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1.
Signal Transduct Target Ther ; 7(1): 103, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35422062

RESUMO

Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here that Pink1 knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation in Pink1 KO neurons. Notably, mice harboring a knockin (KI) phosphor-null Drp1S616A recapitulate spine immaturity and synaptic abnormality identified in Pink1 KO mice. Chemical LTP (cLTP) induces Drp1S616 phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1S616D restores reduced dendritic spine localization of mitochondria in Pink1 KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1S616 phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement.


Assuntos
Dinaminas , Dinâmica Mitocondrial , Animais , Dinaminas/genética , Dinaminas/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/genética , Fosforilação/genética , Proteínas Quinases/genética
2.
Nanomaterials (Basel) ; 12(7)2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35407244

RESUMO

Thin-film transistors (TFTs) made of solution-processable transparent metal oxide semiconductors show great potential for use in emerging large-scale optoelectronics. However, current solution-processed metal oxide TFTs still suffer from relatively poor device performance, hindering their further advancement. In this work, we create a novel ultrathin crystalline indium-boron-oxide (In-B-O) channel layer for high-performance TFTs. We show that high-quality ultrathin (~10 nm) crystalline In-B-O with an atomically smooth nature (RMS: ~0.15 nm) could be grown from an aqueous solution via facile one-step spin-coating. The impacts of B doping on the physical, chemical and electrical properties of the In2O3 film are systematically investigated. The results show that B has large metal-oxide bond dissociation energy and high Lewis acid strength, which can suppress oxygen vacancy-/hydroxyl-related defects and alleviate dopant-induced carrier scattering, resulting in electrical performance improvement. The optimized In-B-O (10% B) TFTs based on SiO2/Si substrate demonstrate a mobility of ~8 cm2/(V s), an on/off current ratio of ~106 and a subthreshold swing of 0.86 V/dec. Furthermore, by introducing the water-processed high-K ZrO2 dielectric, the fully aqueous solution-grown In-B-O/ZrO2 TFTs exhibit excellent device performance, with a mobility of ~11 cm2/(V s), an on/off current of ~105, a subthreshold swing of 0.19 V/dec, a low operating voltage of 5 V and superior bias stress stability. Our research opens up new avenues for low-cost, large-area green oxide electronic devices with superior performance.

3.
Nanomaterials (Basel) ; 12(7)2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35407335

RESUMO

We demonstrate the growth of ultra-thin (~5 nm) indium ytterbium oxide (In-Yb-O) thin film using a simple vacuum-free aqueous solution approach for the first time. The influences of Yb addition on the microstructural, chemical, optical, and electrical properties of In2O3 are well investigated. The analyses indicate that Yb dopant could suppress oxygen vacancy defects effectively owing to the lower standard electrode potential, lower electronegativity, and stronger metal-oxide bond strength than that of In. The optimized In-Yb-O thin-film transistors (TFTs) exhibit excellent electrical performance (mobility of 8 cm2/Vs and on/off ratio of ~108) and enhanced stability. The triumph of In-Yb-O TFTs is owing to the high quality In2O3 matrix, the remarkable suppressor of Yb, and the nanometer-thin and atomically smooth nature (RMS: ~0.26 nm) of channel layer. Therefore, the eco-friendly water-induced ultra-thin In-Yb-O channel provides an excellent opportunity for future large-scale and cost-effective electronic applications.

4.
Neurotherapeutics ; 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35286657

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease with limited therapeutic strategies. Cell cycle checkpoint protein kinase 1 (Chk1) is a Ser/Thr protein kinase which is activated in response to DNA damage, the latter which is an early event in AD. However, whether DNA damage-induced Chk1 activation participates in the development of AD and Chk1 inhibition ameliorates AD-like pathogenesis remain unclarified. Here, we demonstrate that Chk1 activity and the levels of protein phosphatase 2A (PP2A) inhibitory protein CIP2A are elevated in AD human brains, APP/PS1 transgenic mice, and primary neurons with Aß treatment. Chk1 overexpression induces CIP2A upregulation, PP2A inhibition, tau and APP hyperphosphorylation, synaptic impairments, and cognitive memory deficit in mice. Moreover, Chk1 inhibitor (GDC0575) effectively increases PP2A activity, decreases tau phosphorylation, and inhibits Aß overproduction in AD cell models. GDC0575 also reverses AD-like cognitive deficits and prevents neuron loss and synaptic impairments in APP/PS1 mice. In conclusion, our study uncovers a mechanism by which DNA damage-induced Chk1 activation promotes CIP2A-mediated tau and APP hyperphosphorylation and cognitive dysfunction in Alzheimer's disease and highlights the therapeutic potential of Chk1 inhibitors in AD.

