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1.
Blood ; 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359074

RESUMO

Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell-specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and post-injury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from chronic myelogenous leukemia (CML) patients. Anp32b deletion enhances p53 transcriptional activity to impair LSCs function in a murine CML model, and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B, and identify ANP32B as a potential therapeutic target in treating CML.

2.
BMJ Open ; 11(8): e043883, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376438

RESUMO

OBJECTIVE: The transmuscular quadratus lumborum (TQL) block and the oblique subcostal transversus abdominis plane (OSTAP) block both contribute to multimodal analgesia after laparoscopic surgery. The objective of this study was to compare the analgesic effects of the TQL block versus OSTAP block after laparoscopic hysterectomy. DESIGN: Prospective single-centre randomised single-blind trial. SETTING: University-affiliated hospital. PARTICIPANTS: Patients aged between 18 and 65 years scheduled for laparoscopic hysterectomy. INTERVENTIONS: Patients were randomised into two groups (1:1 ratio) and received bilateral TQL block or bilateral OSTAP block with 0.375% ropivacaine 20 mL on each side before surgery. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the cumulative morphine dose in the first 24 hours. The secondary outcome measures were the morphine consumption at each time interval after surgery, the time from the end of surgery to the first need for morphine, the Numerical Rating Scale (NRS) scores for visceral and incisional pain intensity, and the incidence of adverse events. RESULTS: The cumulative morphine dose was significantly lower in the TQL group than in the OSTAP group (17.2 (12.5) vs 26.1 (13.3) mg, p=0.010). Compared with the OSTAP group, the morphine doses from 6 to 12, 12 to 18, and 18 to 24 hours were significantly lower, the time of first need for morphine was significantly longer and the NRS scores for visceral pain intensity were significantly lower in the TQL group. CONCLUSION: Compared with the OSTAP block, the TQL block reduced morphine consumption and provided better visceral pain relief with a longer duration of effect after laparoscopic hysterectomy. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR1800017995); pre-results.


Assuntos
Analgesia , Laparoscopia , Músculos Abdominais , Adolescente , Adulto , Idoso , Analgésicos Opioides , Anestésicos Locais , Método Duplo-Cego , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Método Simples-Cego , Adulto Jovem
3.
Nanotechnology ; 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087806

RESUMO

In this work, a rich variety of self-assembled DNA patterns were obtained in the magnetic field. Herein, atomic force microscopy (AFM) was utilized to investigate the effects of the concentration of DNA solution, intensity and direction of magnetic field and modification of mica surface by different cations on the self-assembly of DNA molecules. It was found that owning to the change of the DNA concentration, even under the same magnetic field, the DNA self-assembly results were different. The in-situ test results showed that the DNA self-assembly in an magnetic field was more likely to occur in liquid phase than in gas phase. In addition, whether in a horizontal or vertical magnetic field, a single stretched dsDNA was obtained in a certain DNA concentration and magnetic field intensity. Besides, the modification of cations on the mica surface significantly increased the force between the DNA molecules and mica surface, and further changed the self-assembly of DNA molecules under the action of magnetic field.

4.
iScience ; 24(3): 102213, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33733073

RESUMO

Morphine is commonly used to relieve moderate to severe pain, but repeated doses cause opioid tolerance. Here, we used ATP sensor and fiber photometry to detect prefrontal ATP level. It showed that prefrontal ATP level decreased after morphine injection and the event amplitude tended to decrease with continuous morphine exposure. Morphine had little effect on prefrontal ATP due to its tolerance. Therefore, we hypothesized that the analgesic effect of morphine might be related to ATP in the medial prefrontal cortex (mPFC). Moreover, local infusion of ATP partially antagonized morphine analgesia. Then we found that inhibiting P2X7R in the mPFC mimicked morphine analgesia. In morphine-tolerant mice, pretreatment with P2X4R or P2X7R antagonists in the mPFC enhanced analgesic effect. Our findings suggest that reduction of prefrontal purinergic signaling is necessary for the morphine analgesia, which help elucidate the mechanism of morphine analgesia and may lead to the development of new clinical treatments for neuropathic pain.

