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1.
Mar Drugs ; 17(12)2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847202

RESUMO

In recent years, the wide application of exopolysaccharides (EPSs) in food, cosmetics, medicine, and other fields has drawn tremendous attention. In this study, an EPS produced by Pseudoalteromonas agarivorans Hao 2018 was isolated and purified, and its fermentation conditions were optimized. Its structure and biological functions were also studied. The purity and molecular weight of EPS were determined by high performance liquid chromatography (HPLC), and the EPS exhibited a number average of 2.26 × 105 and a weight average of 2.84 × 105. EPS has good adsorption for Cu2+ and Pb2+. The adsorption rates can reach up to 69.79% and 82.46%, respectively. The hygroscopic property of EPS was higher than that of chitosan, but slightly lower than that of sodium hyaluronate. However, the water-retaining activity of EPS was similar to that of chitosan and sodium hyaluronate. EPS has strong ability to scavenge free radicals, including OH radical and O2- radical. Further, its activity on O2- radicals has similarities with that of vitamin C. EPS has broad application prospects in many fields, such as cosmetics, environmental protection.

2.
mSystems ; 4(5)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594827

RESUMO

Gut microbiota play important roles in host metabolism, especially in diabetes. However, why different diets lead to similar diabetic states despite being associated with different microbiota is not clear. Mice were fed two high-energy diets (HED) with the same energy density but different fat-to-sugar ratios to determine the associations between the microbiota and early-stage metabolic syndrome. The two diets resulted in different microbiota but similar diabetic states. Interestingly, the microbial gene profiles were not significantly different, and many common metabolites were identified, including l-aspartic acid, cholestan-3-ol (5ß, 3α), and campesterol, which have been associated with lipogenesis and inflammation. Our study suggests that different metabolic-syndrome-inducing diets may result in different microbiota but similar microbiomes and metabolomes. This suggests that the metagenome and metabolome are crucial for the prognosis and pathogenesis of obesity and metabolic syndrome.IMPORTANCE Various types of diet can lead to type 2 diabetes. The gut microbiota in type 2 diabetic patients are also different. So, two questions arise: whether there are any commonalities between gut microbiota induced by different pro-obese diets and whether these commonalities lead to disease. Here we found that high-energy diets with two different fat-to-sugar ratios can both cause obesity and prediabetes but enrich different gut microbiota. Still, these different gut microbiota have similar genetic and metabolite compositions. The microbial metabolites in common between the diets modulate lipid accumulation and macrophage inflammation in vivo and in vitro This work suggests that studies that only use 16S rRNA amplicon sequencing to determine how the microbes respond to diet and associate with diabetic state are missing vital information.

3.
Cell Death Dis ; 10(10): 774, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601780

RESUMO

Neonatal jaundice is prevalent among newborns and can lead to severe neurological deficits, particularly sensorimotor dysfunction. Previous studies have shown that bilirubin (BIL) enhances the intrinsic excitability of central neurons and this can potentially contribute to their overexcitation, Ca2+ overload, and neurotoxicity. However, the cellular mechanisms underlying elevated neuronal excitability remain unknown. By performing patch-clamp recordings from neonatal neurons in the rat medial vestibular nucleus (MVN), a crucial relay station for locomotor and balance control, we found that BIL (3 µM) drastically increases the spontaneous firing rates by upregulating the current-mediated voltage-gated sodium channels (VGSCs), while shifting their voltage-dependent activation toward more hyperpolarized potentials. Immunofluorescence labeling and western immunoblotting with an anti-NaV1.1 antibody, revealed that BIL elevates the expression of VGSCs by promoting their recruitment to the membrane. Furthermore, we found that this VGSC-trafficking process is Ca2+ dependent because preloading MVN neurons with the Ca2+ buffer BAPTA-AM, or exocytosis inhibitor TAT-NSF700, prevents the effects of BIL, indicating the upregulated activity and density of functional VGSCs as the core mechanism accountable for the BIL-induced overexcitation of neonatal neurons. Most importantly, rectification of such overexcitation with a low dose of VGSC blocker lidocaine significantly attenuates BIL-induced cell death. We suggest that this enhancement of VGSC currents directly contributes to the vulnerability of neonatal brain to hyperbilirubinemia, implicating the activity and trafficking of NaV1.1 channels as a potential target for neuroprotection in cases of severe jaundice.