5.
Artigo em Inglês | MEDLINE | ID: mdl-35275355

RESUMO

LINC00662 plays a prominent role in the carcinogenesis and progression of diverse cancers. However, its biological functions in glioma are still unclear. LINC00662 expression in glioma tissue samples and cell lines was examined by quantitative real-time polymerase chain reaction. The correlation between LINC00662 expression and the clinical characteristics of 50 patients with glioma was analyzed. LINC00662 knockdown and overexpression cell lines were constructed, and the effects of LINC00662 on the proliferation, invasion, and apoptosis of glioma cells were evaluated by cell counting kit-8, 5-ethynyl-2'-deoxyuridine, Transwell, and flow cytometry assays, respectively. Besides, the relationships among LINC00662, miR-483-3p, and sex-determining region Y-box 3 (SOX3) were assessed by dual-luciferase reporter assay and RNA immunoprecipitation assay. Western blot was used to detect the regulatory effects of LINC00662 and miR-483-3p on SOX3 expression in glioma cells. LINC00662 expression level was elevated in glioma tissues and cell lines compared to that in normal tissues and cell lines. LINC00662 high expression was associated with the adverse prognosis of patients with glioma. Knockdown of LINC00662 repressed the proliferation and invasion of glioma cells, and promoted apoptosis. Additionally, it was revealed that LINC00662 acted as the molecular sponge of miR-483-3p, and SOX3 was verified as a direct target of miR-483-3p. The inhibition of miR-483-3p expression and SOX3 overexpression reversed the biological effects of LINC00662 knockdown on glioma cells. This study reports the key regulatory role of LINC00662/miR-483-3p/SOX3 axis in the tumorigenesis and progression of glioma, bringing novel insights into the underlying mechanisms of glioma.

6.
JCI Insight ; 7(1)2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35014624

RESUMO

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neurodevelopmental disorders. However, the neuropathogenesis remains largely elusive due to a lack of informative animal models. In this study, we developed a congenital murine CMV (cMCMV) infection mouse model with high survival rate and long survival period that allowed long-term follow-up study of neurodevelopmental disorders. This model involves in utero intracranial injection and mimics many reported clinical manifestations of cCMV infection in infants, including growth restriction, hearing loss, and impaired cognitive and learning-memory abilities. We observed that abnormalities in MRI/CT neuroimaging were consistent with brain hemorrhage and loss of brain parenchyma, which was confirmed by pathological analysis. Neuropathological findings included ventriculomegaly and cortical atrophy associated with impaired proliferation and migration of neural progenitor cells in the developing brain at both embryonic and postnatal stages. Robust inflammatory responses during infection were shown by elevated inflammatory cytokine levels, leukocyte infiltration, and activation of microglia and astrocytes in the brain. Pathological analyses and CT neuroimaging revealed brain calcifications induced by cMCMV infection and cell death via pyroptosis. Furthermore, antiviral treatment with ganciclovir significantly improved neurological functions and mitigated brain damage as shown by CT neuroimaging. These results demonstrate that this model is suitable for investigation of mechanisms of infection-induced brain damage and long-term studies of neurodevelopmental disorders, including the development of interventions to limit CNS damage associated with cCMV infection.


