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1.
Toxicol Appl Pharmacol ; : 114978, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32234387

RESUMO

Parasympathetic nervous system dysfunction is common in patients with liver disease. We have previously shown that muscarinic acetylcholine receptors (mAchRs) play an important role in the regulation of hepatic fibrosis and that the receptor agonists and antagonists affect hepatocyte proliferation. However, little is known about the impact of the different mAchR subtypes and associated signaling pathways on liver injury. Here, we treated the human liver cell line HL7702 with 10 mmol/L carbon tetrachloride (CCL4) to induce hepatocyte damage. We found that CCL4 treatment increased the protein levels of group I mAchRs (M1, M3, M5) but reduced the expression of group II mAchRs (M2, M4) and activated the Nrf2/ARE and MAPK signaling pathways. Although overexpression of M1, M3, or M5 led to hepatocyte damage with an intact Nrf2/ARE pathway, overexpression of M2 or M4 increased, and siRNA-mediated knockdown of either M2 or M4 decreased the protein levels of Nrf2 and its downstream target genes. Moreover, CCL4 treatment increased serum ALT levels more significantly, but only induced slight changes in the expression of mAchRs, NQO1 and HO1, while reducing the expression of M2 and M4 in liver tissues of Nrf2-/- mice compared to wild type mice. Our findings suggest that group II mAchRs, M2 and M4, activate the Nrf2/ARE signaling pathway, which regulates the expression of M2 and M4, to protect the liver from CCL4-induced injury.

2.
J Mater Chem B ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32239064

RESUMO

Due to the untargeted release of chemical drugs, the efficacy of chemotherapy is often compromised along with serious side effects on patients. Recently, the development of targeted delivery systems using nanomaterials as carriers has provided more alternatives for chemical drug transportation. In this study, we developed a novel targeted nanocomplex of GOQD-ICG-DOX@RBCM-FA NPs (GID@RF NPs). First, PEG modified graphene oxide quantum dots (GOQDs) were used to co-load the photosensitizer of indocyanine green (ICG) and DOX, to form GOQD-ICG-DOX NPs (GID NPs). Then, the red blood cell membrane (RBCM) was applied for GID NP camouflage to avoid immune clearance. Finally, folic acid was used to endow the targeting ability of GID@RF NPs. MTT assay showed that the survival rate of HeLa cells reduced by 71% after treatment with GID@RF NPs and laser irradiation. Meanwhile, membrane camouflage significantly prolonged the blood circulation time and enhanced the immune evading ability of GID NPs. Moreover, the drug accumulation at tumor sites was significantly improved through the strong interaction between FA and FA receptor highly expressed on the tumor cells. In vivo assay demonstrated the strongest tumor growth inhibition ability of the combinational chemo/photothermal therapy. H&E analysis indicated no significant abnormalities in the major organs of mice undergoing GID@RF NPs treatment. The level of blood and biochemical parameters remained stable as compared to the control. In summary, this combinational therapy system provides a safe, rapid and effective alternative for the treatment of cervical cancer in the future.

3.
J Proteome Res ; 19(4): 1502-1512, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32168457

RESUMO

Glomerular diseases, which are currently diagnosed using an invasive renal biopsy, encompass numerous disease subtypes that often display similar clinical manifestations even though they have different therapeutic regimes. Therefore, a noninvasive assay is needed to classify and guide the treatment of glomerular diseases. Here, we develop and apply a high-throughput and quantitative microarray platform to characterize the immunoglobulin proteome in the serum from 419 healthy and diseased patients. The immunoglobulin proteome-clinical variable correlation network revealed novel pathological mechanisms of glomerular diseases. Furthermore, an immunoglobulin proteome-multivariate normal distribution (IP-MiND) mathematical model based on the correlation network classified healthy volunteers and patients with idiopathic membranous nephropathy with an average recall of 48% (23-80%) in the discovery cohort and 64% (63-65%) in an independent validation cohort. Our results demonstrate the translational utility of our microarray platform to glomerular diseases as well as its clinical potential in characterizing other human diseases.

