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1.
PLoS Biol ; 19(3): e3001154, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33739978

RESUMO

Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in pain. However, there has not been direct evidence showing that selective microglial activation in vivo is sufficient to induce chronic pain. Here, we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity in both male and female mice. In addition, activation of microglial ReaChR up-regulated neuronal c-Fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased interleukin (IL)-1ß production, which is likely mediated by inflammasome activation and calcium elevation. IL-1 receptor antagonist (IL-1ra) was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.


Assuntos
Dor Crônica/etiologia , Microglia/fisiologia , Nervos Espinhais/metabolismo , Animais , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Channelrhodopsins/metabolismo , Dor Crônica/fisiopatologia , Feminino , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Optogenética/métodos , Transdução de Sinais/fisiologia , Medula Espinal/metabolismo , Nervos Espinhais/fisiologia
2.
Fa Yi Xue Za Zhi ; 38(6): 754-762, 2022 Dec 25.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-36914392

RESUMO

Exosomes are membranous tiny vesicles secreted by cells, which are widely found in the extracellular matrix and various body fluids and carry a variety of biologically functional molecules such as proteins, lipids, messenger RNA (mRNA) and microRNA (miRNA). Exosomes not only play important biological roles in the field of immunology and oncology, but also have potential application value in the field of forensic medicine. This article reviews the discovery, production and degeneration mechanism, biological functions, isolation and identification methods of exosomes, summarizes the research on exosomes and their significance in the field of forensic science, and discusses their applications in body fluid identification, individual identification, postmortem interval estimation to provide ideas for the application of exosomes in forensic work.


Assuntos
Exossomos , MicroRNAs , Exossomos/genética , Exossomos/metabolismo , Medicina Legal , MicroRNAs/genética , MicroRNAs/metabolismo , Ciências Forenses , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
3.
Glia ; 69(5): 1155-1169, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33314324

RESUMO

Gliosis is a histopathological characteristic of epilepsy that comprises activated microglia and astrocytes. It is unclear whether or how crosstalk occurs between microglia and astrocytes in the evolution of epilepsy. Here, we report in a mouse model of status epilepticus, induced by intracerebroventricular injection of kainic acid (KA), sequential activation of microglia and astrocytes and their close spatial interaction in the hippocampal CA3 region. Microglial ablation reduced astrocyte activation and their upregulation of complement C3. When compared to wild-type mice, both C3-/- and C3aR-/- mice had significantly less microglia-astrocyte interaction in response to KA-induced status epilepticus. Additionally, KA-injected C3-/- mice had significantly less histochemical evidence of neurodegeneration. The results suggest that the C3-C3aR pathway contributes to KA-induced neurodegeneration by mediating microglia-astrocyte communication. The C3-C3aR pathway may prove to be a potential therapeutic target for epilepsy treatment.


Assuntos
Epilepsia , Estado Epiléptico , Animais , Astrócitos , Complemento C3/genética , Ácido Caínico/toxicidade , Camundongos , Microglia , Estado Epiléptico/induzido quimicamente
4.
J Neuroinflammation ; 18(1): 201, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526069