Assuntos
Infecções por Citomegalovirus , Modelos Animais de Doenças , Neuroimagem , Animais , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/diagnóstico por imagem , Infecções por Citomegalovirus/fisiopatologia , Infecções por Citomegalovirus/terapia , Feminino , Seguimentos , Camundongos , Camundongos Endogâmicos ICR , Gravidez
7.
Sci Rep ; 12(1): 1537, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-35087161

RESUMO

The third isoform of the Na+-Ca2+ exchanger (NCX3) is crucial for a physiological fine-tuning of the Ca2+ fluxes in excitable tissues. In this view, the NCX3 accounts for the aberrant Ca2+ influx seen during neuronal excitotoxicity, such as in Alzheimer's disease (AD). However, little is known about NCX3 regulation and functional properties. Withania somnifera (L.) Dunal (W. somnifera), a traditional indigenous plant widely recognized for having numerous medicinal values, was undertaken to determine its potential therapeutic benefit against aggregated Aß1-42-induced NCX3 dysregulation and the thereof cognition impairment in 5xFAD mice. The undertaken sourced dried roots of authenticated W. somnifera physicochemical compositional tests satisfied standards of pharmacognostic quality, and further phytochemical analysis of the roots methanol extract revealed the roots constitute several antioxidants. Following an intra-gastric gavage administration of synthesized W. somnifera roots methanolic extract from postnatal day 30 (P30) to P75, in vivo cognitional studies and then neurochemical examinations of the NCX3 expression level, Aß plaque deposition, and antioxidant activities in the AD-associated brain regions of 4-month-old 5xFAD mice suggests that the oxidative stress normalizing effects of W. somnifera constituents, operating on the NCX3, may have a therapeutic role in the improvement of cognition in AD.


Assuntos
Trocador de Sódio e Cálcio
8.
Sci China Life Sci ; 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35089530

RESUMO

The raphe nucleus is critical for feeding, rewarding and memory. However, how the heterogenous raphe neurons are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing VGLUT3. VGLUT3 neurons control the efficacy of spatial memory retrieval by synapsing directly with parvalbumin-expressing GABA interneurons (PGIs) in the dentate gyrus. In a mouse model of Alzheimer's disease (AD mice), VGLUT3→PGIs synaptic transmission is impaired by ETV4 inhibition of VGLUT3 transcription. ETV4 binds to a promoter region of VGLUT3 and activates VGLUT3 transcription in VGLUT3 neurons. Strengthening VGLUT3→PGIs synaptic transmission by ETV4 activation of VGLUT3 transcription upscales the efficacy of spatial memory retrieval in AD mice. This study reports a novel circuit and molecular mechanism underlying the efficacy of spatial memory retrieval via ETV4 inhibition of VGLUT3 transcription and hence provides a promising target for therapeutic intervention of the disease progression.

9.
Mol Neurodegener ; 17(1): 6, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35012591

RESUMO

BACKGROUND: Viral tracers are important tools for mapping brain connectomes. The feature of predominant anterograde transneuronal transmission offers herpes simplex virus-1 (HSV-1) strain H129 (HSV1-H129) as a promising candidate to be developed as anterograde viral tracers. In our earlier studies, we developed H129-derived anterograde polysynaptic tracers and TK deficient (H129-dTK) monosynaptic tracers. However, their broad application is limited by some intrinsic drawbacks of the H129-dTK tracers, such as low labeling intensity due to TK deficiency and potential retrograde labeling caused by axon terminal invasion. The glycoprotein K (gK) of HSV-1 plays important roles in virus entry, egress, and virus-induced cell fusion. Its deficiency severely disables virus egress and spread, while only slightly limits viral genome replication and expression of viral proteins. Therefore, we created a novel H129-derived anterograde monosynaptic tracer (H129-dgK) by targeting gK, which overcomes the limitations of H129-dTK. METHODS: Using our established platform and pipeline for developing viral tracers, we generated a novel tracer by deleting the gK gene from the H129-G4. The gK-deleted virus (H129-dgK-G4) was reconstituted and propagated in the Vero cell expressing wildtype H129 gK (gKwt) or the mutant gK (gKmut, A40V, C82S, M223I, L224V, V309M), respectively. Then the obtained viral tracers of gKmut pseudotyped and gKwt coated H129-dgK-G4 were tested in vitro and in vivo to characterize their tracing properties. RESULTS: H129-dgK-G4 expresses high levels of fluorescent proteins, eliminating the requirement of immunostaining for imaging detection. Compared to the TK deficient monosynaptic tracer H129-dTK-G4, H129-dgK-G4 labeled neurons with 1.76-fold stronger fluorescence intensity, and visualized 2.00-fold more postsynaptic neurons in the downstream brain regions. gKmut pseudotyping leads to a 77% decrease in retrograde labeling by reducing axon terminal invasion, and thus dramatically improves the anterograde-specific tracing of H129-dgK-G4. In addition, assisted by the AAV helper trans-complementarily expressing gKwt, H129-dgK-G4 allows for mapping monosynaptic connections and quantifying the circuit connectivity difference in the Alzheimer's disease and control mouse brains. CONCLUSIONS: gKmut pseudotyped H129-dgK-G4, a novel anterograde monosynaptic tracer, overcomes the limitations of H129-dTK tracers, and demonstrates desirable features of strong labeling intensity, high tracing efficiency, and improved anterograde specificity.