4.
Med Sci Monit ; 26: e921182, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32161254

RESUMO

BACKGROUND The 2018 Global Initiative for Chronic Obstructive Lung Disease Report reveals that the blood eosinophil count could forecast the risk of flare-ups. This study explored the correlations of blood eosinophils with fractional exhaled nitric oxide (FeNO) and pulmonary function parameters in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). MATERIAL AND METHODS The data of patients with AECOPD at our hospital admitted between July 2018 and June 2019 were retrospectively analyzed. All patients were stratified into an eosinophilic group (≥2%) or a noneosinophilic group (<2%) based on the peripheral eosinophil count per centum. Cross-sectional analysis was performed to compare clinical characteristics, percentage of eosinophils, FeNO, and pulmonary function between the 2 groups. RESULTS After applying the inclusion/exclusion criteria, 247 patients were included. FeNO values were higher in eosinophilic group (n=97) than in noneosinophilic group (n=150) (P=0.005). The forced expiratory volume in 1 second% predicted (FEV1% predicted), FEV1, and forced vital capacity (FVC) were higher in the eosinophilic group than in the noneosinophilic group (P=0.043; P=0.040; and P=0.011, respectively). Blood eosinophilia showed positive correlations with FeNO (P=0.004) and spirometry variables (FEV1 [% predicted], P=0.003; FEV1, P<0.001; and FVC, P<0.001). An FeNO level of 22.5 ppb was the best cutoff value to predict blood eosinophilia (P=0.000). CONCLUSIONS Blood eosinophil count is a likely biomarker that can predict positive relationship with FeNO values and pulmonary function parameters.

5.
J Hazard Mater ; 391: 122057, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32044627

RESUMO

The nano zero-valent iron sludge-based biochar (nZVI-SBC) was prepared in this study to eliminate Sb(III) from aqueous solutions, which was characterized by BET, SEM, XRD, TEM, FTIR, XPS. Our results proved that the incorporated nZVI on SBC matrix could significantly enhance eliminating Sb(III), and the max-adsorption capacity (160.40 mg g-1) can be achieved at pH = 4.8 ± 0.2 and temperature of 298 K. The effect of co-existing anions and natural organic matters on the Sb(III) adsorption efficiencies were systematically investigated. The surface complexation is the possible adsorption mechanisms by FTIR and XPS. Furthermore, mechanistic investigation revealed that •OH and hydroquinone radical (H-SQ•-) could be the primary oxidants for the transformation of Sb(III) under oxic conditions, while 9,10-phenanthrene quinone radical (P-SQ•-) were responsible under anoxic conditions. Thus, the enhanced elimination of Sb(III) from aqueous solution was ascribed to the combined adsorption and oxidation. The potential engineering application of nZVI-SBC can be proved through three actual water matrix experiments, including lake water, river water and acid mine drainage. Our present findings proved that nZVI-SBC could be a potential adsorbent, given the excellent performance in the adsorption processes, as well as the toxicity alleviating ability and economic advantages, especially under sub-surface water.

6.
Cell Rep ; 30(8): 2712-2728.e8, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32101747

RESUMO

Histone deacetylases (HDACs) drive innate immune cell-mediated inflammation. Here we identify class IIa HDACs as key molecular links between Toll-like receptor (TLR)-inducible aerobic glycolysis and macrophage inflammatory responses. A proteomic screen identified the glycolytic enzyme pyruvate kinase M isoform 2 (Pkm2) as a partner of proinflammatory Hdac7 in murine macrophages. Myeloid-specific Hdac7 overexpression in transgenic mice amplifies lipopolysaccharide (LPS)-inducible lactate and promotes a glycolysis-associated inflammatory signature. Conversely, pharmacological or genetic targeting of Hdac7 and other class IIa HDACs attenuates LPS-inducible glycolysis and accompanying inflammatory responses in macrophages. We show that an Hdac7-Pkm2 complex acts as an immunometabolism signaling hub, whereby Pkm2 deacetylation at lysine 433 licenses its proinflammatory functions. Disrupting this complex suppresses inflammatory responses in vitro and in vivo. Class IIa HDACs are thus pivotal intermediates connecting TLR-inducible glycolysis to inflammation via Pkm2.