RESUMO

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) is mainly an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. Systemic and local inflammatory responses play a key role in the pathophysiology of NMOSD. However, the role of the crucial immunomodulators CD4+CD25+ forkhead box P3+ (Foxp3) regulatory T cells (Tregs) has not been investigated in NMOSD. METHODS: Twenty-five patients with anti-AQP4-postive NMOSD undergoing an attack and 21 healthy controls (HCs) were enrolled. Frequencies of T cell subsets and Tregs in the peripheral blood were assessed by flow cytometry. Additionally, a model of NMOSD using purified immunoglobulin G from anti-AQP4-antibodies-positive patients with NMOSD and human complement injected into brain of female adult C57BL/6J mice was established. Infiltrated Tregs into NMOSD mouse brain lesions were analyzed by flow cytometry, histological sections, and real-time quantitative Polymerase Chain Reaction. Astrocyte loss, demyelination, and inflammatory response were also evaluated in our NMOSD mouse model. Finally, we examined the effects of both depletion and adoptive transfer of Tregs. RESULTS: The percentage of Tregs, especially naïve Tregs, among total T cells in peripheral blood was significantly decreased in NMOSD patients at acute stage when compared to HCs. Within our animal model, the number and proportion of Tregs among CD4+ T cells were increased in the lesion of mice with NMOSD. Depletion of Tregs profoundly enhanced astrocyte loss and demyelination in these mice, while adoptive transfer of Tregs attenuated brain damage. Mechanistically, the absence of Tregs induced more macrophage infiltration, microglial activation, and T cells invasion, and modulated macrophages/microglia toward a classical activation phenotype, releasing more chemokines and pro-inflammatory cytokines. In contrast, Tregs transfer ameliorated immune cell infiltration in NMOSD mice, including macrophages, neutrophils, and T cells, and skewed macrophages and microglia towards an alternative activation phenotype, thereby decreasing the level of chemokines and pro-inflammatory cytokines. CONCLUSION: Tregs may be key immunomodulators ameliorating brain damage via dampening inflammatory response after NMOSD.


Assuntos
Neuromielite Óptica , Animais , Aquaporina 4 , Autoanticorpos , Encéfalo/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/patologia
5.
Brain Behav Immun ; 92: 78-89, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33221486

RESUMO

Microglia play an important role in the central sensitization and chronic pain. However, a direct connection between microglial function and pain development in vivo remains incompletely understood. To address this issue, we applied chemogenetic approach by using CX3CR1creER/+:R26LSL-hM4Di/+ transgenic mice to enable expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (Gi DREADD) in microglia. We found that microglial Gi DREADD activation inhibited spinal nerve transection (SNT)-induced microglial reactivity as well as chronic pain in both male and female mice. Gi DREADD activation downregulated the transcription factor interferon regulatory factor 8 (IRF8) and its downstream target pro-inflammatory cytokine interleukin 1 beta (IL-1ß). Using in vivo spinal cord recording, we found that activation of microglial Gi DREADD attenuated synaptic transmission following SNT. Our results demonstrate that microglial Gi DREADD reduces neuroinflammation, synaptic function and neuropathic pain after SNT. Thus, chemogenetic approaches provide a potential opportunity for interrogating microglial function and neuropathic pain treatment.


Assuntos
Dor Crônica , Neuralgia , Animais , Feminino , Masculino , Camundongos , Microglia , Medula Espinal , Nervos Espinhais
6.
Immunopharmacol Immunotoxicol ; 42(3): 237-245, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32249638

RESUMO

Objective: Use of methamphetamine (METH) is prevalent among HIV-infected individuals. Previous research has shown that both METH and HIV protease inhibitors exert influences on mitochondrial respiratory metabolism and hepatic nervous system. This study aims to study the joint effect of METH and HIV protease inhibitors on hepatic immune function.Materials and methods: Based on the differentially expressed genes obtained from RNA-seq of the liver from mouse model, the expression levels of CD48 and Macrophage Receptor with Collagenous Structure (MARCO) were examined using qRT-PCR and flow cytometry, and the expression and secretion of cytokines IL-1ß, IL-6, IL-8, IL-10, IFN-γ, IFN-ß, and TNF-α were determined using qRT-PCR and ELISA in THP-1-derived macrophages.Results: Our results indicated that compared with the control group, CD48 molecules were significantly down-regulated by METH-atazanavir co-treatment, and the expression level of CD48 decreased as METH concentration increases. MARCO molecules were increased, especially at larger doses of METH and atazanavir treatment. In addition, in the presence of METH-atazanavir, the expression and secretion of a series of pro-inflammatory cytokines TNF-α, IL-1ß, IL-6, and IL-8 increased while the expression and secretion of anti-inflammatory cytokine IL-10 decreased.Conclusion: These results demonstrated that METH and atazanavir had a combined impact on the liver immunity, suggesting that the co-treatment could enhance inflammatory response and suppress NK cell activation via CD48.


