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1.
Skin Res Technol ; 30(2): e13573, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38303407

RESUMO

BACKGROUND: Facial acne scars are a prevalent concern, leading to the development of various treatment modalities. OBJECTIVES: This review aims to explore the latest advancements in the treatment of facial acne scars, focusing on both surgical and non-surgical methods. METHODS: The non-surgical treatments reviewed include topical medications (such as retinoids and alpha hydroxy acids) and non-invasive procedures (like microdermabrasion and chemical peels). Surgical options discussed are punch excision, subcision, and fractional laser treatments. RESULTS: Combination therapy, integrating both surgical and non-surgical approaches, is frequently utilized to achieve optimal results in scar improvement. CONCLUSION: Recent advancements in the treatment of facial acne scars provide promising options for individuals seeking improvement. However, these treatments have associated risks and potential adverse effects, highlighting the importance of consulting a dermatologist before beginning any treatment regimen.


Assuntos
Acne Vulgar , Abrasão Química , Humanos , Cicatriz/etiologia , Cicatriz/terapia , Cicatriz/patologia , Acne Vulgar/terapia , Acne Vulgar/cirurgia , Dermabrasão , Retinoides/uso terapêutico , Resultado do Tratamento
2.
Mol Psychiatry ; 27(5): 2414-2424, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35449295

RESUMO

The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation, and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux, and conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.


Assuntos
Macroautofagia , Proteínas Proto-Oncogênicas c-akt , Animais , Enzimas Desubiquitinantes/metabolismo , Mamíferos/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Sinapses/metabolismo , Serina-Treonina Quinases TOR/metabolismo
3.
Int Wound J ; 20(6): 2190-2206, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36726192

RESUMO

Pathological scarring is an abnormal outcome of wound healing, which often manifests as excessive proliferation and transdifferentiation of fibroblasts (FBs), and excessive deposition of the extracellular matrix. FBs are the most important effector cells involved in wound healing and scar formation. The factors that promote pathological scar formation often act on the proliferation and function of FB. In this study, we describe the factors that lead to abnormal FB formation in pathological scarring in terms of the microenvironment, signalling pathways, epigenetics, and autophagy. These findings suggest that understanding the causes of abnormal FB formation may aid in the development of precise and effective preventive and treatment strategies for pathological scarring that are associated with improved quality of life of patients.


Assuntos
Queloide , Humanos , Queloide/patologia , Qualidade de Vida , Cicatrização , Fibroblastos/metabolismo , Matriz Extracelular
4.
Mol Psychiatry ; 26(7): 3444-3460, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-32929213

RESUMO

Schizophrenia (SCZ) is a neuropsychiatric disorder with aberrant expression of multiple genes. However, identifying its exact causal genes remains a considerable challenge. The brain-specific transcription factor POU3F2 (POU domain, class 3, transcription factor 2) has been recognized as a risk factor for SCZ, but our understanding of its target genes and pathogenic mechanisms are still limited. Here we report that POU3F2 regulates 42 SCZ-related genes in knockdown and RNA-sequencing experiments of human neural progenitor cells (NPCs). Among those SCZ-related genes, TRIM8 (Tripartite motif containing 8) is located in SCZ-associated genetic locus and is aberrantly expressed in patients with SCZ. Luciferase reporter and electrophoretic mobility shift assays (EMSA) showed that POU3F2 induces TRIM8 expression by binding to the SCZ-associated SNP (single nucleotide polymorphism) rs5011218, which affects POU3F2-binding efficiency at the promoter region of TRIM8. We investigated the cellular functions of POU3F2 and TRIM8 as they co-regulate several pathways related to neural development and synaptic function. Knocking down either POU3F2 or TRIM8 promoted the proliferation of NPCs, inhibited their neuronal differentiation, and impaired the excitatory synaptic transmission of NPC-derived neurons. These results indicate that POU3F2 regulates TRIM8 expression through the SCZ-associated SNP rs5011218, and both genes may be involved in the etiology of SCZ by regulating neural development and synaptic function.