7.
Neurochem Res ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32052258

RESUMO

Neuroinflammation plays a vital role in the process of a variety of retinal ganglion cells (RGCs) degenerative diseases including traumatic optic neuropathy (TON). Retinal microglial activation is believed as a harbinger of TON, and robust microglial activation can aggravate trauma-induced RGCs degeneration, which ultimately leads to RGCs loss. Toll like receptor 4 (TLR4)-triggered inflammation is of great importance in retinal inflammatory response after optic nerve injury. CD11b on macrophage and brain microglia can inhibit TLR4-triggered inflammation. However, the functional role of CD11b in retinal microglia is not well understood. Here, using an optic nerve crush model and CD11b gene deficient mice, we found that CD11b protein expression was mainly on retinal microglia, significantly increased after optic nerve injury, and still maintained at a high level till at least 28 days post crush. Compared with wild type mice, following acute optic nerve injury, CD11b deficient retinae exhibited more exacerbated microglial activation, accelerated RGCs degeneration, less growth associated protein-43 expression, as well as more proinflammatory cytokines such as interleukin-6 and tumor necrosis factor α while less anti-inflammatory factors such as arginase-1 and interleukin-10 production. We conclude that CD11b is essential in regulating retinal microglial activation and neuroinflammatory responses after acute optic nerve injury, which is critical for subsequent RGCs degeneration and loss.

8.
Neuron ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32027825

RESUMO

The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities.

9.
J Environ Manage ; 260: 110125, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941637

RESUMO

Sulfate-radical-based advanced oxidation processes (SR-AOPs) have been widely applied in environmental remediation during the past decade, especially in the degradation of refractory organic contaminants. The electrochemical method, which is considered as one of the most efficient ways to generate sulfate radical, has been extensively investigated for the activation of persulfate recently. This work presented a thorough assessment towards the performance of electrochemically activated persulfate for the removal of persistent organic pollutants (POPs) in aqueous systems. The mechanism and superiority of electrochemically activated persulfates were revealed accordingly. Some major factors (e.g., electrode material, pH, current density, and persulfate concentration) influencing the electrochemical activation of persulfates to remove POPs were also discussed. Considering the increasing quantity of publications on this subject, it is significant to broader guidelines such as the efficiency for practical application, quantization of organic by-products, and cost-effectiveness of the electrochemical method to optimize active persulfate in the water treatment processes.


Assuntos
Poluentes Ambientais , Recuperação e Remediação Ambiental , Poluentes Químicos da Água , Purificação da Água , Oxirredução , Sulfatos , Água
10.
Int J Pharm ; 578: 119043, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31962190

RESUMO

This study aimed to develop an evaluation approach for supersaturation by employing an in vitro bio-mimicking apparatus designed to predict in vivo performance. The Biphasic Gastrointestinal Simulator (BGIS) is composed of three chambers with absorption phases that represent the stomach, duodenum, and jejunum, respectively. The concentration of apatinib in each chamber was detected by fiber optical probes in situ. The dissolution data and the pharmacokinetic data were correlated by GastroplusTM. The precipitates were characterized by polarizing microscope, Scanning Electron Microscopy, Powder X-ray diffraction and Differential scanning calorimetry. According to the results, Vinylpyrrolidone-vinyl acetate copolymer (CoPVP) prolonged supersaturation by improving solubility and inhibiting crystallization, while Hydroxypropyl methylcellulose (HPMC) prolonged supersaturation by inhibiting crystallization alone. Furthermore, a predictive in vitro-in vivo correlation was established, which confirmed the anti-precipitation effect of CoPVP and HPMC on in vitro performance and in vivo behavior. In conclusion, CoPVP and HPMC increased and prolonged the supersaturation of apatinib, and then improved its bioavailability. Moreover, BGIS was demonstrated to be a significant approach for simulating in vivo conditions for in vitro-in vivo correlation in a supersaturation study. This study presents a promising approach for evaluating supersaturation, screening precipitation inhibitors in vitro, and predicting their performances in vivo.