Assuntos
Sulfato de Atazanavir/efeitos adversos , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Inibidores da Protease de HIV/efeitos adversos , Fígado/efeitos dos fármacos , Metanfetamina/efeitos adversos , Animais , Sulfato de Atazanavir/administração & dosagem , Antígeno CD48/genética , Citocinas/genética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Expressão Gênica/imunologia , Inibidores da Protease de HIV/administração & dosagem , Humanos , Imunidade Inata/efeitos dos fármacos , Fígado/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Metanfetamina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Receptores Imunológicos/genética , Células THP-1
7.
J Am Chem Soc ; 139(33): 11337-11340, 2017 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-28787145

RESUMO

Although histone modifications are associated with gene activities, studies of their causal relationships have been difficult. For this purpose, we developed an inducible system integrating dCas9-based targeting and chemically induced proximity technologies to allow small molecule induced recruitment of P300 acetyltransferase and the acetylation of H3K27 at precise gene loci in cells. Employing the new technique, we elucidated the temporal order of histone acetylation and gene activation, as well as the stability of the installed histone modification.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Código das Histonas , Acetilação/efeitos dos fármacos , Proteína p300 Associada a E1A/genética , Marcação de Genes , Loci Gênicos/efeitos dos fármacos , Células HEK293 , Código das Histonas/efeitos dos fármacos , Histonas/genética , Humanos , Bibliotecas de Moléculas Pequenas/farmacologia
8.
Anal Chem ; 89(24): 13245-13251, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29164866

RESUMO

In this work, a new strategy for electrochemical analysis of enzyme has been proposed based on a self-assembled lipid bilayer on an electrode surface mediated by hydrazone chemistry. Taking aldolase as an example, the enzyme can catalyze the formation of products containing carbonyl groups. These groups can react with hydrazine groups of the functional lipid derivative, resulting in the self-assembly of a lipid bilayer on a guanidinium modified electrode surface. The lipid bilayer will then prevent the movement of hydrophilic electrochemical probes. Consequently, the catalytic reaction of the enzyme may result in the change of the obtained electrochemical peak current. Experimental results reveal that aldolase activity can be analyzed over a widely linear detection range from 5 mU/L to 100 U/L with a low detection limit of 1 mU/L. Meanwhile, the method can exhibit good precision and reproducibility and it can be applied for real sample analysis. What is more, because the lipid bilayer is the universal basis for cell-membrane structure, while hydrazone chemistry is popular in nature, this work may also provide a new insight for the development of electrochemical analysis and electrochemical biosensors.


Assuntos
Técnicas Biossensoriais , Técnicas Eletroquímicas , Frutose-Bifosfato Aldolase/análise , Frutose-Bifosfato Aldolase/química , Hidrazonas/química , Bicamadas Lipídicas/química , Animais , Biocatálise , Eletrodos , Frutose-Bifosfato Aldolase/metabolismo , Músculos/enzimologia , Coelhos , Propriedades de Superfície
9.
J Neuroophthalmol ; 37(1): 24-29, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27749786

RESUMO

OBJECTIVE: This study retrospectively analyzed the frequency of anti-thyroid antibodies (ATAs) and thyroid disease in patients with optic neuritis (ON). METHODS: Tests of serum thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies and thyroid function were performed in 97 ON patients. Blood also was drawn to test for AQP4-Ab using cell-based and enzyme-linked immunosorbent assays. Comparisons of the frequencies of ATAs, thyroid diseases and thyroid function were performed based on AQP4-Ab status. RESULTS: Seropositive AQP4-Ab was found in 47/97 (48.5%) patients. ATA was considered positive in 34/97 (35.1%) patients. The prevalence of ATA was two times higher (P = 0.019) in the AQP4-Ab+ group compared to the AQP4-Ab- group. AQP4-Ab+ ON patients exhibited lower FT3 (P = 0.006) and FT4 (P = 0.025) levels and a higher prevalence of definite Hashimoto thyroiditis (HT) (P = 0.005). Among AQP4-Ab+ patients, those with HT had a worse visual outcome than non-HT patients. CONCLUSION: A high prevalence of ATAs and HT was found in AQP4-Ab+ ON patients, and AQP4-Ab+ patients with HT exhibited worse visual outcomes than non-HT patients.