5.
Stem Cells Int ; 2021: 6662831, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33747095

RESUMO

Paraquat (PQ) poisoning can cause acute lung injury and progress to pulmonary fibrosis and eventually death without effective therapy. Mesenchymal stem cells (MSCs) and hepatocyte growth factor (HGF) have been shown to partially reverse this damage. MSCs can be derived from bone marrow (BM-MSCs), adipose tissue (AD-MSCs), umbilical cord (UC-MSCs), dental pulp (DPSCs), and other sources. The biological characteristics of MSCs are specific to the tissue source. To develop an effective treatment for PQ poisoning, we compared the anti-inflammatory and antifibrotic effects of UC-MSCs and DPSCs and chose and modified a suitable source with HGF to investigate their therapeutic effects in vitro and in vivo. In this study, MSCs' supernatant was beneficial to the viability and proliferation of human lung epithelial cell BEAS-2B. Inflammatory and fibrosis-related cytokines were analyzed by real-time PCR. The results showed that MSCs' supernatant could suppress the expression of proinflammatory and profibrotic cytokines and increase the expression of anti-inflammatory and antifibrotic cytokines in BEAS-2B cells and human pulmonary fibroblast MRC-5. Extracellular vesicles (EVs) derived from MSCs performed more effectively than MSCs' supernatant. The effect of DPSCs was stronger than that of UC-MSCs and was further strengthened by HGF modification. PQ-poisoned mice were established, and UC-MSCs, DPSCs, and DPSCs-HGF were administered. Histopathological assessments revealed that DPSCs-HGF mitigated lung inflammation and collagen accumulation more effectively than the other treatments. DPSCs-HGF reduced lung permeability and increased the survival rate of PQ mice from 20% to 50%. Taken together, these results indicated that DPSCs can suppress inflammation and fibrosis in human lung cells better than UC-MSCs. The anti-inflammatory and antifibrotic effects were significantly enhanced by HGF modification. DPSCs-HGF ameliorated pulmonitis and pulmonary fibrosis in PQ mice, effectively improving the survival rate, which might be mediated by paracrine mechanisms. The results suggested that DPSCs-HGF transplantation was a potential therapeutic approach for PQ poisoning.

6.
BMC Anesthesiol ; 20(1): 101, 2020 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-32359348

RESUMO

BACKGROUND: Butorphanol, a synthetic opioid partial agonist analgesic, has been widely used to control perioperative pain. However, the ideal dose and availability of butorphanol for gastrointestinal (GI) endoscopy are not well known. The aim of this study was to evaluated the 95% effective dose (ED95) of butorphanol and sufentanil in GI endoscopy and compared their clinical efficacy, especially regarding the recovery time. METHODS: The study was divided into two parts. For the first part, voluntary patients who needed GI endoscopy anesthesia were recruited to measure the ED95 of butorphanol and sufentanil needed to achieve successful sedation before GI endoscopy using the sequential method (the Dixon up-and-down method). The second part was a double-blind, randomized study. Two hundred cases of painless GI endoscopy patients were randomly divided into two groups (n = 100), including group B (butorphanol at the ED95 dose) and group S (sufentanil at the ED95 dose). Propofol was infused intravenously as the sedative in both groups. The recovery time, visual analogue scale (VAS) score, hand grip strength, fatigue severity scores, incidence of nausea and vomiting, and incidence of dizziness were recorded. RESULTS: The ED95 of butorphanol for painless GI endoscopy was 9.07 µg/kg (95% confidence interval: 7.81-19.66 µg/kg). The ED95 of sufentanil was 0.1 µg/kg (95% CI, 0.079-0.422 µg/kg). Both butorphanol and sufentanil provided a good analgesic effect for GI endoscopy. However, the recovery time for butorphanol was significantly shorter than that for sufentanil (P < 0.05, group B vs. group S:21.26 ± 7.70 vs. 24.03 ± 7.80 min). CONCLUSIONS: Butorphanol at 9.07 µg/kg was more effective than sufentanil for GI endoscopy sedation and notably reduced the recovery time. TRIAL REGISTRATION: Chinese Clinical Trail Registry (Registration number # ChiCTR1900022780; Date of Registration on April 25rd, 2019).