Assuntos
Proteínas de Transporte , Proteínas de Homeodomínio , Proteínas do Tecido Nervoso , Células-Tronco Neurais , Fatores do Domínio POU , Esquizofrenia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Fatores do Domínio POU/genética , Fatores do Domínio POU/metabolismo , Esquizofrenia/genética
5.
J Neurogenet ; 35(4): 358-369, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34092163

RESUMO

Addiction results from drug-elicited alterations of synaptic plasticity mechanisms in dopaminergic reward circuits. Impaired metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and accumulation of synaptic Ca2+-permeable AMPA receptors (CP-AMPARs) following drug exposure have emerged as important mechanisms underlying drug craving and relapse. Here we show that repeated cocaine exposure in vivo causes transient but complete loss of mGluR1- and mTOR (mammalian target of rapamycin)-dependent LTD in layer 5 pyramidal neurons of mouse prefrontal cortex (PFC), a major dopaminergic target in the reward circuitry. This mGluR1-LTD impairment was prevented by in vivo administration of an mGluR1 positive allosteric modulator (PAM) and rescued by inhibition of dopamine D1 receptors, suggesting that impaired mGluR1 tone and excessive D1 signaling underlie this LTD deficit. Concurrently, CP-AMPARs were generated, indicated by increased sensitivity to the CP-AMPAR inhibitor Naspm and rectification of synaptic AMPAR currents, which were reversed by PAM in cocaine-exposed mice. Finally, these CP-AMPARs mediate an abnormal spike-timing-dependent long-term potentiation enabled by cocaine exposure. Our findings reveal a mechanism by which cocaine impairs LTD and remodels synaptic AMPARs to influence Hebbian plasticity in the PFC. Failure to undergo LTD may prevent the reversal of drug-potentiated brain circuits to their baseline states, perpetuating addictive behaviors.HIGHLIGHTSA mGluR1- and mTOR-dependent LTD is present in the mouse medial prefrontal cortex.Repeated cocaine exposure in vivo temporally but completely abolishes prefrontal mGluR1-LTD.Impaired mGluR1 function and excessive D1 DA signaling likely underlie cocaine impairment of mGluR1-LTD.Ca2+-permeable AMPA receptors are generated by cocaine exposure, likely resulting from mGluR1-LTD impairment, and contribute to a cocaine-induced extended spike timing LTP.


Assuntos
Cocaína , Receptores de Glutamato Metabotrópico , Animais , Cocaína/farmacologia , Camundongos , Plasticidade Neuronal , Córtex Pré-Frontal/metabolismo , Receptores de AMPA , Receptores de Glutamato Metabotrópico/metabolismo
6.
Proc Natl Acad Sci U S A ; 114(41): E8760-E8769, 2017 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-28973854

RESUMO

Ubiquitination-directed proteasomal degradation of synaptic proteins, presumably mediated by lysine 48 (K48) of ubiquitin, is a key mechanism in synapse and neural circuit remodeling. However, more than half of polyubiquitin (polyUb) species in the mammalian brain are estimated to be non-K48; among them, the most abundant is Lys 63 (K63)-linked polyUb chains that do not tag substrates for degradation but rather modify their properties and activity. Virtually nothing is known about the role of these nonproteolytic polyUb chains at the synapse. Here we report that K63-polyUb chains play a significant role in postsynaptic protein scaffolding and synaptic strength and plasticity. We found that the postsynaptic scaffold PSD-95 (postsynaptic density protein 95) undergoes K63 polyubiquitination, which markedly modifies PSD-95's scaffolding potentials, enables its synaptic targeting, and promotes synapse maturation and efficacy. TNF receptor-associated factor 6 (TRAF6) is identified as a direct E3 ligase for PSD-95, which, together with the E2 complex Ubc13/Uev1a, assembles K63-chains on PSD-95. In contrast, CYLD (cylindromatosis tumor-suppressor protein), a K63-specific deubiquitinase enriched in postsynaptic densities, cleaves K63-chains from PSD-95. We found that neuronal activity exerts potent control of global and synaptic K63-polyUb levels and, through NMDA receptors, drives rapid, CYLD-mediated PSD-95 deubiquitination, mobilizing and depleting PSD-95 from synapses. Silencing CYLD in hippocampal neurons abolishes NMDA-induced chemical long-term depression. Our results unveil a previously unsuspected role for nonproteolytic polyUb chains in the synapse and illustrate a mechanism by which a PSD-associated K63-linkage-specific ubiquitin machinery acts on a major postsynaptic scaffold to regulate synapse organization, function, and plasticity.