Assuntos
Aquaporina 4/imunologia , Autoanticorpos/sangue , Neurite Óptica/imunologia , Doenças da Glândula Tireoide/diagnóstico , Adulto , Aquaporina 4/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Masculino , Neurite Óptica/diagnóstico , Neurite Óptica/etiologia , Estudos Retrospectivos , Doenças da Glândula Tireoide/complicações , Doenças da Glândula Tireoide/imunologia
10.
Exp Eye Res ; 146: 318-329, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26992777

RESUMO

OBJECTIVES: This study aimed to investigate the protective role of heme oxygenase-1 (HO-1) in H2O2-induced oxidative stress and apoptosis in human lens epithelial cells (hLEC; SRA01/04). METHODS: SRA01/04 cells were exposed to a hydrogen peroxide (H2O2) concentration gradient and inducers of HO-1 such as cobalt protoporphyrin (CoPP) and zinc protoporphyrin (ZnPP), respectively. In addition, an RNA silencing experiment was conducted to investigate the HO-1 function in this study. A Cell Counting Kit-8 (CCK-8) assay was used to measure cell viability. Western blot and ELISA were used to detect the level of HO-1 expression. In our study, hLECs were exposed to 400 µM hydrogen peroxide (H2O2) for 24 h with or without pretreatment with 10µΜ CoPP or 10µΜ ZnPP, respectively. Double immunofluorescence staining was used for cell identification and the qualitative expression of HO-1. Expression of HO-1 was monitored using Western blot and ELISA. Intracellular reactive oxygen species (ROS) were detected by flow cytometry analyses; commercial enzymatic kits were used to measure the levels of glutathione (GSH), as well as superoxide dismutase (SOD). The proportion of cell apoptosis was quantified by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. The expression of caspase family (-8, -3) proteins was measured by Western blot analysis. RESULTS: HO-1 significantly restored the cell viability under H2O2 injury via reducing the generation of ROS and increasing the levels of SOD and GSH activity. Moreover, HO-1 also inhibited H2O2-induced caspase-8 and caspase-3 proteins, thus significantly reducing the apoptosis of SRA01/04. An RNA silencing experiment demonstrated the increased resistance of LECs to oxidative stress specifically for increased levels of HO-1. CONCLUSIONS: These findings suggested that HO-1 protects human lens epithelial cells from H2O2-induced oxidant stress by upregulating antioxidant enzyme activity, reducing ROS generation, and thus inhibiting caspase family-dependent apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/metabolismo , Heme Oxigenase-1/fisiologia , Peróxido de Hidrogênio/farmacologia , Cristalino/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Glutationa Sintase/metabolismo , Humanos , Superóxido Dismutase/metabolismo
11.
Zhonghua Yan Ke Za Zhi ; 51(12): 901-6, 2015 Dec.
Artigo em Zh | MEDLINE | ID: mdl-26888271

RESUMO

OBJECTIVE: To explore the predictive value of the prognosis and outcome for optic neuritis (ON) and neuromyelitis optica (NMO) by investigating the levels and variation of CXCL12, PDGF and CXCL14 in CSF of patients with ON and NMO. METHODS: Retrospective study. Thirty-five patients with ON, 10 patients with NMO and 10 patients with cerebral venous sinus thrombosis (CVST) were scheduled in the research unit from September 2012 to September 2013 in Neuro-Ophthalmology Department of PLA General Hospital. Clinical data and cerebrospinal fluid (CSF) parameters were collected. CXCL12, PDGF and CXCL14 concentrations were measured in CSF using enzyme linked immunosorbent assay (ELISA). The CXCL12, PDGF and CXCL14 levels in CSF were compared by using ANOVA in different diseases with different phases and recurrent cases found by MRI. Multiple comparisons were used by LSD method. The comparison of positive rate for MRI in ON different phases was used by exact probability. Meanwhile, correlation analysis was conducted between CXCL12, PDGF, CXCL14 and white blood cells (WBC), IgG and protein in CSF. RESULTS: Compared with NMO group (3.69±0.35, 2.04±0.24, 7.05±0.94), the CXCL12, PDGF and CXCL14 levels in CSF were higher in ON (4.39±0.51, 2.51±0.39, 8.65±1.55) and CVST(4.84± 0.49, 2.79±0.47, 10.53±1.11) group (F=14.593, 10.060, 10.003,P<0.001, <0.001, <0.001), especially the CXCL12, PDGF and CXCL14 levels in CSF of CVST group patients were higher than that in ON group. Among them, the CXCL12 and PDGF levels in CSF were higher in acute phase of ON (4.63±0.50, 2.65±0.40) and CVST(4.84±0.49, 2.79±0.47) group than stationary phase of ON (4.13±0.39, 2.34±0.32) group (F=8.823, 4.906, P=0.001, 0.012). In addition, 28 of 35 ON patients were conducted the cerebral or orbital magnetic resonance imaging (MRI). The result showed that the CXCL12 and PDGF levels in CSF of patients with positive finding in MRI (3.96±0.30, 2.23±0.16) were higher than those patients with negative finding in MRI (4.64±0.42, 2.62±0.42) (t=-4.754, -2.977, all P<0.01). Besides that, there was higher correlation between the CXCL12 level and PDGF in CSF (P<0.01). CONCLUSIONS: Reduced concentration of cytokine that promoted remyelination such as CXCL12 and PDGF in cerebrospinal fluid of the ON and NMO patients may predict a bad myelin regeneration.


