with the log-rank test. Finally, Cox risk regression model was used to analyze the independent risk factors for prognostic survival. Results: The level of PD-L1+NEUT, Foxp3+Treg, and NLR in peripheral blood of patients with poorly differentiated HCC were significantly increased (all P < .001). Both PD-L1+NEUT and NLR were positively correlated with Foxp3+Treg (r = 0.479, P = .0017; r = 0.58, P < .0001). The level of PD-L1+NEUT and Foxp3+Treg as well as PD-L1 and Foxp3 in cancer tissue and patients with poorly differentiated HCC were obviously increased (all P < .01), respectively. Cox regression analysis indicated that PD-L1+NEUT, NLR, and Foxp3+Treg were independent risk factors for the prognosis (P = .000, .000, .006) with a RR and 95%CI of 2.704-(2.155-3.393), 3.139-(2.361-4.173), 1.409-(1.105-1.798), respectively. Conclusion: PD-L1+NEUT, NLR, and Foxp3+Treg are independent risk factors for prognosis which maybe new marker of lower survival benefits.

17.
Br J Pharmacol ; 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34599829

RESUMO

BACKGROUND AND PURPOSE: There is emerging evidence for a critical role for epigenetic modifiers in the development of inflammatory bowel disease (IBD). Protein arginine methyltransferase 2 (PRMT2) is responsible for the methylation of arginine residues on histones and targets transcription factors involved in many cellular processes, including gene transcription, mRNA splicing, cell proliferation, and cell differentiation. In this study, the role and underlying mechanisms of PRMT2 in colitis were studied. EXPERIMENTAL APPROACH: A mouse dextran sulfate sodium (DSS)-induced experimental colitis model was used to study PRMT2 in colitis. Lentivirus-induced PRMT2 silencing or overexpression in vivo was applied to address the role of PRMT2 in colitis. Detailed western blot and expression analysis were done to understand epigenetic changes induced by PRMT2 in colitis. KEY RESULTS: PRMT2 is highly expressed in inflammatory bowel disease patients, in inflamed murine colon and in TNF-α stimulated murine gut epithelial cells. PRMT2 overexpression aggravates, while knockdown alleviates DSS-induced colitis, suggesting that PRMT2 is a pivotal mediator of colitis in mice. Mechanistically, PRMT2 mediates colitis by increasing repressive histone mark H3R8 asymmetric methylation (H3R8me2a) at the promoter region of the suppressor of cytokine signalling 3 promoter (SOCS3). Resultant inhibition of SOCS3 expression and inhibition of SOCS3-mediated degradation of TNF receptor associated factor 5 (TRAF5) via ubiquitination led to elevated TRAF5 expression and TRAF5-mediated downstream NF-κB/MAPK activation. CONCLUSION AND IMPLICATIONS: Our study demonstrates that PRMT2 acts as a transcriptional co-activator for proinflammatory genes during colitis. Hence, targeting PRMT2 may provide a novel therapeutic approach for colitis.

18.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1411-1416, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34627418

RESUMO

OBJECTIVE: To investigate the incidence of Runt-related transcription factor 1 (RUNX1) gene and its associated gene mutations in patients with acute myeloid leukemia (AML), and analyze its clinical characteristics and prognosis. METHODS: The genomic DNA-PCR method was used to detect the exon of RUNX1 gene, and the gene mutations were analyzed by genetic sequencing. NPM1, DNMT3A, FLT3-ITD, IDH1/2, K/N-RAS, CEPBA, TET2, and WT1 co-mutations were also detected. Patients were followed up to determine efficacy and prognosis. RESULTS: Among 171 patients, the RUNX1 gene mutation was detected in 17 cases, and the mutation rate was 9.9%. The type of RUNX1 gene mutation was 9 missense mutations, 4 frameshift mutations, and 4 nonsense mutations. The peripheral blood leukocyte count of the patients in mutation group was 3 (1-101) ×109/L, which was significantly lower than those in the non-mutation group [26 (1-298)×109/L] (P=0.002), while the platelet count was 79 (22-166)×109/L, which was higher than 50 (8-351)×109/L in the non-mutation group (P=0.010), and the proportion of bone marrow blasts of the patients in the mutation group was 37 (0-72)%, which was lower than 53 (0-98)% in the non-mutation group (P=0.020). The RUNX1 mutation rate in M0 type was 55.6%, and in M4 type was 13.6%, which was significantly higher than other FAB subtypes (P=0.003). There was no significant difference in age, sex, hemoglobin concentration, and counts of peripheral blood mononuclear cells (P>0.05). The prognosis of cytogenetics in the patients in the middle and high-risk groups was 88.1% and 89.7%, which were significantly higher than that in the low-risk group, and the difference showed statistically significant (P=0.018). There was no significantly relationship between RUNX1 and specific karyotype abnormalities, including Trisomy 8, Del (7q), t (8; 21), and Inv (16) (P>0.05). There was a significant relationship between RUNX1 gene mutation and IDH1/2, N/K-RAS gene mutation (P<0.01). The complete response rate (CR) of the patients with chemotherapy in the RUNX1 mutation group(37.5%) was significantly lower than 79.4% in the non-mutated group (P=0.001). The overall survival (OS) of the patients in RUNX1 gene mutation group was lower than that in non-mutation group (P<0.05). CONCLUSION: AML patients with RUNX1 gene mutation shows unique clinical and biological characteristics, RUNX1 mutation can be regarded as a molecular marker of poor prognosis in AML patients.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Humanos , Cariótipo , Leucemia Mieloide Aguda/genética , Leucócitos Mononucleares , Mutação
19.
Aging (Albany NY) ; 13(19): 22772-22791, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635604