7.
Transl Neurodegener ; 9(1): 18, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398165

RESUMO

BACKGROUND: Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy, and irritability occur in prodromal phases of clinical Alzheimer's disease (AD), which might be an increased risk for later developing AD. Here we treated young APP/PS1 AD model mice prophylactically with serotonin-selective re-uptake inhibitor (SSRI) paroxetine and investigated the protective role of anti-depressant agent in emotional abnormalities and cognitive defects during disease progress. METHODS: To investigate the protective role of paroxetine in emotional abnormalities and cognitive defects during disease progress, we performed emotional behaviors of 3 months old APP/PS1 mouse following oral administration of paroxetine prophylactically starting at 1 month of age. Next, we tested the cognitive, biochemical and pathological, effects of long term administration of paroxetine at 6 months old. RESULTS: Our results showed that AD mice displayed emotional dysfunction in the early stage. Prophylactic administration of paroxetine ameliorated the initial emotional abnormalities and preserved the eventual memory function in AD mice. CONCLUSION: Our data indicate that prophylactic administration of paroxetine ameliorates the emotional dysfunction and memory deficit in AD mice. These neuroprotective effects are attributable to functional restoration of glutamate receptor (GluN2A) in AD mice.

8.
Anesthesiology ; 133(2): 377-392, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32412932

RESUMO

BACKGROUND: Dexmedetomidine induces a sedative response that is associated with rapid arousal. To elucidate the underlying mechanisms, the authors hypothesized that dexmedetomidine increases the activity of dopaminergic neurons in the ventral tegmental area, and that this action contributes to the unique sedative properties of dexmedetomidine. METHODS: Only male mice were used. The activity of ventral tegmental area dopamine neurons was measured by a genetically encoded Ca indicator and patch-clamp recording. Dopamine neurotransmitter dynamics in the medial prefrontal cortex and nucleus accumbens were measured by a genetically encoded dopamine sensor. Ventral tegmental area dopamine neurons were inhibited or activated by a chemogenetic approach, and the depth of sedation was estimated by electroencephalography. RESULTS: Ca signals in dopamine neurons in the ventral tegmental area increased after intraperitoneal injection of dexmedetomidine (40 µg/kg; dexmedetomidine, 16.917 [14.882; 21.748], median [25%; 75%], vs. saline, -0.745 [-1.547; 0.359], normalized data, P = 0.001; n = 6 mice). Dopamine transmission increased in the medial prefrontal cortex after intraperitoneal injection of dexmedetomidine (40 µg/kg; dexmedetomidine, 10.812 [9.713; 15.104], median [25%; 75%], vs. saline, -0.498 [-0.664; -0.355], normalized data, P = 0.001; n = 6 mice) and in the nucleus accumbens (dexmedetomidine, 8.543 [7.135; 11.828], median [25%; 75%], vs. saline, -0.329 [-1.220; -0.047], normalized data, P = 0.001; n = 6 mice). Chemogenetic inhibition or activation of ventral tegmental area dopamine neurons increased or decreased slow waves, respectively, after intraperitoneal injection of dexmedetomidine (40 µg/kg; delta wave: two-way repeated measures ANOVA, F[2, 33] = 8.016, P = 0.002; n = 12 mice; theta wave: two-way repeated measures ANOVA, F[2, 33] = 22.800, P < 0.0001; n = 12 mice). CONCLUSIONS: Dexmedetomidine activates dopamine neurons in the ventral tegmental area and increases dopamine concentrations in the related forebrain projection areas. This mechanism may explain rapid arousability upon dexmedetomidine sedation.