Assuntos
Quimiocina CXCL12/líquido cefalorraquidiano , Quimiocinas CXC/líquido cefalorraquidiano , Neuromielite Óptica/líquido cefalorraquidiano , Neurite Óptica/líquido cefalorraquidiano , Fator de Crescimento Derivado de Plaquetas/líquido cefalorraquidiano , Análise de Variância , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Contagem de Leucócitos , Bainha de Mielina/fisiologia , Neuromielite Óptica/sangue , Neurite Óptica/sangue , Prognóstico , Regeneração , Estudos Retrospectivos , Trombose dos Seios Intracranianos/líquido cefalorraquidiano
12.
Autophagy ; 20(9): 2000-2016, 2024 09.
Artigo em Inglês | MEDLINE | ID: mdl-38762757

RESUMO

Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/ß-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.


Assuntos
Autofagia , Bleomicina , Senescência Celular , Lisossomos , Espécies Reativas de Oxigênio , Bleomicina/farmacologia , Senescência Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Animais , Humanos , Camundongos , Membranas Intracelulares/metabolismo , Membranas Intracelulares/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Camundongos Endogâmicos C57BL
13.
Adv Mater ; 36(40): e2406879, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39177117

RESUMO

Intrinsically stretchable organic photovoltaics (is-OPVs) hold significant promise for integration into self-powered wearable electronics. However, their potential is hindered by the lack of sufficient consistency between optoelectronic and mechanical properties. This is primarily due to the limited availability of stretchable transparent electrodes (STEs) that possess both high conductivity and stretchability. Here, a hybrid STE with exceptional conductivity, stretchability, and thermal stability is presented. Specifically, STEs are composed of the modified PH1000 (referred to as S-PH1000) and silver nanowires (AgNWs). The S-PH1000 endows the STE with good stretchability and smoothens the surface, while the AgNWs enhance the charge transport. The resulting hybrid STEs enable is-OPVs to a remarkable power conversion efficiency (PCE) of 16.32%, positioning them among the top-performing is-OPVs. With 10% elastomer, the devices retain 82% of the initial PCE after 500 cycles at 20% strain. Additionally, OPVs equipped with these STEs exhibit superior thermal stability compared to those using indium tin oxide electrodes, maintaining 75% of the initial PCE after annealing at 85 °C for 390 h. The findings underscore the suitability of the designed hybrid electrodes for efficient and stable is-OPVs, offering a promising avenue for the future application of OPVs.