Assuntos
Proteína 4 Homóloga a Disks-Large/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Poliubiquitina/metabolismo , Densidade Pós-Sináptica , Complexo de Endopeptidases do Proteassoma/metabolismo , Sinapses/fisiologia , Animais , Hipocampo/citologia , Lisina , Camundongos , Camundongos Knockout , Neurônios/citologia , Ubiquitinação
7.
J Neurosci ; 37(4): 986-997, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28123030

RESUMO

Addictive drugs usurp neural plasticity mechanisms that normally serve reward-related learning and memory, primarily by evoking changes in glutamatergic synaptic strength in the mesocorticolimbic dopamine circuitry. Here, we show that repeated cocaine exposure in vivo does not alter synaptic strength in the mouse prefrontal cortex during an early period of withdrawal, but instead modifies a Hebbian quantitative synaptic learning rule by broadening the temporal window and lowers the induction threshold for spike-timing-dependent LTP (t-LTP). After repeated, but not single, daily cocaine injections, t-LTP in layer V pyramidal neurons is induced at +30 ms, a normally ineffective timing interval for t-LTP induction in saline-exposed mice. This cocaine-induced, extended-timing t-LTP lasts for ∼1 week after terminating cocaine and is accompanied by an increased susceptibility to potentiation by fewer pre-post spike pairs, indicating a reduced t-LTP induction threshold. Basal synaptic strength and the maximal attainable t-LTP magnitude remain unchanged after cocaine exposure. We further show that the cocaine facilitation of t-LTP induction is caused by sensitized D1-cAMP/protein kinase A dopamine signaling in pyramidal neurons, which then pathologically recruits voltage-gated l-type Ca2+ channels that synergize with GluN2A-containing NMDA receptors to drive t-LTP at extended timing. Our results illustrate a mechanism by which cocaine, acting on a key neuromodulation pathway, modifies the coincidence detection window during Hebbian plasticity to facilitate associative synaptic potentiation in prefrontal excitatory circuits. By modifying rules that govern activity-dependent synaptic plasticity, addictive drugs can derail the experience-driven neural circuit remodeling process important for executive control of reward and addiction. SIGNIFICANCE STATEMENT: It is believed that addictive drugs often render an addict's brain reward system hypersensitive, leaving the individual more susceptible to relapse. We found that repeated cocaine exposure alters a Hebbian associative synaptic learning rule that governs activity-dependent synaptic plasticity in the mouse prefrontal cortex, characterized by a broader temporal window and a lower threshold for spike-timing-dependent LTP (t-LTP), a cellular form of learning and memory. This rule change is caused by cocaine-exacerbated D1-cAMP/protein kinase A dopamine signaling in pyramidal neurons that in turn pathologically recruits l-type Ca2+ channels to facilitate coincidence detection during t-LTP induction. Our study provides novel insights on how cocaine, even with only brief exposure, may prime neural circuits for subsequent experience-dependent remodeling that may underlie certain addictive behavior.


Assuntos
Cocaína/administração & dosagem , Potenciação de Longa Duração/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Potenciais Sinápticos/efeitos dos fármacos , Animais , Canais de Cálcio Tipo L/fisiologia , Feminino , Injeções Intraperitoneais , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Córtex Pré-Frontal/fisiologia , Distribuição Aleatória , Sinapses/fisiologia , Potenciais Sinápticos/fisiologia
8.
J Neurogenet ; 31(4): 325-336, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29117754