Assuntos
Dexmedetomidina/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hipnóticos e Sedativos/farmacologia , Área Tegmentar Ventral/metabolismo , Animais , Neurônios Dopaminérgicos/química , Neurônios Dopaminérgicos/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Fotometria/métodos , Área Tegmentar Ventral/química , Área Tegmentar Ventral/efeitos dos fármacos
9.
Drug Des Devel Ther ; 13: 4161-4171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849448

RESUMO

Background: Acute lung injury (ALI) is characterized by high prevalence and high mortality. Thus far, no effective pharmacological treatment has been made for ALI in clinics. Inflammation is critical to the development of ALI. Curcumin analog C66, having reported as an inhibitor of c-Jun N-terminal kinase (JNK), exhibits anti-inflammatory property both in vitro and in vivo. However, whether C66 is capable of reducing lipopolysaccharide (LPS)-induced ALI through the inhibition of inflammation by targeting JNK remains unknown. Methods: Intratracheal injection of LPS was employed to build a mouse ALI model. H&E staining, wet/dry ratio, immunofluorescence staining, inflammatory cell detection, and inflammatory gene expression were used to evaluate lung injury and lung inflammation. In vitro, LPS was used to induce the expression of inflammatory cytokines both in protein and gene levels. Results: The results of our studies showed that the pretreatment with C66 and JNK inhibitor SP600125 was capable of attenuating the LPS-induced ALI by detecting pulmonary edema, pathological changes, total protein concentration, and inflammatory cell number in bronchoalveolar lavage fluid (BALF). Besides, C66 and SP600125 also suppressed LPS-induced inflammatory cytokine expression in BALF, serum, and lung tissue. In vitro, LPS-induced production of TNF-α and IL-6 and gene expression of TNF-α, IL-6, IL-1ß, and COX-2 could be inhibited by the pretreatment with C66 and SP600125. It was found that C66 and SP600125 could inhibit LPS-induced phosphorylation of JNK both in vitro and in vivo. Conclusion: In brief, our results suggested that C66 protects LPS-induced ALI through the inhibition of inflammation by targeting the JNK pathway. These findings further confirmed the pivotal role of JNK in ALI and implied that C66 is likely to serve as a potential therapeutic agent for ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Antracenos/farmacologia , Curcumina/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Antracenos/administração & dosagem , Antracenos/química , Células Cultivadas , Curcumina/análogos & derivados , Curcumina/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Injeções Intravenosas , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Relação Estrutura-Atividade
10.
Mol Psychiatry ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772302

RESUMO

Social interaction and communication are evolutionary conserved behaviours that are developed in mammals to establish partner cognition. Deficit in sociability has been represented in human patients and animal models of neurodevelopmental disorders, which are connected with genetic variants of synaptic glutamate receptors and associated PDZ-binding proteins. However, it remains elusive how these key proteins are specialized in the cellular level for the initial social behaviour during postnatal developmental stage. Here we identify a hippocampal CA3 specifically expressed PDZ scaffold protein Lnx1 required for initial social behaviour. Through gene targeting we find that Lnx1 deficiency led to a hippocampal subregional disorder in neuronal activity and social memory impairments for partner discrimination observed in juvenile mice which also show cognitive defects in adult stage. We further demonstrate that Lnx1 deletion causes NMDA receptor (NMDAR) hypofunction and this is attributable to decreased GluN2B expression in PSD compartment and disruption of the Lnx1-NMDAR-EphB2 complex. Specific restoration of Lnx1 or EphB2 protein in the CA3 area of Lnx1-/- mice rescues the defective synaptic function and social memory. These findings thus reveal crucial roles of postsynaptic NMDAR multiprotein complex that regulates the formation of initial social memory during the adolescent period.