RESUMO

Anti-retroviral therapy (ART) improves life expectancy in people living with HIV (PWH), but it remains unclear how chronic HIV infection affects normal aging of the immune system. Plasma cell-free protein expression and immune phenotypes were assessed in blood from ART treated PWH (19-77yrs, n = 106) and age-matched, HIV-negative controls (HC, n = 103). Using univariate spearman correlation, we identified 277 and 491 age-associated parameters out of a total 1,357 in HC and PWH, respectively. PWH exhibited shared and distinct age-associated immune profiles compared to HC highlighting the effect of HIV infection on immunological aging. Our analysis resulted in an 8-parameter, plasma-detectable inflammatory index that correlated with chronological age of all study participants but was higher overall in PWH. Additionally, predictive modeling for age in HC participants and age-associated parameters generated a 25-parameter signature, IMAP-25, with 70% and 53% accuracy in HC and PWH, respectively. Applying the IMAP-25 signature to immunological data from PWH revealed accelerated aging in PWH by 5.6 yrs. Overall, our results demonstrate that immune signatures, easily monitored in human blood samples, can be used as an indicator of one's 'immunological age' during ART-treated HIV infection and can be applied to other disease states that affect the immune system.

20.
Viruses ; 13(10)2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34696469

RESUMO

Foot and mouth disease virus (FMDV), whose transmission occurs through mucosal surfaces, can also be transmitted through aerosols, direct contact, and pollutants. Therefore, mucosal immunity can efficiently inhibit viral colonization. Since vaccine material delivery into immune sites is important for efficient oral mucosal vaccination, the M cell-targeting approach is important for effective vaccination given M cells are vital for luminal antigen influx into the mucosal lymph tissues. In this study, we coupled M cell-targeting ligand Co1 to multi-epitope TB1 of FMDV to obtain TB1-Co1 in order to improve delivery efficiency of the multi-epitope protein antigen TB1. Lactococcus lactis (L. lactis) was engineered to express heterologous antigens for applications as vaccine vehicles with the ability to elicit mucosal as well as systemic immune responses. We successfully constructed L. lactis (recombinant) with the ability to express multi-epitope antigen proteins (TB1 and TB1-Co1) of the FMDV serotype A (named L. lactis-TB1 and L. lactis-TB1-Co1). Then, we investigated the immunogenic potential of the constructed recombinant L. lactis in mice and guinea pigs. Orally administered L. lactis-TB1 as well as L. lactis-TB1-Co1 in mice effectively induced mucosal secretory IgA (SIgA) and IgG secretion, development of a strong cell-mediated immune reactions, substantial T lymphocyte proliferation in the spleen, and upregulated IL-2, IFN-γ, IL-10, and IL-5 levels. Orally administered ligand-conjugated TB1 promoted specific IgG as well as SIgA responses in systemic and mucosal surfaces, respectively, when compared to orally administered TB1 alone. Then, guinea pigs were orally vaccinated with L. lactis-TB1-Co1 plus adjuvant CpG-ODN at three different doses, L. lactis-TB1-Co1, and PBS. Animals that had been immunized with L. lactis-TB1-Co1 plus adjuvant CpG-ODN and L. lactis-TB1-Co1 developed elevated antigen-specific serum IgG, IgA, neutralizing antibody, and mucosal SIgA levels, when compared to control groups. Particularly, in mice, L. lactis-TB1-Co1 exhibited excellent immune effects than L. lactis-TB1. Therefore, L. lactis-TB1-Co1 can induce elevations in mucosal as well as systemic immune reactions, and to a certain extent, provide protection against FMDV. In conclusion, M cell-targeting approaches can be employed in the development of effective oral mucosa vaccines for FMDV.

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