Assuntos
Herpesvirus Humano 1 , Animais , Axônios , Encéfalo , Herpesvirus Humano 1/genética , Camundongos , Neurônios
10.
Dis Markers ; 2021: 9556513, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34876932

RESUMO

OBJECTIVE: Inactivation of NLRP3 inflammasome plays a role in reducing the permeability of endothelial cells and improving blood-brain barrier (BBB) dysfunction following traumatic brain injury (TBI). However, the mechanism controlling NLRP3 inflammasome activation remains unclear. This study is aimed at defining the role of miR-29a-5p in NLRP3 inflammasome activation and permeability of endothelial cells under TBI. METHODS: The scratch injury model on brain bEnd.3 microvascular endothelial cells was used as in vitro TBI model cells. Effects of miR-29a mimics and inhibitors on TBI model cells were observed by examining their action on FITC, TEER, and protein contents of ZO-1 and occludin, and cell permeability-associated protein. Luciferase reporter assay evaluated miR-29a-5p targeting to NLRP3. ELISA examined of IL-1ß and IL-18 levels. miR-29a-5p mimic was injected into TBI mouse and its effect on BBB, indicated by Evans blue (EB) staining assay and cerebral water content, and NLRP3 activation was examined. RESULTS: miR-29a-3p and miR-29a-5p mimics decrease the concentration of FITC, and increase TEER and the protein contents of ZO-1 and occludin in TBI model cells. miR-29a-5p silencing disrupted the permeability of mouse bEnd.3 cells. miR-29a-5p targets to NLRP3 through the binding on its 3'UTR and negatively regulates its expression in TBI model cells. NLRP3 inhibition and miR-29a-5p silencing together caused significantly decreased FITC concentration and increased TEER value and release of IL-1ß and IL-18. miR-29a-5p mimic alleviated the BBB and cerebral water content and inactivates NLRP3 in the mouse TBI model. CONCLUSIONS: miR-29a-5p mimics protect TBI-induced increased endothelial cell permeability and BBB dysfunction via suppressing NLRP3 expression and activation.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Permeabilidade Capilar/genética , MicroRNAs/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Humanos , Camundongos
11.
Membranes (Basel) ; 11(12)2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34940453

RESUMO

Black phosphorus (BP), a single elemental two-dimensional (2D) material with a sizable band gap, meets several critical material requirements in the development of future nanoelectronic applications. This work reports the ambipolar characteristics of few-layer BP, induced using 2D transparent hexagonal boron nitride (h-BN) capping. The 2D h-BN capping have several advantages over conventional Al2O3 capping in flexible and transparent 2D device applications. The h-BN capping technique was used to achieve an electron mobility in the BP devices of 73 cm2V-1s-1, thereby demonstrating n-type behavior. The ambipolar BP devices exhibited ultrafast photodetector behavior with a very high photoresponsivity of 1980 mA/W over the ultraviolet (UV), visible, and infrared (IR) spectral ranges. The h-BN capping process offers a feasible approach to fabricating n-type behavior BP semiconductors and high photoresponse BP photodetectors.