5.
Sci Data ; 6(1): 10, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30918266

RESUMO

Members of the marine genus Pseudoalteromonas have attracted great interest because of their ability to produce a large number of biologically active substances. Here, we report the complete genome sequence of Pseudoalteromonas agarivorans Hao 2018, a strain isolated from an abalone breeding environment, using second-generation Illumina and third-generation PacBio sequencing technologies. Illumina sequencing offers high quality and short reads, while PacBio technology generates long reads. The scaffolds of the two platforms were assembled to yield a complete genome sequence that included two circular chromosomes and one circular plasmid. Transcriptomic data for Pseudoalteromonas were not available. We therefore collected comprehensive RNA-seq data using Illumina sequencing technology from a fermentation culture of P. agarivorans Hao 2018. Researchers studying the evolution, environmental adaptations and biotechnological applications of Pseudoalteromonas may benefit from our genomic and transcriptomic data to analyze the function and expression of genes of interest.


Assuntos
Genoma Bacteriano , Transcriptoma , Genômica , Pseudoalteromonas/genética
6.
Mol Nutr Food Res ; 63(11): e1800987, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30920128

RESUMO

SCOPE: The aim of the study is to explore which properties of selected peptides will positively predict their antidiabetic activity in vitro and in vivo. METHODS AND RESULTS: Streptozotocin-induced diabetic C57BL/6J mice are administered with soybean peptide (SP), mung bean peptide (MP), corn peptide (CP), and wheat peptide (WP) (500 mg kg-1  d-1 ) for 10 weeks. CP and WP improve hyperglycemia homeostasis in streptozotocin-induced diabetic mice. Female nonobese diabetic (NOD) mice are treated with CP, WP, fractions C1 and C2 (isolated from CP), and W1 and W2 (isolated from WP) beginning at 3 weeks of age. CP, C2, and W2 delay the initiation of diabetes and decrease serum IL-6 levels in NOD mice. CP also reduces insulitis and increases the ß-cell area in NOD mice. MIN-6 cells are incubated with the selected peptides. CP, C2, and W2 result in the reduced expression of LPS-induced IL-6 mRNA in MIN-6 cells. CP inhibits signaling pathways related to apoptosis and inflammation. The antioxidative, hydrophobic, and proliferative properties of the selected peptides are analyzed. The hypoglycemic effects of cereal peptides are not associated with their antioxidant activity, hydrophobicity, or proliferative ability. CONCLUSION: Findings suggest that the effect of cereal peptides on the development of T1D is associated with their anti-inflammatory ability.

7.
Sci Rep ; 9(1): 1743, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30742012

RESUMO

We designed a prospective study to evaluate changes in tinnitus after vestibular schwannoma (VS) surgery. Subjects included 41 patients who were diagnosed with a VS and underwent translabyrinthine microsurgery (TLM) between January 2015 and May 2016. All patients underwent related examinations and were asked to answer the Tinnitus Handicap Inventory (THI) scale and a visual analog scale (VAS) of tinnitus severity both pre- and postoperatively. Of the 41 patients, 31 (75.6%) suffered from tinnitus before surgery. Microsurgery was associated with an overall decrease in tinnitus (p < 0.001). There was a significant improvement in THI and VAS scores after surgery (p = 0.001 and p = 0.005, respectively). The decrease in THI scores in the low-frequency group was significantly larger than that of the mid- and high-frequency groups after surgery (p = 0.034 and p = 0.001, respectively). The loudness of tinnitus decreased significantly after surgery (p = 0.031). Tinnitus in patients with VS improved after TLM. Patients with mid-/high-frequency tinnitus and louder tinnitus preoperatively seemed to have a worse prognosis than those with low-frequency and quieter tinnitus.