11.
Sci Total Environ ; 708: 134614, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31806319

RESUMO

In this work, a fluorescent nanoparticles labeling-free fluorescence enzyme-linked immunoassay (FELISA) has been established for the ultrasensitive detection of microcystin-LR (MC-LR) in water and fish samples. Polyclonal antibody against MC-LR was labeled with horseradish peroxidase (HRP) and used as signal probe for binding with analyte in sample or for coating antigen. After washing of the unbound antibody, the substrate system (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS)/H2O2) was added. The oxidation product of ABTS (ox-ABTS) catalyzed by HRP effectively caused the fluorescence quenching of subsequently added silane-doped carbon dots (Si-CDs), and the change in fluorescence intensity of Si-CDs was used to realize the quantitative detection of MC-LR. Under the optimum conditions, the Si-CDs based FELISA method showed a good linear relationship from 0.001 to 3.20 µg L-1 (R2 = 0.994) and provided a low detection limit of 0.6 ng L-1, which was approximately 30-fold lower than that of traditional indirect competitive ELISA. Average recovery values from 79.9% to 109.2% was obtained from spiked water and crucian samples, suggesting its potential application on the monitoring of MR-LR at a trace level.

12.
Nano Lett ; 20(1): 644-651, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31790260

RESUMO

Solar-blind deep ultraviolet photodetectors (DUVPDs) based on conventional inorganic ultrawide bandgap semiconductors (UWBS) have shown promising application in various civil and military fields and yet they can hardly be used in wearable optoelectronic devices and systems for lack of mechanical flexibility. In this study, we report a non-UWBS solar-blind DUVPD by designing ultrathin polymer nanofibrils with a virtual ultrawide bandgap, which was obtained by grafting P3HT with PHA via a polymerization process. Optoelectronic analysis reveals that the P3HT-b-PHA nanofibrils are sensitive to DUV light with a wavelength of 254 nm but are virtually blind to both 365 nm and other visible light illuminations. The responsivity is 120 A/W with an external quantum efficiency of up to 49700%, implying a large photoconductive gain in the photoresponse process. The observed solar-blind DUV photoresponse is associated with the resonant mode due to the leakage mode of the ultrathin polymer nanofibrils. Moreover, a flexible image sensor composed of 10 × 10 pixels can also be fabricated to illustrate their capability for image sensing application. These results signify that the present ultrathin P3HT-b-PHA nanofibrils are promising building blocks for assembly of low-cost, flexible, and high-performance solar-blind DUVPDs.

13.
Cell Biol Int ; 44(2): 569-582, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31642564

RESUMO

Recent studies have found that the acetaldehyde dehydrogenase 1A3 (ALDH1A3) gene is a marker of glioma stem cells. A total of 115 brain glioma specimens were collected and classified into grade I-IV, while non-tumor brain tissue specimens, taken from 12 patients of vascular malformation surgery, were used as control. ALDH1A3 gene promoter methylation in glioma tissues was detected by pyrosequencing, while immunohistochemistry and western blot were used to detect ALDH1A3 protein expressions in different grades of glioma tissues and normal brain tissues. The expression of ALDH1A3 in the glioma cell line U87 was detected by quantitative real-time polymerase chain reaction and RNA-Seq technology was applied to investigate differentially expressed genes before and after silencing the ALDH1A3 gene. Among the 115 glioma tissue specimens, 50 (43.48%) showed low and 65 (56.52%) high expression of ALDH1A3, but no expression was detected in the control. Univariate and multivariate COX regression analyses showed that the patient's tumor pathological grade, the methylation status of ALDH1A3 promoter, and the expression of ALDH1A3 protein were risk factors for progression-free survival (PFS) and overall survival (OS) (all P < 0.05) and the OS of mice with silenced ALDH1A3 in a glioma nude mouse model was prolonged. U87 experiments revealed that ALDH1A3 expression had significant effects on apoptosis, proliferation, cell cycle, mitochondrial membrane potential, glucose consumption, lactate production, invasion ability, and expression of the pyruvate kinase M2 (PKM2) and hexokinase 2 (HK2) in glioma cells. ALDH1A3 protein expression is a marker for poor PFS and OS in glioma patients.