14.
Nat Neurosci ; 27(3): 449-461, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38177340

RESUMO

Microglia are resident immune cells of the central nervous system and play key roles in brain homeostasis. During anesthesia, microglia increase their dynamic process surveillance and interact more closely with neurons. However, the functional significance of microglial process dynamics and neuronal interaction under anesthesia is largely unknown. Using in vivo two-photon imaging in mice, we show that microglia enhance neuronal activity after the cessation of isoflurane anesthesia. Hyperactive neuron somata are contacted directly by microglial processes, which specifically colocalize with GABAergic boutons. Electron-microscopy-based synaptic reconstruction after two-photon imaging reveals that, during anesthesia, microglial processes enter into the synaptic cleft to shield GABAergic inputs. Microglial ablation or loss of microglial ß2-adrenergic receptors prevents post-anesthesia neuronal hyperactivity. Our study demonstrates a previously unappreciated function of microglial process dynamics, which enable microglia to transiently boost post-anesthesia neuronal activity by physically shielding inhibitory inputs.


Assuntos
Anestesia , Microglia , Camundongos , Animais , Microglia/fisiologia , Encéfalo/fisiologia , Sinapses/fisiologia , Neurônios/fisiologia
15.
ACS Appl Mater Interfaces ; 15(43): 50312-50320, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37852300

RESUMO

The visible-blind narrowband photodetector (NPD) with spectral selective sensitivity to near-infrared (NIR) light is an important technology in the field of cardiovascular health assessment. However, the biological information carried by NIR light constantly changes signals with small amplitude and fast speed, which puts high requirements on the performance of detectors. Herein, visible-blind NIR NPDs were constructed by integrating solution-processable films of perovskite, CuSCN, and organic semiconductors. The NIR response was provided by the organic bulk heterojunction (OBHJ) film with a narrow band gap. A thick perovskite layer was applied to screen the incident visible light and suppress the leakage current in the dark state. CuSCN with a high LUMO level blocked the extraction of the visible-light-induced free electrons. The width of the response window was restricted by adjusting the band gap of the perovskite and the donor/acceptor ratio of the OBHJ film. The optimized NIR NPD exhibits a comprehensive performance including visible-blind response, a tunable response spectrum, a high responsivity/detectivity, and a short response time. In practical photoplethysmography measurements, the detector can record the human heart rate in real time through a noninvasive technique and precisely monitor the whole cardiac cycle, which provides an effective method for early detection of cardiovascular symptoms for timely diagnosis and treatment.

16.
Sci Adv ; 9(39): eadf8782, 2023 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-37774026

RESUMO

Specifically targeted antimicrobial peptides (STAMPs) are novel alternatives to antibiotics, whereas the development of STAMPs for colonic infections is hindered by limited de novo design efficiency and colonic bioavailability. In this study, we report an efficient de novo STAMP design strategy that combines a traversal design, machine learning model, and phage display technology to identify STAMPs against Clostridium perfringens. STAMPs could physically damage C. perfringens, eliminate biofilms, and self-assemble into nanoparticles to entrap pathogens. Further, a gut-targeted engineering particle vaccine (EPV) was used for STAMPs delivery. In vivo studies showed that both STAMP and EPV@STAMP effectively limited C. perfringens infections and then reduced inflammatory response. Notably, EPV@STAMP exhibited stronger protection against colonic infections than STAMPs alone. Moreover, 16S ribosomal RNA sequencing showed that both STAMPs and EPV@STAMP facilitated the recovery of disturbed gut microflora. Collectively, our work may accelerate the development of the discovery and delivery of precise antimicrobials.


Assuntos
Peptídeos Antimicrobianos , Infecções por Clostridium , Humanos , Clostridium perfringens/genética , Antibacterianos , Biofilmes
17.
Gene ; 808: 145971, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34543688

RESUMO

Trehalose is an important disaccharide that plays an important role in extreme environmental conditions. Trehalose-6-phosphate synthase (TPS) gene is the key gene for trehalose synthesis in Marsupenaeus japonicus. In this study, a TPS gene was isolated and characterized from M. japonicus. The full-length cDNA of TPS gene of M. japonicus (MjTPS) was 3308 bp, encoding 844 amino acids. The protein of the deduced MjTPS contained a glycol_transf_20 domain and a trehalose_PPase domain. The mRNA expression level of MjTPS was the highest in hepatopancreas. The further analysis found that MjTPS gene expression was up-regulated in a short time under low-salinity and high-nitrite stress, indicating that MjTPS gene had certain resistance to low-salinity and high-nitrite stress. Compared with the control group, both the expression of MjTPS and the trehalose content significantly decreased from 3 h to 24 h after MjTPS gene interference,. After RNAi, the mortality of M. japonicus increased, the expression level of MjTPS and the synthesis of downstream products decreased under low-salinity and high-nitrite stress, and what's more, the expression of immune genes PMO25, ERP, CD, HSP90, HSP70, HSP60, HMC and CLEC2 were significantly changed, implying that MjTPS might be participated in the immune response of M. japonicus. In addition, MjTPS gene silencing could affect the expression of CHI1 and CHS, suggesting that MjTPS might be involved in molting behavior of M. japonicus. These results provide new information for further studying the function of trehalose-6-phosphate synthase in shrimp.