12.
Clin Proteomics ; 18(1): 30, 2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34915845

RESUMO

BACKGROUND: Communicating hydrocephalus (CH) is a common neurological disorder caused by a blockage of cerebrospinal fluid. In this study, we aimed to explore the potential molecular mechanism underlying CH development. METHODS: Quantitative proteomic analysis was performed to screen the differentially expressed proteins (DEPs) between patients with and without CH. A CH rat model was verified by Hoechst staining, and the co-localization of the target protein and neuron was detected using immunofluorescence staining. Loss-of-function experiments were performed to examine the effect of KLK6 on the synapse structure. RESULTS: A total of 11 DEPs were identified, and kallikrein 6 (KLK6) expression was found to be significantly upregulated in patients with CH compared with that in patients without CH. The CH rat model was successfully constructed, and KLK6 was found to be co-localized with neuronal nuclei in brain tissue. The expression level of IL-1ß, TNF-α, and KLK6 in the CH group was higher than that in the control group. After knockdown of KLK6 expression using small-interfering RNA (siRNA), the expression levels of synapsin-1 and PSD95 in neuronal cells were increased, and the length, number, and structure of synapses were significantly improved. Following siRNA interference KLK6 expression, 5681 differentially expressed genes (DEGs) were identified in transcriptome profile. The upregulated DEGs of Appl2, Nav2, and Nrn1 may be involved in the recovery of synaptic structures after the interference of KLK6 expression. CONCLUSIONS: Collectively, KLK6 participates in the development of CH and might provide a new target for CH treatment.

13.
Cell Rep ; 37(13): 110177, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34965426

RESUMO

The hippocampus is a temporal lobe structure critical for cognition, such as learning, memory, and attention, as well as emotional responses. Hippocampal dysfunction can lead to persistent anxiety and/or depression. However, how millions of neurons in the hippocampus are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing the coagulation factor c homolog (COCH) gene. COCH-expressing neurons or COCH neurons are topographically segregated in the distal region of the ventral CA3 hippocampus and express Mtf1 and Cacna1h. MTF1 activation of Cacna1h transcription in COCH neurons encodes the ability of COCH neurons to burst action potentials and cause social-stress-induced anxiety-like behaviors by synapsing directly with a subset of GABAergic inhibitory neurons in the lateral septum. Together, this study provides a molecular and circuitry-based framework for understanding how COCH neurons in the hippocampus are assembled to engage social behavior.


Assuntos
Potenciais de Ação , Ansiedade/patologia , Região CA3 Hipocampal/patologia , Proteínas da Matriz Extracelular/metabolismo , Neurônios GABAérgicos/patologia , Comportamento Social , Estresse Psicológico , Animais , Ansiedade/etiologia , Ansiedade/metabolismo , Região CA3 Hipocampal/metabolismo , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Emoções , Proteínas da Matriz Extracelular/genética , Medo , Neurônios GABAérgicos/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
Appl Phys A Mater Sci Process ; 127(11): 870, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34720447

RESUMO

The electrical and optical properties of Ag/p-GaN contacts have been investigated as a function of the annealing temperature, oxygen concentration, and annealing time. Specific contact resistance (ρ c) values as low as 1.2 × 10-4 Ω·cm2 were obtained from the Ag/p-GaN contact annealed at 400 °C for 60 s in ambient O2/N2 (1:10). We found that the participation of oxygen improves the formation of ohmic contacts. Oxygen might remove the H in Mg-H complexes to activate the Mg acceptors and enhance Ga out-diffusion to form an Ag-Ga solid solution. We also found that the reflectivity of the Ag layer decreases with increasing annealing temperature in the O2-containing ambient environment. Thus, an optimal annealing condition of Ag/p-GaN for blue and green LEDs is suggested based on these results. We also used the suggested annealing conditions to form ohmic contacts on DUV LEDs and achieved good electrical performance. The forward voltages of UVC LEDs fabricated with annealed Ag contacts were 6.60 V (7.66 V) at a 40 mA (100 mA) injection current.