14.
Clin Cancer Res ; 26(2): 384-390, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615934

RESUMO

PURPOSE: To examine whether submucosal saline injection (SSI) can improve traditional endoscopic ultrasound (EUS) accuracy in distinguishing between T1a and T1b stage esophageal squamous cell carcinoma (ESCC). EXPERIMENTAL DESIGN: Patients with T1N0M0 stage ESCC (n = 180) ages 18 to 85 years were enrolled between February 14, 2012 to June 4, 2018 at Sun Yat-sen University Cancer Center (Guangdong, China). They were randomly assigned (1:1) to receive either EUS examination after 3-5 mL SSI or EUS only examination. All the patients were referred to thoracic surgeons to receive endoscopic resection (ER) or esophagectomy 5 to 10 days after EUS examination. Standard EUS criteria were used to preoperatively stage the ESCC cases, and surgical pathology reports after referral were used to postoperatively stage the cases. The primary endpoint was the diagnostic accuracy of T1b staging [defined as the sum of the true positive (T1b) and true negative (T1a) cases divided by the total number of cases]. RESULTS: Among the per-protocol population, the SSI+EUS group (n = 81) was superior to the EUS-only group (n = 85) in terms of the diagnostic accuracy for T1b staging [93.8% (95% confidence interval (CI), 88.6-99.1) vs. 65.9% (95% CI, 55.8-76.0); P < 0.001]. The positive predictive value of SSI+EUS for diagnosing T1b ESCC reached 90.9% (95% CI, 81.1-100), which was significantly superior to that of EUS only [0.576 (0.450-0.702), P = 0.001]. CONCLUSIONS: SSI significantly improves the diagnostic accuracy of EUS in distinguishing between T1a and T1b ESCC, which might help avoid unnecessary esophagectomy and diagnostic ER.

15.
J Leukoc Biol ; 107(2): 251-262, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31468585

RESUMO

In innate immune cells, pathogens and danger signals activate TLRs, unleashing potent and tailored inflammatory responses. Previously, we reported that an immune-specific transmembrane adaptor, SLP adaptor and CSK interacting membrane protein (SCIMP), interacts with TLR4 via direct binding to its cytoplasmic TIR domain. SCIMP scaffolds a Src family kinase, Lyn, for TLR4 phosphorylation and activation. Consequently, SCIMP is able to direct selective production of the proinflammatory cytokines IL-6 and IL-12p40 downstream of TLR4 in macrophages. Here, we set out to investigate whether SCIMP also acts as an adaptor for other TLR family members. We report here that SCIMP is phosphorylated and activated in response to agonists of multiple TLRs, including TLR2, TLR3, TLR4, and TLR9. SCIMP also interacts with TLRs that are known to signal from both the cell surface and endosomal compartments. In so doing, this transmembrane adaptor presents Lyn, along with other effectors such as Grb2, Csk, and SLP65, to multiple TLRs during cellular activation. CRISPR-mediated knockout or silencing of SCIMP in macrophages alters TLR signaling outputs and the production of IL-6 and IL-12p40 downstream of multiple TLRs, and upon challenge with live bacteria. Furthermore, the selectivity in cytokine responses is preserved downstream of TLR3, with inducible expression of Il-12p40 and IL-6, but not IFNß, being SCIMP dependent. SCIMP is thus a universal TLR adaptor for scaffolding the Lyn tyrosine kinase and its effectors to enable responses against a wide range of danger signals.