RESUMO

Our earlier genetic screen uncovered a paraquat-sensitive leg-shaking mutant quiver1 (qvr1), whose gene product interacts with the Shaker (Sh) K+ channel. We also mapped the qvr locus to EY04063 and noticed altered day-night activity patterns in these mutants. Such circadian behavioral defects were independently reported by another group, who employed the qvr1 allele we supplied them, and attributed the extreme restless phenotype of EY04063 to the qvr gene. However, their report adopted a new noncanonical gene name sleepless (sss) for qvr. In addition to qvr1 and qvrEY, our continuous effort since the early 2000s generated a number of novel recessive qvr alleles, including ethyl methanesulfonate (EMS)-induced mutations qvr2 and qvr3, and P-element excision lines qvrip6 (imprecise jumpout), qvrrv7, and qvrrv9 (revertants) derived from qvrEY. Distinct from the original intron-located qvr1 allele that generates abnormal-sized mRNAs, qvr2, and qvr3 had their lesion sites in exons 6 and 7, respectively, producing nearly normal-sized mRNA products. A set of RNA-editing sites are nearby the lesion sites of qvr3 and qvrEY on exon 7. Except for the revertants, all qvr alleles display a clear ether-induced leg-shaking phenotype just like Sh, and weakened climbing abilities to varying degrees. Unlike Sh, all shaking qvr alleles (except for qvrf01257) displayed a unique activity-dependent enhancement in excitatory junction potentials (EJPs) at larval neuromuscular junctions (NMJs) at very low stimulus frequencies, with qvrEY displaying the largest EJP and more significant NMJ overgrowth than other alleles. Our detailed characterization of a collection of qvr alleles helps to establish links between novel molecular lesions and different behavioral and physiological consequences, revealing how modifications of the qvr gene lead to a wide spectrum of phenotypes, including neuromuscular hyperexcitability, defective motor ability and activity-rest cycles.


Assuntos
Alelos , Proteínas de Drosophila/genética , Canais de Potássio/genética , Superfamília Shaker de Canais de Potássio/genética , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Proteínas de Membrana , Junção Neuromuscular/genética , Junção Neuromuscular/metabolismo , Canais de Potássio/metabolismo , Superfamília Shaker de Canais de Potássio/metabolismo
9.
J Neurosci ; 35(13): 5097-108, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25834037

RESUMO

Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at <50 loci, including the homeodomain transcription factor Meis2. Small RNA-mediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Memória de Curto Prazo/fisiologia , Proteína de Leucina Linfoide-Mieloide/metabolismo , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Comportamento Animal/fisiologia , Proteínas do Citoesqueleto/metabolismo , Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Masculino , Metilação , Camundongos , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso/metabolismo , Prosencéfalo/fisiologia , Células Piramidais/fisiologia
10.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 32(2): 368-72, 2015 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-26211256

RESUMO

The flushing pump which is applied to clean operative wound has no temperature controlling function up to now, and doctors have to prepare the flushing fluid that has previously been warmed. The flushing pump system with medical constant temperature designed in our laboratory can absorb flushing fluid at the room temperature, and then eject flushing fluid with the temperature in accordance with the requirements of operations at a controlled constant flow rate. The system combines flow rate control with temperature control functions. The flushing pump system includes flushing part, temperature controlling part, key inputting part, liquid crystal displaying part and exceptional situation monitoring part. The present paper introduces the design method and principle of each part of the system at first, and then gives the debug method of all the system parameters. Finally the paper discusses the performance of the system according to the result of the experiment.


Assuntos
Equipamentos e Provisões , Temperatura , Desenho de Equipamento
11.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 31(1): 69-75, 2014 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-24804487

RESUMO

This paper presents the preliminary design of data acquisition system of a portable uroflowmeter. The system uses double-hole cantilever pressure sensor. The signal is transferred to ATmega644PA microprogrammed control unit (MCU), converted by A/D (analog to digital) convertor. Then the further data are processed and get the corresponding relationship of weight-time and two curves of urine flow and urinary flow rate. In the measurement accuracy of the device about urine flow, two factors about the placement and height of the data acquisition are analyzed to show the accuracy of the equipment through the Origin 8.0 data analysis software. The design is characterized by low cost and high speed of data collection, real-time, high accuracy.