15.
Cell Biosci ; 11(1): 167, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446102

RESUMO

BACKGROUND: Annexin A1 (ANXA1) exerts anti-nociceptive effect through ANXA1 receptor formyl peptide receptor 2 (FPR2/ALX (receptor for lipoxin A4), FPR2) at the dorsal root ganglia (DRG) level. However, the mechanisms remain elucidated. By using radiant heat, hot/cold plate, tail flick, von Frey, and Randall-Selitto tests to detect nociception in intact and chemical (capsaicin, menthol, mustard oil, formalin or CFA) injected AnxA1 conditional knockout (AnxA1-/-) mice, applying calcium imaging and patch clamp recordings in cultured DRG neurons to measure neuronal excitability, conducting immunofluorescence and western blotting to detect the protein levels of TRPV1, FPR2 and its downstream molecules, and performing double immunofluorescence and co-immunoprecipitation to investigate the interaction between Calmodulin (CaM) and TRPV1; we aim to uncover the molecular and cellular mechanisms of ANXA1's role in antinociception. RESULTS: AnxA1-/- mice exhibited significant sensitivity to noxious heat (mean ± SD, 6.2 ± 1.0 s vs. 9.9 ± 1.6 s in Hargreaves test; 13.6 ± 1.5 s vs. 19.0 ± 1.9 s in hot plate test; n = 8; P < 0.001), capsaicin (101.0 ± 15.3 vs. 76.2 ± 10.9; n = 8; P < 0.01), formalin (early phase: 169.5 ± 32.8 s vs. 76.0 ± 21.9 s; n = 8; P < 0.05; late phase: 444.6 ± 40.1 s vs. 320.4 ± 33.6 s; n = 8; P < 0.01) and CFA (3.5 ± 0.8 s vs. 5.9 ± 1.4 s; n = 8; P < 0.01). In addition, we found significantly increased capsaicin induced Ca2+ response, TRPV1 currents and neuronal firing in AnxA1 deficient DRG neurons. Furthermore, ANXA1 mimic peptide Ac2-26 robustly increased intracellular Ca2+, inhibited TRPV1 current, activated PLCß and promoted CaM-TRPV1 interaction. And these effects of Ac2-26 could be attenuated by FPR2 antagonist Boc2. CONCLUSIONS: Selective deletion of AnxA1 in DRG neurons enhances TRPV1 sensitivity and deteriorates noxious heat or capsaicin induced nociception, while ANXA1 mimic peptide Ac2-26 desensitizes TRPV1 via FPR2 and the downstream PLCß-Ca2+-CaM signal. This study may provide possible target for developing new analgesic drugs in inflammatory pain.

16.
Aging Dis ; 12(3): 786-800, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34094642

RESUMO

Stroke activates microglia pro-inflammatory response that not only induces the early neuronal injuries but also causes the secondary brain infarction. Yet, the underlying mechanisms for how microglia become activated in stroke are still unknown. Here, using the next-generation of RNA sequencing we find a total of 778 genes increasingly expressed in brain of stroke mice. Of these, we identified Hmgb2 as a microglia pro-inflammatory mediator by promoting the transcription of Ctss. Inhibition of either Hmgb2 or Ctss blocks microglia pro-inflammatory response and protects against brain damages and improves the neurological functions of stroke mice. This study uncovers Hmgb2 and Ctss as the major microglia inflammatory response mediators in stroke and hence warrants the promising targets for stroke therapies.

17.
Front Cell Dev Biol ; 9: 667412, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33898468

RESUMO

Cholinergic degeneration is one of the key pathological hallmarks of Alzheimer's disease (AD), a condition that is characterized by synaptic disorders and memory impairments. Nerve growth factor (NGF) is secreted in brain regions that receive projections from the basal forebrain cholinergic neurons. The trophic effects of NGF rely on the appropriate maturation of NGF from its precursor, proNGF. The ratio of proNGF/NGF is known to be increased in patients with AD; however, the mechanisms that underlie this observation have yet to be elucidated. Here, we demonstrated that levels of miR-144-3p are increased in the hippocampi and the medial prefrontal cortex of an APP/PS1 mouse model of AD. These mice also exhibited cholinergic degeneration (including the loss of cholinergic fibers, the repression of choline acetyltransferase (ChAT) activity, the reduction of cholinergic neurons, and an increased number of dystrophic neurites) and synaptic/memory deficits. The elevated expression of miR-144-3p specifically targets the mRNA of tissue plasminogen activator (tPA) and reduces the expression of tPA, thus resulting in the abnormal maturation of NGF. The administration of miR-144-3p fully replicated the cholinergic degeneration and synaptic/memory deficits observed in the APP/PS1 mice. The injection of an antagomir of miR-144-3p into the hippocampi partially rescued cholinergic degeneration and synaptic/memory impairments by restoring the levels of tPA protein and by correcting the ratio of proNGF/NGF. Collectively, our research revealed potential mechanisms for the disturbance of NGF maturation and cholinergic degeneration in AD and identified a potential therapeutic target for AD.