16.
J Ethnopharmacol ; 250: 112438, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31816367

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Mealworm larvae (MWL) (Tenebrio molitor) have been traditionally used in Asian countries for the treatment of liver diseases, including cancer. However, to date, there is marginal information on the mechanisms underlying the anticancer activity of MWL oil. AIM OF THE STUDY: This study aims to determine the in vitro effect of MWL oil on human hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (Caco-2) cells growth in order to produce insect-derived chemotherapeutic agents against cancer. MATERIALS AND METHODS: MWL oil was extracted, and its effects on cancer cells growth were investigated, by the MTT reduction, AO/EB staining, Hoechst 33258 nuclear staining, apoptosis, comet, and caspase activity assays. RESULTS: MWL oil inhibited HepG2 and Caco-2 growth, with IC50 (48 h) values of 0.98% for HepG2 and 0.37% for Caco-2 cells. In addition, flow cytometry analysis demonstrated that 24 h-MWL oil treatment increased early and late apoptosis from 0.04% to 39.77% and from 2.06% to 74.34% on HepG2 and Caco-2 cells, respectively. The mechanism of apoptosis was associated with the death receptor pathway by the activation of caspases -8, -9, and -3, and correlated to its fatty acids action. CONCLUSION: Results of this study demonstrated the potential of MWL oil in the development of natural anticancer therapeutic agents.

17.
Sci Total Environ ; 701: 134751, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31710903

RESUMO

Biochar and compost have been widely used for pollution remediation of heavy metals in soil. However, little research was conducted to explore the efficiency of biochar, compost and their combination to reduce heavy metals availability, and the effects of their additive on soil biological properties are often neglected. Therefore, this study investigated the effects of biochar, compost and their combination on availability of heavy metals, physicochemical features and enzyme activities in soil. Results showed that adding amendments to polluted soil significantly altered soil properties. Compared to the separate addition of biochar or compost, their combined application was more effective to improve soil pH, organic matter (OM), organic carbon (TOC) and available potassium (AK). All amendments significantly decreased the availability of Cd and Zn, but slightly activated As and Cu. In addition, soil enzyme activities were activated by compost and inhibited by biochar, but exhibited highly variable responses to their combinations. Pearson correlation analysis indicated that electrical conductivity (EC) and AK were the most important environmental factors affecting metal availability and soil enzyme activities including dehydrogenase, catalase, ß-glucosidase, urease, acid and alkaline phosphatase, arylsulfatase except for protease and invertase. Availability of As, Cu, Cd and Zn affected dehydrogenase, catalase and urease activities. These results indicated that biochar, compost and their combination have significant effects on physicochemical features, metals availability and enzyme activities in heavy metal-polluted soil.


Assuntos
Carvão Vegetal/química , Recuperação e Remediação Ambiental/métodos , Metais Pesados/análise , Poluentes do Solo/análise , Solo/química , Compostagem
18.
BMC Microbiol ; 19(1): 297, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842748