Assuntos
Coleta de Dados , Fluxômetros , Monitorização Ambulatorial/instrumentação , Micção/fisiologia , Humanos , Software , Urodinâmica/fisiologia
12.
Phytochemistry ; 223: 114115, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38710377

RESUMO

A total of twenty-two diterpenoid alkaloids, including ten unprecedented ones, namely refractines C-L, were isolated from the roots of Aconitum refractum (Finet et Gagnep.) Hand.-Mazz. Refractine C was the first example of a natural diterpenoid alkaloid wherein C-19 is linked to N position by an oxaziridine ring. Refractine L was a rare glycosidic diterpenoid alkaloid with fructofuranoside. Most of the isolated compounds obtained from a previous study were screened for their anti-inflammatory and myocardial protective activities. The autophagy-inducing effects of some of these compounds on RAW 264.7 cells were evaluated by assessing the expression of microtubule-associated protein 1 light chain 3 (LC3-II/LC3-I). Results revealed that some compounds exerted varying levels of inhibitory effects on the proliferative activity of RAW 264.7 cells.


Assuntos
Aconitum , Alcaloides , Autofagia , Diterpenos , Aconitum/química , Camundongos , Animais , Autofagia/efeitos dos fármacos , Células RAW 264.7 , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/química , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Raízes de Plantas/química
13.
bioRxiv ; 2023 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-37781625

RESUMO

Deubiquitinases present locally at synapses regulate synaptic development, function, and plasticity. It remains largely unknown, however, whether deubiquitinases localized outside of the synapse control synapse remodeling. Here we identify ubiquitin specific protease 48 (USP48; formerly USP31) as a nuclear deubiquitinase mediating robust synapse removal. USP48 is expressed primarily during the first postnatal week in the rodent brain and is virtually restricted to nuclei, mediated by a conserved, 13-amino acid nuclear localization signal. When exogenously expressed, USP48, in a deubiquitinase and nuclear localization-dependent manner, induces striking filopodia elaboration, marked spine loss, and significantly reduced synaptic protein clustering in vitro, and erases ~70% of functional synapses in vivo. USP48 interacts with the transcription factor NF-κB, deubiquitinates NF-κB subunit p65 and promotes its stability and activation, and up-regulates NF-κB target genes known to inhibit synaptogenesis. Depleting NF-κB prevents USP48-dependent spine pruning. These findings identify a novel nucleus-enriched deubiquitinase that plays critical roles in synapse remodeling.

14.
Int Immunopharmacol ; 118: 110005, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36924566

RESUMO

BACKGROUND: Accumulating evidence has shown that gut microbiota plays a key role in the progression of atopic dermatitis (AD). Fecal microbiota transplantation (FMT), as an effective method to restore gut microbiota homeostasis, has been successfully applied for treating many inflammatory diseases. However, the therapeutic effect of FMT on AD remains unclear. The following study examined the effect and mechanism of FMT on AD-skin lesions in an AD mouse model. METHODS: In this study, we exposed the shaved back skin of BALB/c mice to calcipotriol (MC903) to induce AD model. Mice were then treated with FMT, which was performed with gut microbiota from healthy mice. The gut microbiota of treated mice was tracked by 16S rRNA gene sequencing. Mice skin tissues were examined by histopathology and inflammatory cytokines change in serum by ELISA. RESULTS: FMT had a faster trend on the reversion of the increases in skin epidermal layer thicknesses and suppressed some of the representative inflammatory cytokines. The gut microbial community in the natural recovery process varied significantly in the FMT group at day 7 (ANOSIM P = 0.0229, r = 0.2593). Notably, FMT had a long-lasting and beneficial impact on the gut microbial compositions of AD mice by increasing the ratio of Firmicutes to Bacteroidetes and the amount of butyric-producing bacteria (BPB), including Erysipelotrichaceae, Lactobacillaceae, and Eubacteriacea. Furthermore, the relative abundances of gut microbiota-mediated functional pathways involved in the cell growth and death, amino acid, energy, lipid, and carbohydrate metabolisms, and immune system increased after FMT treatment. CONCLUSION: FMT modulated the gut microbiota homeostasis and affected the recovery from AD-related inflammations, suggesting that it could be used as a treatment strategy for AD patients in the clinic.