Assuntos
Glucosiltransferases/genética , Penaeidae/genética , Sequência de Aminoácidos , Animais , China , Clonagem Molecular/métodos , Expressão Gênica , Glucosiltransferases/metabolismo , Penaeidae/metabolismo , Filogenia , Frutos do Mar , Trealose/metabolismo
18.
EBioMedicine ; 77: 103912, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35292270

RESUMO

BACKGROUND: α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans. METHODS: We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q). FINDINGS: We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence. INTERPRETATION: Senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials. FUNDING: This work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network.


Assuntos
Envelhecimento , Senoterapia , Idoso , Animais , Encéfalo , Senescência Celular , Humanos , Camundongos , Quercetina/farmacologia
19.
Hu Li Za Zhi ; 58(3 Suppl): 22-30, 2011 Jun.
Artigo em Zh | MEDLINE | ID: mdl-21678264

RESUMO

BACKGROUND: Oral health professionals identified inadequate levels of patient oral health in our intensive care unit (ICU). A post-review analysis of collected data and field observation notes concluded that this problem resulted from several factors including: (1) Failure of ICU nurses to follow mouth care standards; (2) lack of oral injury care procedures; (3) lack of oral injury consultation procedures; (4) lack of oral care monitoring; (5) substandard oral care assistive devices. PURPOSE: The authors designed this project to raise general nursing staff knowledge of oral hygiene standards and increase the ability of nurses to implement proper oral healthcare. RESOLUTION: After discussions with oral health professionals and reviewing articles in the literature, the authors implemented Critical Patient Oral Care Standards and Oral Injury Consultation Procedures and purchased new assistive care devices. The authors also conducted regular on-the-job training sessions for hospital staff that were reinforced by regular monitoring. RESULTS: Training significantly increased nursing staff recognition of oral health care. Oral health care test scores rose from an initial average of 16% correct to a final average of 90% correct. Accurate implementation of oral health care in the ICU rose from an initial 19.69% to 78.66% of cases. CONCLUSION: This project significantly enhanced the accuracy and appropriateness of nurse oral health care delivery and quality health care promotion in the ICU.


Assuntos
Unidades de Terapia Intensiva , Higiene Bucal/enfermagem , Humanos , Saúde Bucal , Higiene Bucal/normas , Qualidade da Assistência à Saúde
20.
Mitochondrial DNA B Resour ; 6(8): 2299-2301, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34345684

RESUMO

Lucilia shenyangensis Fan, 1965 (Diptera: Calliphoridae) is of potential importance in epidemiology, veterinary medicine, and forensic entomology due to their necrophilous habit and behaviors associated with mammals. In this study, we report the complete mitochondrial genome (mitogenome) of L. shenyangensis. The mitogenome is 14,989 bp in length, comprising 13 protein-coding genes (PCGs), two ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and a non-coding control region. The arrangement of genes is identical to that of the ancestral metazoan. Nucleotide composition revealed a high A/T bias, accounting for 76.50% total mitogenome nucleotides (A 39.2%, G 9.6%, C 14.0%, T 37.3%). Phylogenetic analysis indicated that L. shenyangensis was clear separated from other blow flies and emerged as the sister lineage to the rest species from genus Lucilia (L. illustris, L. sericata, L. coeruleiviridis, and L. porphyrina). The mitogenome data of L. shenyangensis could facilitate further evolutionary genetic researches on blow flies.

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