RESUMO

BACKGROUND: Siberian sturgeon (Acipenser baeri Brandt) and Beluga sturgeon (Huso huso) are two important commercial fish in China, and the feeding habits of them are very different. Diets and feeding habits are two significant factors to affect the gastrointestinal microbiota in fish. The intestinal microbiota has been reported to play a key role in nutrition and immunity. However, it is rarely reported about the relationship between the intestinal microbiota and feeding habits/diets on different Acipenseridae fish. This study is to comparative analysis of gut microbial community in Siberian sturgeon and Beluga sturgeon fed with the same diet/Beluga sturgeon fed with different diets in order to determine the effects of different feeding habits/diets on the fish intestinal microbiota. RESULTS: According to the experimental objectives, BL and BH groups were Beluga sturgeon (Huso huso) fed with low fishmeal diet and high fishmeal diet, respectively. SH group represented Siberian sturgeon (Acipenser baeri Brandt) fed with the same diet as BH group. After 16 weeks feeding trial, the intestinal microbiota was examined by 16S rRNA high-throughput sequencing technology. On the phylum level, Proteobacteria and Bacteroidetes were significantly higher in BL group than BH group, and Cyanobacteria showed the opposite trend. Compared with BH group, Proteobacteria and Firmicutes were significantly increased in SH group, whereas Cyanobacteria were clearly decreased. At the genus level, Pseudomonas and Citrobacter in BL group were significantly higher comparing with BH group, while Bacillus, Luteibacter, Staphylococcus and Oceanobacillus was lower in BH group than SH group. CONCLUSIONS: Alpha and beta diversities indicated that the intestinal microflora were significant difference between Siberian sturgeon and Beluga sturgeon when they fed with the same diet. Meanwhile, Beluga sturgeon fed with low fishmeal diet can increase the species diversity of intestinal microbiota than it fed high fishmeal diet. Therefore, feeding habits clearly affected the gastrointestinal microbiota of sturgeons. Moreover, the impact of changes in food on the gut microbiota of sturgeons should be taken into consideration during the process of sturgeon aquaculture.

19.
Cell Rep ; 29(7): 1848-1861.e6, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31722202

RESUMO

Follicular regulatory T (TFR) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain TFR lineage identity and suppressive activity remain largely unknown. Here, we show that expression of Blimp1 by FoxP3+ TFR cells is essential for TFR lineage stability, entry into the GC, and expression of regulatory activity. Deletion of Blimp1 in TFR cells reduced FoxP3 and CTLA-4 expression and increased pro-inflammatory cytokines and spontaneous production of autoantibodies, including elevated IgE. Maintenance of TFR stability reflected Blimp1-dependent repression of the IL-23R-STAT3 axis and activation of the CD25-STAT5 pathway, while silenced IL-23R-STAT3 or increased STAT5 activation rescued the Blimp1-deficient TFR phenotype. Blimp1-dependent control of CXCR5/CCR7 expression also regulated TFR homing into the GC. These findings uncover a Blimp1-dependent TFR checkpoint that enforces suppressive activity and acts as a gatekeeper of GC entry.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31636065

RESUMO

GLS4 is a novel inhibitor of the hepatitis B virus (HBV) capsid assembly with inhibitory activities against nucleot(s)ide-resistant HBV strains. This study investigated the pharmacokinetics, safety, and tolerability of GLS4 and the effects of food and ritonavir in healthy adults. GLS4 was administered in a single-ascending-dose study over 1 to 240 mg and multiple-ascending-dose study that ranged from 30 mg once daily to 180 mg three times daily. The drug interaction study included sequential design (day 1 for 120 mg GLS4 alone, day 5 for 100 mg ritonavir alone, followed by 9 days of both drugs) and a placebo control (9 days of both 240 mg GLS4 and 100 mg ritonavir). The results showed that the steady-state trough concentration of multiple dosing of GLS4 alone was significantly lower than the 90% effective concentration of 55.7 ng/ml, even with increasing dosing frequency and dosage. An initial dose of 100 mg ritonavir significantly boosted plasma concentration at 24 h of 120 mg GLS4 from 2.40 to 49.8 ng/ml (geometric mean ratio, 20.7; 90% confidence interval, 17.0 to 25.3), while a milder effect was observed on the area under the curve from 0 to 24 h, with a 7.42-fold increase, and on the maximum concentration, with a 4.82-fold increase. The pharmacokinetics change in GLS4 persisted after 9 days of chronic dosing, with a trough concentration of 182 ng/ml. Both single and multiple doses of GLS4 up to 240 mg with or without ritonavir were well tolerated. These results support the investigation of a novel HBV treatment regimen containing GLS4 with 100 mg ritonavir added solely to enhance GLS4 concentrations in plasma. (This study was registered at the China Platform for Registry and Publicity of Drug Clinical Trials [http://www.chinadrugtrials.org.cn] under numbers CTR20132137 and CTR20150230.).

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