8.
J Clin Hypertens (Greenwich) ; 21(2): 280-290, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30667162

RESUMO

Previous studies have reported the effects of obstructive sleep apnea (OSA) and cardiometabolic disorders on cardiovascular disease (CVD), but associations between cardiometabolic biomarkers and two cardinal features of OSA (chronic intermittent hypoxia and sleep fragmentation) and their interactions on CVD in OSA populations remain unclear. A total of 1727 subjects were included in this observational study. Data on overnight polysomnography parameters, biochemical biomarkers, and anthropometric measurements were collected. Metabolic syndrome (MS), including blood pressure, waist circumference (WC), fasting glucose, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), was diagnosed based on modified criteria of the Adult Treatment Panel III. WC, mean arterial pressure, TG and low-density lipoprotein cholesterol (LDL-C) were independently associated with apnea-hypopnea index (AHI) after adjustment for confounding factors (ß = 0.578, P = 0.000; ß = 0.157, P = 0.001; ß = 1.003, P = 0.019; and ß = 4.067, P = 0.0005, respectively). Furthermore, the interaction analysis revealed joint effects between hypertension, obesity, hyperglycemia, and LDL-C dyslipidemia and AHI on CVD. The relative excess risks of CVD due to the interactions with OSA were 2.06, 1.02, 0.48, and 1.42, respectively (all P < 0.05). In contrast, we found no independent effect of the microarousal index (MAI) on CVD. However, LDL-C level and some MS components (WC, TG) were associated with MAI. Our findings indicate that hypoxemia and cardiometabolic disorders in OSA may potentiate their unfavorable effects on CVD. Sleep fragmentation may indirectly predispose patients with OSA to an increased risk of CVD. Thus, cardiometabolic disorders and OSA synergistically influence cardiometabolic risk patterns.

9.
J Nippon Med Sch ; 85(6): 302-308, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30568055

RESUMO

BACKGROUND: Antibiotic resistance of pathogenic bacteria is well recognized among clinicians; however, studies that directly evaluate the bacterial resistance to commonly used disinfectants in clinical settings are lacking. Currently available reports focus on the resistance of single strains to single disinfectants and do not adequately examine the degree of resistance and cross-resistance to antimicrobials in the large-scale clinical use of disinfectants. METHODS: We investigated the resistance capacity to 11 antibiotics and 7 chemical disinfectants by bacterial strains collected from body fluids of patients in 10 hospitals in Beijing, China over a 1-year period. Bacterial resistance to disinfectants was tested using minimum inhibitory concentration and minimum bactericidal concentration using agar dilution methods based on commercially available reference strains. RESULTS: A total of 1,104 pathogenic strains were identified, of which 23% were Gram-positive bacteria, 74% were Gram-negative bacteria, and 3% were fungi. Overall, resistance to antibiotics for the most common strains was significantly higher than their resistance to disinfectants. The least effective antibiotics and disinfectants were aztreonam and glutaral, respectively, exhibiting the highest overall resistance rates; while amikacin and alcohol had the lowest resistance rates. Consistently, Acinetobacter baumannii exhibited the most resistance, while Escherichia coli had the least resistance for both antibiotics and disinfectants. CONCLUSIONS: Based on the pathogen spectrum for bacterial infective pathogens evaluated in this study, as well as the status quo of their resistance to antimicrobial agents and common clinical disinfectants, it is essential for healthcare professionals to pay attention not only to the standardized use of antimicrobial agents but also to the rational application of disinfectants.


Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/prevenção & controle , Desinfetantes/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Anti-Infecciosos/classificação , Bactérias/classificação , Bactérias/patogenicidade , Infecções Bacterianas/microbiologia , Pequim , Líquidos Corporais/microbiologia , Desinfetantes/classificação , Humanos , Testes de Sensibilidade Microbiana , Virulência
10.
Medicine (Baltimore) ; 97(22): e10985, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29851854

RESUMO

The assessment of pain in patients with brain injury is challenging due to impaired ability to communicate. We aimed to test the reliability and validity of the critical-care pain observation tool (CPOT) and the bispectral index (BIS) for pain detection in critically brain-injured patients.This prospective observational study was conducted in a neurosurgical intensive care unit in a University-Affiliated Hospital. Adult brain-injured patients undergoing mechanical ventilation were enrolled. Nociceptive (endotracheal suctioning) and non-nociceptive (gentle touching) procedures were performed in a random crossover fashion. Before and immediately after the procedure, CPOT was evaluated by 2 residents and 2 chief nurses, and BIS was documented. The ability to self-report pain was also assessed. The inter-observer reliability of CPOT was analyzed. The criterion and discriminant validities of the CPOT and the BIS were tested.During the study, we enrolled 400 brain-injured patients. The ability to self-report pain was maintained in 214 (54%) and 218 (55%) patients during suctioning and gentle touching, respectively. The intraclass correlation coefficients (95% confidence interval) for inter-observer reliability of CPOT ranged from 0.86 (0.83-0.89) to 0.93 (0.91-0.94). Using self-reported pain as the reference, the area under the receiver operating characteristic curve (95% confidence interval) was 0.84 (0.80-0.88) for CPOT and 0.76 (0.72-0.81) for BIS. When the 2 instruments were combined as either CPOT ≥2 or BIS ≥88 after the procedure, the sensitivity and specificity were 0.90 (0.85-0.93) and 0.59 (0.52-0.66), respectively; and when the 2 instruments were combined as both CPOT ≥2 and BIS ≥88, the sensitivity and specificity were 0.62 (0.55-0.68) and 0.89 (0.83-0.93). Both CPOT and BIS increased significantly after suctioning (all P < .001) but remained unchanged after gentle touching (P ranging from .06 to .14).Our criterion and discriminant validity results supported the use of CPOT and BIS to detect pain in critically brain-injured patients. Combining use of CPOT and BIS in different ways might provide comprehensive pain assessment for different purposes.


Assuntos
Lesões Encefálicas/diagnóstico , Monitores de Consciência/estatística & dados numéricos , Cuidados Críticos/métodos , Medição da Dor/métodos , Dor/diagnóstico , Adulto , Lesões Encefálicas/terapia , Estado Terminal , Estudos Cross-Over , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Reprodutibilidade dos Testes , Respiração Artificial , Autorrelato , Sensibilidade e Especificidade
11.
Front Mol Neurosci ; 11: 183, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29904342

RESUMO

In developing sensory systems, elaborate morphological connectivity between peripheral cells and first-order central neurons emerges via genetic programming before the onset of sensory activities. However, how the first-order central neurons acquire the capacity to interface with peripheral cells remains elusive. By making patch-clamp recordings from mouse brainstem slices, we found that a subset of neurons in the cochlear nuclei, the first central station to receive peripheral acoustic impulses, exhibits spontaneous firings (SFs) as early as at birth, and the fraction of such neurons increases during the prehearing period. SFs are reduced but not eliminated by a cocktail of blockers for excitatory and inhibitory synaptic inputs, implicating the involvement of intrinsic pacemaker channels. Furthermore, we demonstrate that these intrinsic firings (IFs) are largely driven by hyperpolarization- and cyclic nucleotide-gated channel (HCN) mediated currents (Ih), as evidenced by their attenuation in the presence of HCN blockers or in neurons from HCN1 knockout mice. Interestingly, genetic deletion of HCN1 cannot be fully compensated by other pacemaker conductances and precludes age-dependent up regulation in the fraction of spontaneous active neurons and their firing rate. Surprisingly, neurons with SFs show accelerated development in excitability, spike waveform and firing pattern as well as synaptic pruning towards mature phenotypes compared to those without SFs. Our results imply that SFs of the first-order central neurons may reciprocally promote their wiring and firing with peripheral inputs, potentially enabling the correlated activity and crosstalk between the developing brain and external environment.