Assuntos
Dermatite Atópica , Microbioma Gastrointestinal , Animais , Camundongos , Transplante de Microbiota Fecal/métodos , Dermatite Atópica/terapia , RNA Ribossômico 16S/genética , Citocinas , Homeostase , Fezes/microbiologia
15.
eNeuro ; 9(1)2022.
Artigo em Inglês | MEDLINE | ID: mdl-34876473

RESUMO

In Drosophila, molecular pathways affecting longevity have been extensively studied. However, corresponding neurophysiological changes underlying aging-related functional and behavioral deteriorations remain to be fully explored. We examined different motor circuits in Drosophila across the life span and uncovered distinctive age-resilient and age-vulnerable trajectories in their established functional properties. In the giant fiber (GF) and downstream circuit elements responsible for the jump-and-flight escape reflex, we observed relatively mild deterioration toward the end of the life span. In contrast, more substantial age-dependent modifications were seen in the plasticity of GF afferent processing, specifically in use dependence and habituation properties. In addition, there were profound changes in different afferent circuits that drive flight motoneuron activities, including flight pattern generation and seizure spike discharges evoked by electroconvulsive stimulation. Importantly, in high-temperature (HT)-reared flies (29°C), the general trends in these age-dependent trajectories were largely maintained, albeit over a compressed time scale, lending support for the common practice of HT rearing for expediting Drosophila aging studies. We discovered that shortened life spans in Cu/Zn superoxide dismutase (Sod) mutant flies were accompanied by altered aging trajectories in motor circuit properties distinct from those in HT-reared flies, highlighting differential effects of oxidative versus temperature stressors. This work helps to identify several age-vulnerable neurophysiological parameters that may serve as quantitative indicators for assessing genetic and environmental influences on aging progression in Drosophila.


Assuntos
Envelhecimento , Drosophila , Animais , Drosophila melanogaster , Neurônios Motores , Superóxido Dismutase , Temperatura
16.
JCI Insight ; 7(14)2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35866480

RESUMO

Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B-depleted (Phf21b-depleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b's roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity-related genes and a candidate therapeutic target for neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.


Assuntos
Proteínas de Homeodomínio , Doenças do Sistema Nervoso , Plasticidade Neuronal , Animais , Epigênese Genética , Regulação da Expressão Gênica , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Camundongos , Plasticidade Neuronal/genética
17.
Proc Natl Acad Sci U S A ; 105(21): 7506-10, 2008 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-18508973

RESUMO

Beneficial effects of social interaction on aging have been studied in humans and other species. We found that short-lived Drosophila mutants of the antioxidant enzyme Cu/Zn superoxide dismutase displayed a robust lifespan extension, with improved stress resistance and motor ability, upon cohousing with active flies of longer lifespan or younger age. Genetic, surgical, and environmental manipulations revealed motor and sensory components in behavioral interactions required for the lifespan extension induced by cohousing. Our results provide a definitive case of beneficial social interaction on lifespan and a useful entry point for analyzing the underlying molecular networks and physiological mechanisms.


Assuntos
Comunicação Animal , Proteínas de Drosophila/genética , Drosophila/fisiologia , Longevidade/genética , Comportamento Social , Superóxido Dismutase/genética , Alelos , Animais , Drosophila/genética , Feminino , Masculino , Mutação
18.
Brain Res ; 1727: 146569, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31783001

RESUMO

Ubiquitination and its reverse process, deubiquitination, play essential roles in neural development, function, and plasticity. A20, a ubiquitin editing enzyme that can remove K63-polyubiquitin chains from substrates and attach K48-polyubiquitin chains to them, is a critical component in the NF-κB signaling pathway in the immune system. This dual ubiquitin enzyme is also present in mammalian brains, but its potential role in neurons and synapses is unknown. We show that A20 in pyramidal neurons potently regulates dendritic arborization, spine morphogenesis, and synaptic transmission through an NF-κB-dependent mechanism. In cultured hippocampal neurons, overexpression of A20 reduced dendritic complexity and spine size and density, whereas A20 knockdown increased spine size and density, as well as clustering of the postsynaptic scaffold PSD-95 and glutamate receptor subunit GluA1. A20 effects in vitro were recapitulated in vivo where increasing or decreasing A20 expression in mouse brains reduced and enhanced spine density, respectively. Functionally, A20 knockdown significantly increased the amplitude, but not frequency of miniature excitatory postsynaptic currents, suggesting a role in postsynaptic efficacy. A20 negatively regulated NF-κB activation in neurons and A20 mutants deficient in either the deubiquitinase or the ubiquitin ligase activity failed to suppress NF-κB activation or reduce spine morphogenesis. Finally, selective inhibition of NF-κB abolished A20 knockdown-elicited spine formation, suggesting that A20 exerts its modulation on synapses through NF-κB signaling. Together, our study reveals a previously unknown role for A20, the only known ubiquitin editing enzyme with both deubiquitinase and ubiquitin ligase activity, in dendritic arborization, spine remodeling, and synaptic plasticity.