11.
Nanotechnology ; 30(50): 502004, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31505472

RESUMO

Two-dimensional (2D) transition metal dichalcogenides (TMDCs) have attracted tremendous research interests due to their exciting optical properties, large surface area, intercalatable morphologies and excellent electrochemically catalytic activity. Acting as the most typical member in TMDCs family, layer-dependent molybdenum disulfide (MoS2) with particular direct bandgap of 1.8 eV in monolayer has been widely applied in various biosensors with high sensitivity and selectivity. In this review, the preparation methods of MoS2, together with MoS2-based biosensors for detecting cells and biomolecules (such as glucose, DNA and antigens) would be summarized. In addition, the current challenges and future perspectives are outlined for the applications of biosensors based on 2D MoS2.


Assuntos
Técnicas Biossensoriais/métodos , Dissulfetos/química , Molibdênio/química , Nanoestruturas/química , Animais , Antígenos/análise , Técnicas Biossensoriais/instrumentação , DNA/análise , Desenho de Equipamento , Glucose/análise , Humanos , Nanotecnologia/instrumentação , Nanotecnologia/métodos
12.
Int J Surg ; 69: 132-138, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150800

RESUMO

BACKGROUND: Pain due to coughing after thoracoscopic surgery remains a clinical problem, and its relief by intrapleural analgesia has not been extensively studied. This study attempts to determine the suitable volume of 0.75% ropivacaine needed for intrapleural analgesia after thoracoscopic surgery. METHODS: A double-blind, randomized, controlled trial was performed. Forty-five patients were randomly divided into three groups: R20, R15, and R10 (n = 15); 20 ml, 15 ml, or 10 ml of 0.75% ropivacaine was injected into the pleural cavity of each patient in the 3 groups, respectively, when the pain score from postoperative coughing was ≥4. The primary outcome was pain score upon coughing (C-NRS), and the secondary outcomes were pain score at rest (R-NRS), morphine consumption, time of onset, and duration of intrapleural analgesia. RESULTS: All patients in the R20 and R15 groups reported effective pain relief after intrapleural injection when postoperative coughing occurred. However, only 7 patients in the R10 group reported effective relief of pain. Compared with the patients in the R10 group, patients in the R20 and R15 groups had lower C-NRS scores, less morphine consumption at 8 h and 24 h, a shorter time to pain relief, and a longer duration of analgesia. There was no significant difference of R-NRS among the three groups. CONCLUSION: Intrapleural analgesia with 0.75% ropivacaine at a volume of 15 ml or 20 ml effectively relieved pain due to coughing after thoracoscopic surgery. TRIAL REGISTRATION: ChiCTR1800017515.


Assuntos
Anestésicos Locais/administração & dosagem , Tosse/fisiopatologia , Manejo da Dor/métodos , Ropivacaina/administração & dosagem , Cirurgia Torácica Vídeoassistida/efeitos adversos , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pleura
13.
Cell Death Dis ; 10(7): 486, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217475

RESUMO

Liver kinase B1 (LKB1) regulates both cell growth and energy metabolism. Inactivated mutations of LKB1, observed in 20-30% of nonsmall cell lung cancers (NSCLC), contribute significantly to lung cancer malignancy progression. However, the upstream signalings regulating LKB1 activity remain incompletely understood. Here, we present evidence that FBXO22 interacts with and promotes polyubiquitination of LKB1. More intriguingly, FBXO22 mediates Lys-63-linked LKB1 polyubiquitination and inhibits kinase activity of LKB1. Furthermore, over-expression of FBXO22 promotes NSCLC cell growth through inhibiting LKB1-AMPK-mTOR signaling in vitro and in vivo. Clinically, FBXO22 is highly expressed in human lung adenocarcinoma and high FBXO22 expression predicts significant poor prognosis. Our study provides new insights into the upstream regulation of LKB1 activation and identifies FBXO22 as a potential therapeutic target for lung cancer treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas F-Box/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Ensaio de Unidades Formadoras de Colônias , Proteínas F-Box/genética , Feminino , Células HEK293 , Células HeLa , Humanos , Immunoblotting , Imuno-Histoquímica , Imunoprecipitação , Neoplasias Pulmonares/genética , Camundongos , Camundongos Nus , Proteínas Serina-Treonina Quinases/genética , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Ubiquitinação/genética , Ubiquitinação/fisiologia
14.
J Cell Biol ; 217(11): 4007-4024, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185604