12.
J Thorac Dis ; 10(3): 1941-1950, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29707350

RESUMO

Background: Standard management has been recommended for obstructive sleep apnea (OSA) by several guidelines, but patient choice in the practical setting is unclear. Methods: A survey nested in two prospective cohort studies of OSA (enrollment: 2001-2010) in China. The last interview was conducted between July 2014 and May 2015, using a comprehensive 10-point questionnaire administered in a face-to-face or telephone interview, and assessed (I) whether the participant had received any OSA treatment; (II) why he or she had decided for or against treatment; (III) what treatment was received; (IV) whether the participant used continuous positive airway pressure (CPAP) or OA daily; and (V) the perceived efficacy of therapy. Results: A total of 4,097 subjects with a mean age of 45 years [37-55] responded to this survey, with a response rate of 79.4% (4,097/5,160); 2,779 subjects (67.8%) did not receive any treatment: 1,485 (53.4%) believed that their condition was not serious, despite severe OSA in 53.7% of the patients. A multivariate regression showed that the decision to receive treatment was associated with: age between 45-59 years [odds ratio (OR) 0.805, 95% CI: 0.691-0.936; P<0.001], female gender (OR 0.492, 95% CI: 0.383-0.631; P<0.001), severe OSA (OR 1.92, 95% CI: 1.01-3.64; P<0.001), hypertension (OR 1.414, 95% CI: 1.209-1.654; P<0.001) and diabetes (OR 1.760, 95% CI: 1.043-2.972; P=0.034). In subjects receiving treatment (n=1,318), 50.9% reported negative perceptions about the treatments. Conclusions: Nearly two thirds of Chinese patients choose not to receive treatment after OSA diagnosis, and nearly half are negative about their treatments for OSA. This requires clinical attention, and warrants further study in different geographic settings.

13.
Front Immunol ; 8: 1345, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29097999

RESUMO

Recent evidence indicates that indigenous Clostridium species induce colonic regulatory T cells (Tregs), and gut lymphocytes are able to migrate to pancreatic islets in an inflammatory environment. Thus, we speculate that supplementation with the well-characterized probiotics Clostridium butyricum CGMCC0313.1 (CB0313.1) may induce pancreatic Tregs and consequently inhibit the diabetes incidence in non-obese diabetic (NOD) mice. CB0313.1 was administered daily to female NOD mice from 3 to 45 weeks of age. The control group received an equal volume of sterile water. Fasting glucose was measured twice a week. Pyrosequencing of the gut microbiota and flow cytometry of mesenteric lymph node (MLN), pancreatic lymph node (PLN), pancreatic and splenic immune cells were performed to investigate the effect of CB0313.1 treatment. Early oral administration of CB0313.1 mitigated insulitis, delayed the onset of diabetes, and improved energy metabolic dysfunction. Protection may involve increased Tregs, rebalanced Th1/Th2/Th17 cells and changes to a less proinflammatory immunological milieu in the gut, PLN, and pancreas. An increase of α4ß7+ (the gut homing receptor) Tregs in the PLN suggests that the mechanism may involve increased migration of gut-primed Tregs to the pancreas. Furthermore, 16S rRNA gene sequencing revealed that CB0313.1 enhanced the Firmicutes/Bacteroidetes ratio, enriched Clostridium-subgroups and butyrate-producing bacteria subgroups. Our results provide the basis for future clinical investigations in preventing type 1 diabetes by oral CB0313.1 administration.