Assuntos
Células Piramidais/fisiologia , Sinapses/fisiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/fisiologia , Animais , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Células Piramidais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/administração & dosagem
19.
Nat Commun ; 6: 10045, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26620774

RESUMO

Homeostatic synaptic plasticity is a compensatory response to alterations in neuronal activity. Chronic deprivation of neuronal activity results in an increase in synaptic AMPA receptors (AMPARs) and postsynaptic currents. The biogenesis of GluA2-lacking, calcium-permeable AMPARs (CP-AMPARs) plays a crucial role in the homeostatic response; however, the mechanisms leading to CP-AMPAR formation remain unclear. Here we show that the microRNA, miR124, is required for the generation of CP-AMPARs and homeostatic plasticity. miR124 suppresses GluA2 expression via targeting its 3'-UTR, leading to the formation of CP-AMPARs. Blockade of miR124 function abolishes the homeostatic response, whereas miR124 overexpression leads to earlier induction of homeostatic plasticity. miR124 transcription is controlled by an inhibitory transcription factor EVI1, acting by association with the deacetylase HDAC1. Our data support a cellular cascade in which inactivity relieves EVI1/HDAC-mediated inhibition of miR124 gene transcription, resulting in enhanced miR124 expression, formation of CP-AMPARs and subsequent induction of homeostatic synaptic plasticity.


Assuntos
MicroRNAs/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Animais , Hipocampo/citologia , Hipocampo/metabolismo , Homeostase , Humanos , MicroRNAs/genética , Ratos Sprague-Dawley , Receptores de AMPA/genética , Receptores de AMPA/metabolismo
20.
Artigo em Inglês | MEDLINE | ID: mdl-24795571

RESUMO

Spike timing-dependent plasticity (STDP) of glutamatergic synapses is a Hebbian associative plasticity that may underlie certain forms of learning. A cardinal feature of STDP is its dependence on the temporal order of presynaptic and postsynaptic spikes during induction: pre-post (positive) pairings induce t-LTP (timing-dependent long-term potentiation) whereas post-pre (negative) pairings induce t-LTD (timing-dependent long-term depression). Dopamine (DA), a reward signal for behavioral learning, is believed to exert powerful modulations on synapse strength and plasticity, but its influence on STDP has remained incompletely understood. We previously showed that DA extends the temporal window of t-LTP in the prefrontal cortex (PFC) from +10 to +30 ms, gating Hebbian t-LTP. Here, we examined DA modulation of synaptic plasticity induced at negative timings in layer V pyramidal neurons on mouse medial PFC slices. Using a negative timing STDP protocol (60 post-pre pairings at 0.1 Hz, δt = -30 ms), we found that DA applied during post-pre pairings did not produce LTD, but instead enabled robust LTP. This anti-Hebbian t-LTP depended on GluN2B-containing NMDA receptors. Blocking D1- (D1Rs), but not D2- (D2Rs) class DA receptors or disrupting cAMP/PKA signaling in pyramidal neurons also abolished this atypical t-LTP, indicating that it was mediated by postsynaptic D1R-cAMP/PKA signaling in excitatory synapses. Unlike DA-enabled Hebbian t-LTP that requires suppression of GABAergic inhibition and cooperative actions of both D1Rs and D2Rs in separate PFC excitatory and inhibitory circuits, DA-enabled anti-Hebbian t-LTP occurred under intact inhibitory transmission and only required D1R activation in excitatory circuit. Our results establish DA as a potent modulator of coincidence detection during associative synaptic plasticity and suggest a mechanism by which DA facilitates input-target association during reward learning and top-down information processing in PFC circuits.


Assuntos
Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Dopamina/farmacologia , Potenciação de Longa Duração/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
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