RESUMO

Neuronal connections are initiated by axon targeting to form synapses. However, how the maturation of axon terminals is modulated through interacting with postsynaptic elements remains elusive. In this study, we find that ligand of Numb protein X 1 (Lnx1), a postsynaptic PDZ protein expressed in hippocampal CA3 pyramidal neurons, is essential for mossy fiber (MF) axon targeting during the postnatal period. Lnx1 deletion causes defective synaptic arrangement that leads to aberrant presynaptic terminals. We further identify EphB receptors as novel Lnx1-binding proteins to form a multiprotein complex that is stabilized on the CA3 neuron membrane through preventing proteasome activity. EphB1 and EphB2 are independently required to transduce distinct signals controlling MF pruning and targeting for precise DG-CA3 synapse formation. Furthermore, constitutively active EphB2 kinase rescues structure of the wired MF terminals in Lnx1 mutant mice. Our data thus define a retrograde trans-synaptic regulation required for integration of post- and presynaptic structure that participates in building hippocampal neural circuits during the adolescence period.


Assuntos
Axônios/metabolismo , Região CA3 Hipocampal/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Células Piramidais/metabolismo , Sinapses/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Camundongos , Camundongos Knockout , Terminações Pré-Sinápticas/metabolismo , Receptor EphB1/genética , Receptor EphB1/metabolismo , Receptor EphB2/genética , Receptor EphB2/metabolismo , Sinapses/genética , Ubiquitina-Proteína Ligases/genética
15.
Rev Sci Instrum ; 89(7): 073302, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30068102

RESUMO

A two-dimensional position-sensitive microchannel plate detector, with a Ø100 mm sensitive area and equipped with four integrated amplifiers, is realized with a new anode scheme. The anode is constructed by two independent one-dimensional resistive anodes, each consisting of an array of parallel copper strips connected by resistors in series on a printed circuit board (PCB). The arrays are perpendicularly aligned to realize two-dimensional position resolution, with the intervals between the adjacent strips on the PCB nearer to the microchannel plate cut out to allow electrons passing through. The detector is tested with an 55Fe x-ray source, and a position resolution of 0.38 mm is achieved.

16.
Nan Fang Yi Ke Da Xue Xue Bao ; 38(3): 296-304, 2018 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-29643035

RESUMO

OBJECTIVE: To analyze the correlation between the expressions of vascular endothelial growth factor (VEGF) and transient receptor potential canonical 6 (TRPC6) and their role in podocyte injury in rats with diabetic nephropathy. METHODS: Forty SD rats with diabetic nephropathy induced by intraperitoneal injection of 65 mg/kg streptozotocin were randomized equally into 5 groups, including a diabetic nephropathy model group and 4 treatment groups, with 8 normal SD rats as the normal control group. In the 4 treatment groups, the rats received intraperitoneal injections with SU5416 at 5 mg/kg or 10 mg/kg twice a week or with LY294002 at 1 mg/kg or 2 mg/kg once daily for 8 weeks. Blood glucose, serum creatinine, blood urea nitrogen, and 24-h urinary protein levels of the rats were detected at different time points, and the pathologies in the renal tissue were observed using HE staining, PAS staining and immunohistochemistry. The expressions of VEGF, nephrin, and TRPC6 at mRNA and protein levels were detected using RT-PCR and Western blotting. RESULTS: Compared with normal control rats, the diabetic rats showed significantly increased fasting blood glucose, serum creatinine, blood urea nitrogen and 24-h urinary protein levels with decreased expressions of nephrin mRNA and protein (P<0.05) and increased expressions of VEGF and TRPC6 (P<0.05). Compared with the untreated diabetic rats, the rats with SU5416 treatment showed increased 24-h urinary protein, urea nitrogen, and nephrin expression and decreased TRPC6 expression without significant changes in fasting blood glucose, serum creatinine, or VEGF expression. The rats treated with LY294002 showed decreased 24-h urinary protein and TRPC6 expression without significant changes in fasting blood glucose, serum creatinine, urea nitrogen, or expressions of nephrin and VEGF. CONCLUSION: The regulatory effect of VEGF on TRPC6 can be blocked by inhibiting VEGFR-2 or blocking PI3K/Akt signaling pathway.