14.
Cell Mol Immunol ; 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28458392

RESUMO

Interleukin 17 (IL-17) is increasingly recognized as a key factor that contributes to the pathogenesis of multiple sclerosis (MS) and its experimental mouse autoimmune encephalomyelitis (EAE) model. However, the roles and regulatory mechanisms of IL-17-induced pro-inflammatory cytokine production in EAE mice remain largely unclear. In this study, the expression of IL-17, hypoxia inducible factor-1α (HIF-1α), IL-1ß, IL-6 and microRNA-497 (miR-497), as well as their intrinsic associations, was investigated using EAE model mice and cultured astrocytes exposed to IL-17 in vitro. We observed markedly increased production of IL-17, HIF-1α, IL-1ß and IL-6 in the brain tissues of EAE mice, while the expression and secretion of HIF-1α, IL-1ß and IL-6 were also significantly increased when cultured primary astrocytes from mice were stimulated with IL-17. Meanwhile, the expression of miR-497 was downregulated both in vivo and in vitro. Subsequent in vitro experiments revealed that IL-17 induced the production of IL-1ß and IL-6 in astrocytes through the upregulation of HIF-1α as a transcriptional factor, indicating that IL-17-mediated downregulation of miR-497 enhanced HIF-1α expression. Furthermore, astrocyte-specific knockdown of IL-17RA and HIF-1α or astrocyte-specific overexpression of miR-497 by infection with different lentiviral vectors containing an astrocyte-specific promotor markedly decreased IL-1ß and IL-6 production in brain tissues and alleviated the pathological changes and score of EAE mice. Collectively, these findings indicate that decreased miR-497 expression is responsible for IL-17-triggered high HIF-1α expression and consequent IL-1ß and IL-6 production by astrocytes in EAE mice.Cellular & Molecular Immunology advance online publication, 1 May 2017; doi:10.1038/cmi.2017.12.

15.
Sci Rep ; 7(1): 431, 2017 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-28348377

RESUMO

Neonatal brain is particularly vulnerable to pathological levels of bilirubin which elevates and overloads intracellular Ca2+, leading to neurotoxicity. However, how voltage-gated calcium channels (VGCCs) are functionally involved in excess calcium influx remains unknown. By performing voltage-clamp recordings from bushy cells in the ventral cochlear nucleus (VCN) in postnatal rat pups (P4-17), we found the total calcium current density was more than doubled over P4-17, but the relative weight of VGCC subtypes changed dramatically, being relatively equal among T, L, N, P/Q and R-type at P4-6 to predominantly L, N, R over T and P/Q at P15-17. Surprisingly, acute administration of bilirubin augmented the VGCC currents specifically mediated by high voltage-activated (HVA) P/Q-type calcium currents. This augment was attenuated by intracellular loading of Ca2+ buffer EGTA or calmodulin inhibitory peptide. Our findings indicate that acute exposure to bilirubin increases VGCC currents, primarily by targeting P/Q-type calcium channels via Ca2+ and calmodulin dependent mechanisms to overwhelm neurons with excessive Ca2+. Since P/Q-subtype calcium channels are more prominent in neonatal neurons (e.g. P4-6) than later stages, we suggest this subtype-specific enhancement of P/Q-type Ca2+ currents likely contributes to the early neuronal vulnerability to hyperbilirubinemia in auditory and other brain regions.


Assuntos
Bilirrubina/metabolismo , Canais de Cálcio/metabolismo , Cálcio/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Técnicas de Patch-Clamp , Ratos
16.
Front Cell Neurosci ; 11: 21, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28217084

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is an important molecule with extensive biological functions in various cellular processes, including protection against cell injuries. However, little is known regarding the roles of NAD+ in neuronal excitation and excitotoxicity associated with many neurodegenerative disorders and diseases. Using patch-clamp recordings, we studied its potential effects on principal neurons in the ventral cochlear nucleus (VCN), which is particularly vulnerable to bilirubin excitotoxicity. We found that NAD+ effectively decreased the size of evoked excitatory postsynaptic currents (eEPSCs), increased paired-pulse ratio (PPR) and reversed the effect of bilirubin on eEPSCs, implicating its inhibitory effects on the presynaptic release probability (Pr). Moreover, NAD+ not only decreased the basal frequency of miniature EPSCs (mEPSCs), but also reversed bilirubin-induced increases in the frequency of mEPSCs without affecting their amplitude under either condition. Furthermore, we found that NAD+ decreased the frequency of spontaneous firing of VCN neurons as well as bilirubin-induced increases in firing frequency. Whole-cell current-clamp recordings showed that NAD+ could directly decrease the intrinsic excitability of VCN neurons in the presence of synaptic blockers, suggesting NAD+ exerts its actions in both presynaptic and postsynaptic loci. Consistent with these observations, we found that the latency of the first postsynaptic spike triggered by high-frequency train stimulation of presynaptic afferents (i.e., the auditory nerve) was prolonged by NAD+. These results collectively indicate that NAD+ suppresses presynaptic transmitter release and postsynaptic excitability, jointly weakening excitatory neurotransmission. Our findings provide a basis for the exploration of NAD+ for the prevention and treatment of bilirubin encephalopathy and excitotoxicity associated with other neurological disorders.