18.
Cell Res ; 31(9): 951-964, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33824424

RESUMO

As an excitatory transmitter system, the glutamatergic transmitter system controls excitability and conductivity of neurons. Since both cardiomyocytes and neurons are excitable cells, we hypothesized that cardiomyocytes may also be regulated by a similar system. Here, we have demonstrated that atrial cardiomyocytes have an intrinsic glutamatergic transmitter system, which regulates the generation and propagation of action potentials. First, there are abundant vesicles containing glutamate beneath the plasma membrane of rat atrial cardiomyocytes. Second, rat atrial cardiomyocytes express key elements of the glutamatergic transmitter system, such as the glutamate metabolic enzyme, ionotropic glutamate receptors (iGluRs), and glutamate transporters. Third, iGluR agonists evoke iGluR-gated currents and decrease the threshold of electrical excitability in rat atrial cardiomyocytes. Fourth, iGluR antagonists strikingly attenuate the conduction velocity of electrical impulses in rat atrial myocardium both in vitro and in vivo. Knockdown of GRIA3 or GRIN1, two highly expressed iGluR subtypes in atria, drastically decreased the excitatory firing rate and slowed down the electrical conduction velocity in cultured human induced pluripotent stem cell (iPSC)-derived atrial cardiomyocyte monolayers. Finally, iGluR antagonists effectively prevent and terminate atrial fibrillation in a rat isolated heart model. In addition, the key elements of the glutamatergic transmitter system are also present and show electrophysiological functions in human atrial cardiomyocytes. In conclusion, our data reveal an intrinsic glutamatergic transmitter system directly modulating excitability and conductivity of atrial cardiomyocytes through controlling iGluR-gated currents. Manipulation of this system may open potential new avenues for therapeutic intervention of cardiac arrhythmias.


Assuntos
Fibrilação Atrial , Células-Tronco Pluripotentes Induzidas , Potenciais de Ação , Animais , Átrios do Coração , Humanos , Miócitos Cardíacos , Ratos
20.
ACS Omega ; 6(10): 6699-6707, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33748583

RESUMO

High-performance solar-blind UV detector with high response and fast speed is needed in multiple types of areas, which is hard to achieve in one device with a simple structure and device fabrication process. Here, the effects of Ag nanoparticles (NPs) with different sizes on UV response characteristics of the device are studied, the Ag NPs with different sizes that are made from a simple vacuum anneal method. Ag NPs with different sizes could modulate the peak response position of the mixed-phase MgZnO detector from near UV range (350 nm) to deep UV range (235 nm), and the enhancement effect of the Ag NPs on the UV response differs much with the crystal structure and the basic UV response of the MgZnO thin film. When high density 20-40 nm Ag NPs is induced, the deep UV (235 nm) response of the mixed-phase MgZnO detector is increased by 226 times, the I uv/I dark ratio of the modified device is increased by 17.5 times. The slight enhancement in UV light intensity from 20 to 40 nm Ag NPs induces multiple tunnel breakdown phenomena within the mixed-phase MgZnO thin film, which is the main reason for the abnormal great enhancement effect on deep UV response of the device, so the recovery speed of the modified device is not influenced. Therefore, Ag NPs with different sizes could effectively modulate the UV response peak position of mixed-phase MgZnO thin films, and the introduction of Ag NPs with high density and small size is a simple way to greatly increase the sensitivity of the mixed-phase MgZnO detector at deep UV light without decreasing the device speed.

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