Assuntos
Nefropatias Diabéticas/patologia , Podócitos/patologia , Canais de Cátion TRPC/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Cromonas/farmacologia , Diabetes Mellitus Experimental , Nefropatias Diabéticas/metabolismo , Indóis/farmacologia , Rim/fisiopatologia , Proteínas de Membrana/metabolismo , Morfolinas/farmacologia , Pirróis/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
17.
Sci Rep ; 7: 40614, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28094295

RESUMO

Traumatic brain injury (TBI) is a principal cause of death and disability worldwide, which is a major public health problem. Death caused by TBI accounts for a third of all damage related illnesses, which 75% TBI occurred in low and middle income countries. With the increasing use of motor vehicles, the incidence of TBI has been at a high level. The abnormal brain functions of TBI patients often show the acute and long-term neurological dysfunction, which mainly associated with the pathological process of malignant brain edema and neuroinflammation in the brain. Owing to the neuroinflammation lasts for months or even years after TBI, which is a pivotal causative factor that give rise to neurodegenerative disease at late stage of TBI. Studies have shown that platelet activating factor (PAF) inducing inflammatory reaction after TBI could not be ignored. The morphological and behavioral abnormalities after TBI in wild type mice are rescued by general knockout of PAFR gene that neuroinflammation responses and cognitive ability are improved. Our results thus define a key inflammatory molecule PAF that participates in the neuroinflammation and helps bring about cerebral dysfunction during the TBI acute phase.


Assuntos
Lesões Encefálicas Traumáticas/etiologia , Lesões Encefálicas Traumáticas/fisiopatologia , Inflamação/genética , Glicoproteínas da Membrana de Plaquetas/genética , Receptores Acoplados a Proteínas G/genética , Animais , Astrócitos/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Marcação de Genes , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/ultraestrutura , Mediadores da Inflamação/metabolismo , Masculino , Memória , Camundongos , Camundongos Knockout , Neuroglia/metabolismo , Aprendizagem Espacial
18.
J Neurosci ; 36(39): 10151-62, 2016 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-27683910

RESUMO

UNLABELLED: The amygdala serves as emotional center to mediate innate fear behaviors that are reflected through neuronal responses to environmental aversive cues. However, the molecular mechanism underlying the initial neuron responses is poorly understood. In this study, we monitored the innate defensive responses to aversive stimuli of either elevated plus maze or predator odor in juvenile mice and found that glutamatergic neurons were activated in amygdala. Loss of EphB2, a receptor tyrosine kinase expressed in amygdala neurons, suppressed the reactions and led to defects in spine morphogenesis and fear behaviors. We further found a coupling of spinogenesis with these threat cues induced neuron activation in developing amygdala that was controlled by EphB2. A constitutively active form of EphB2 was sufficient to rescue the behavioral and morphological defects caused by ablation of ephrin-B3, a brain-enriched ligand to EphB2. These data suggest that kinase-dependent EphB2 intracellular signaling plays a major role for innate fear responses during the critical developing period, in which spinogenesis in amygdala glutamatergic neurons was involved. SIGNIFICANCE STATEMENT: Generation of innate fear responses to threat as an evolutionally conserved brain feature relies on development of functional neural circuit in amygdala, but the molecular mechanism remains largely unknown. We here identify that EphB2 receptor tyrosine kinase, which is specifically expressed in glutamatergic neurons, is required for the innate fear responses in the neonatal brain. We further reveal that EphB2 mediates coordination of spinogenesis and neuron activation in amygdala during the critical period for the innate fear. EphB2 catalytic activity plays a major role for the behavior upon EphB-ephrin-B3 binding and transnucleus neuronal connections. Our work thus indicates an essential synaptic molecular signaling within amygdala that controls synapse development and helps bring about innate fear emotions in the postnatal developing brain.