17.
BMC Neurol ; 17(1): 33, 2017 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-28209139

RESUMO

BACKGROUND: Stroke is the leading cause of mortality and disability worldwide. Several definite risk factors have been identified for stroke, although infectious factors might also contribute to stroke episodes through increased susceptibility or direct induction. CASE PRESENTATION: A 46-year-old Chinese male initially presented with fever, headache, and impaired memory and developed disturbance of consciousness after admission. A clinical diagnosis of Staphylococcus aureus sepsis, massive cerebral infarction and haemorrhagic transformation (left internal carotid arterial system, inflammatory thrombus) were made based on brain radiography, blood culture and postoperative pathological examinations. These symptoms improved following antibiotic therapy with vancomycin and conventional treatments for stroke. CONCLUSION: For stroke patients without traditional cerebrovascular risk factors but with signs of infection, infectious causes should be considered.


Assuntos
Arterite/complicações , Trombose das Artérias Carótidas/complicações , Acidente Vascular Cerebral/etiologia , Infarto Cerebral/complicações , Humanos , Masculino , Pessoa de Meia-Idade
18.
Stem Cells Transl Med ; 5(5): 561-71, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27013738

RESUMO

UNLABELLED: The genetic correction of induced pluripotent stem cells (iPSCs) induced from somatic cells of patients with sensorineural hearing loss (caused by hereditary factors) is a promising method for its treatment. The correction of gene mutations in iPSCs could restore the normal function of cells and provide a rich source of cells for transplantation. In the present study, iPSCs were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T; P-iPSCs), the asymptomatic father of the patient (MYO7A c.1184G>A mutation; CF-iPSCs), and a normal donor (MYO7A(WT/WT); C-iPSCs). One of MYO7A mutation sites (c.4118C>T) in the P-iPSCs was corrected using CRISPR/Cas9. The corrected iPSCs (CP-iPSCs) retained cell pluripotency and normal karyotypes. Hair cell-like cells induced from CP-iPSCs showed restored organization of stereocilia-like protrusions; moreover, the electrophysiological function of these cells was similar to that of cells induced from C-iPSCs and CF-iPSCs. These results might facilitate the development of iPSC-based gene therapy for genetic disorders. SIGNIFICANCE: Induced pluripotent stem cells (iPSCs) were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T). One of the MYO7A mutation sites (c.4118C>T) in the iPSCs was corrected using CRISPR/Cas9. The genetic correction of MYO7A mutation resulted in morphologic and functional recovery of hair cell-like cells derived from iPSCs. These findings confirm the hypothesis that MYO7A plays an important role in the assembly of stereocilia into stereociliary bundles. Thus, the present study might provide further insight into the pathogenesis of sensorineural hearing loss and facilitate the development of therapeutic strategies against monogenic disease through the genetic repair of patient-specific iPSCs.


Assuntos
Sistemas CRISPR-Cas , Forma Celular , Células Ciliadas Auditivas , Perda Auditiva Neurossensorial/genética , Células-Tronco Pluripotentes Induzidas , Mutação , Miosinas/genética , Reparo Gênico Alvo-Dirigido/métodos , Diferenciação Celular , Linhagem Celular , Análise Mutacional de DNA , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/transplante , Células Ciliadas Auditivas/ultraestrutura , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/cirurgia , Hereditariedade , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Células-Tronco Pluripotentes Induzidas/ultraestrutura , Masculino , Potenciais da Membrana , Linhagem , Fenótipo , Recuperação de Função Fisiológica , Transfecção
19.
PLoS One ; 11(1): e0146913, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26812647