Assuntos
Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Glutamatos/metabolismo , Instinto , Neurogênese/fisiologia , Neurônios/fisiologia , Receptor EphB2/metabolismo , Envelhecimento/fisiologia , Animais , Mecanismos de Defesa , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Transdução de Sinais/fisiologia
19.
Nat Commun ; 7: 11096, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-27008987

RESUMO

Innate emotion response to environmental stimuli is a fundamental brain function that is controlled by specific neural circuits. Dysfunction of early emotional circuits may lead to neurodevelopmental disorders such as autism and schizophrenia. However, how the functional circuits are formed to prime initial emotional behaviours remain elusive. We reveal here using gene-targeted mutations an essential role for ephrin-B3 ligand-like activity in the development of innate fear in the neonatal brain. We further demonstrate that ephrin-B3 controls axon targeting and coordinates spinogenesis and neuronal activity within the amygdala. The morphological and behavioural abnormalities in ephrin-B3 mutant mice are rescued by conditional knock-in of wild-type ephrin-B3 during the critical period when axon targeting and fear responses are initiated. Our results thus define a key axonal molecule that participates in the wiring of amygdala circuits and helps bring about fear emotion during the important adolescence period.


Assuntos
Tonsila do Cerebelo/metabolismo , Axônios/metabolismo , Efrina-B3/metabolismo , Medo/fisiologia , Instinto , Neurogênese , Animais , Núcleo Celular/metabolismo , Efrina-B3/genética , Camundongos , Mutação/genética , Sinapses/metabolismo , Fatores de Tempo
20.
Environ Sci Technol ; 38(24): 6809-16, 2004 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-15669343

RESUMO

Limited data are available on the emission rates of speciated volatile and semivolatile organic compounds, as well as the physical and chemical characteristics of fine particulate matter (PM) from mobile, in-use diesel engines operated on the road. A design for the sampling of these fractions and the first data from in-use diesel sources are presented in this paper. Emission rates for carbonyls, 1,3-butadiene, benzene, toluene, xylene, PM, and elemental and organic carbon (EC and OC) are reported for a vehicle driven while following the California Air Resources Board (ARB) four-mode heavy heavy-duty diesel truck (HHDDT) cycle and while transiting through a major transportation corridor. Results show that distance specific emission rates are substantially greater in congested traffic as compared with highway cruise conditions. Specifically, emissions of toxic compounds are 3-15 times greater, and PM is 7 times greater under these conditions. The dependence of these species on driving mode suggests that health and source apportionment studies will need to account for driving patterns in addition to emission factors. Comparison of the PM/NOx ratios obtained for the above tests provides insight into the presence and importance of "off-cycle" emissions during on-road driving. Measurements from a stationary source (operated and tested at constant engine speed) equipped with an engine similar to that in the HHDDT yielded a greater understanding of the relative dependence of emissions on load versus engine transients. These data are indicative of the type of investigations made possible by the development of this novel laboratory.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental/instrumentação , Hidrocarbonetos/análise , Emissões de Veículos/análise , Condução de Veículo , Tamanho da Partícula , Volatilização
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