RESUMO

PURPOSE: To assess the inter session reproducibility of automatic segmented MRI-derived measures by FreeSurfer in a group of subjects with normal-appearing MR images. MATERIALS AND METHODS: After retrospectively reviewing a brain MRI database from our institute consisting of 14,758 adults, those subjects who had repeat scans and had no history of neurodegenerative disorders were selected for morphometry analysis using FreeSurfer. A total of 34 subjects were grouped by MRI scanner model. After automatic segmentation using FreeSurfer, label-wise comparison (involving area, thickness, and volume) was performed on all segmented results. An intraclass correlation coefficient was used to estimate the agreement between sessions. Wilcoxon signed rank test was used to assess the population mean rank differences across sessions. Mean-difference analysis was used to evaluate the difference intervals across scanners. Absolute percent difference was used to estimate the reproducibility errors across the MRI models. Kruskal-Wallis test was used to determine the across-scanner effect. RESULTS: The agreement in segmentation results for area, volume, and thickness measurements of all segmented anatomical labels was generally higher in Signa Excite and Verio models when compared with Sonata and TrioTim models. There were significant rank differences found across sessions in some labels of different measures. Smaller difference intervals in global volume measurements were noted on images acquired by Signa Excite and Verio models. For some brain regions, significant MRI model effects were observed on certain segmentation results. CONCLUSIONS: Short-term scan-rescan reliability of automatic brain MRI morphometry is feasible in the clinical setting. However, since repeatability of software performance is contingent on the reproducibility of the scanner performance, the scanner performance must be calibrated before conducting such studies or before using such software for retrospective reviewing.


Assuntos
Encéfalo/anatomia & histologia , Imagem por Ressonância Magnética/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
Toxicol Lett ; 240(1): 1-9, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26476400

RESUMO

Hyperbilirubinemia is a common clinical phenomenon observed in human newborns. A high level of bilirubin can result in severe jaundice and bilirubin encephalopathy. However, the cellular mechanisms underlying bilirubin excitotoxicity are unclear. Our previous studies showed the action of gamma-aminobutyric acid (GABA)/glycine switches from excitatory to inhibitory during development in the ventral cochlear nucleus (VCN), one of the most sensitive auditory nuclei to bilirubin toxicity. In the present study, we investigated the roles of GABAA/glycine receptors in the induction of bilirubin hyperexcitation in early developing neurons. Using the patch clamp technique, GABAA/glycine receptor-mediated spontaneous inhibitory synaptic currents (sIPSCs) were recorded from bushy and stellate cells in acute brainstem slices from young mice (postnatal day 2-6). Bilirubin significantly increased the frequency of sIPSCs, and this effect was prevented by pretreatments of slices with either fast or slow Ca(2+) chelators BAPTA-AM and EGTA-AM suggesting that bilirubin can increase the release of GABA/glycine via Ca(2+)-dependent mechanisms. Using cell-attached recording configuration, we found that antagonists of GABAA and glycine receptors strongly attenuated spontaneous spiking firings in P2-6 neurons but produced opposite effect in P15-19 neurons. Furthermore, these antagonists reversed bilirubin-evoked hyperexcitability in P2-6 neurons, indicating that excitatory action of GABA/glycinergic transmission specifically contribute to bilirubin-induced hyperexcitability in the early stage of development. Our results suggest that bilirubin-induced enhancement of presynaptic release GABA/Glycine via Ca(2+)-dependent mechanisms may play a critical role in mediating neuronal hyperexcitation associated with jaundice, implicating potential new strategies for predicting, preventing, and treating bilirubin neurotoxicity.


Assuntos
Bilirrubina/efeitos adversos , Glicina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Núcleo Coclear/efeitos dos fármacos , Núcleo Coclear/metabolismo , Ácido Egtázico/análogos & derivados , Ácido Egtázico/metabolismo , Hiperbilirrubinemia/induzido quimicamente , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Receptores da Glicina/metabolismo
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