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Although approximately 50% of cases have a known genetic defect, the precise pathogenesis of Hirschsprung disease (HSCR) is still unclear. We recently reported that expression of fibronectin (FN), which is involved in the migration, colonization, and differentiation of enteric neural crest cells (ENCCs), is increased in aganglionic colonic segments obtained from patients. We hypothesized that abnormally high levels of FN might play a role in the etiology of HSCR. Here, to test this hypothesis, we investigated aganglionic, transitional, and ganglionic colon segments from 63 children with HSCR and distal colon from thirty healthy Wistar rats at embryonic day 20, in addition to in vitro studies with PC12 Adh neural crest cells. We measured the protein and mRNA expression levels of FN, together with a panel of excitatory (VGLUT1, GluA1, GluN1, PSD-95, and NL-1) and inhibitory (GAD67, GABA AR-α1, NL-2, and SLC32) synaptic markers. Expression of all these synaptic markers was significantly decreased in aganglionic colon, compared to ganglionic colon, whereas expression of FN was significantly increased. In a neural crest cell line, PC12 Adh, knockdown of FN with small-interfering RNA increased the expression of synaptic markers. Co-culture of colons from embryonic day 20 rats with RGD recombinant protein, which contains the RGD motif of FN, reduced the expression of excitatory and inhibitory synaptic markers. These results are consistent with the idea that the etiology of HSCR involves aberrant overexpression of FN, which may impair synaptic function and enteric nervous system development, leading to motor dysfunction of intestinal muscles.
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Fibronectinas/metabolismo , Enfermedad de Hirschsprung/metabolismo , Inhibición Neural , Sinapsis/metabolismo , Animales , Biomarcadores/metabolismo , Niño , Preescolar , Colon/patología , Femenino , Enfermedad de Hirschsprung/patología , Humanos , Lactante , Recién Nacido , Masculino , Plexo Mientérico/metabolismo , Células PC12 , Ratas , Ratas WistarRESUMEN
OBJECTIVE: Ganoderic Acid A (GAA), a primary bioactive component in Ganoderma, has demonstrated ameliorative effects on depressive-like behaviors in a Chronic Social Defeat Stress (CSDS) mouse model. This study aims to elucidate the underlying molecular mechanisms through proteomic analysis. METHODS: C57BL/6 J mice were allocated into control (CON), chronic social defeat stress (CSDS), GAA, and imipramine (IMI) groups. Post-depression induction via CSDS, the GAA and IMI groups received respective treatments of GAA (2.5 mg/kg) and imipramine (10 mg/kg) for five days. Behavioral assessments utilized standardized tests. Proteins from the prefrontal cortex were analyzed using LC-MS, with further examination via bioinformatics and PRM for differential expression. Western blot analysis confirmed protein expression levels. RESULTS: Chronic social defeat stress (CSDS) induced depressive-like behaviors in mice, which were significantly alleviated by GAA treatment, comparably to imipramine (IMI). Proteomic analysis identified distinct proteins in control (305), GAA-treated (949), and IMI-treated (289) groups. Enrichment in mitochondrial and synaptic proteins was evident from GO and PPI analyses. PRM analysis revealed significant expression changes in proteins crucial for mitochondrial and synaptic functions (namely, Naa30, Bnip1, Tubgcp4, Atxn3, Carmil1, Nup37, Apoh, Mrpl42, Tprkb, Acbd5, Dcx, Erbb4, Ppp1r2, Fam3c, Rnf112, and Cep41). Western blot validation in the prefrontal cortex showed increased levels of Mrpl42, Dcx, Fam3c, Ppp1r2, Rnf112, and Naa30 following GAA treatment. CONCLUSION: GAA exhibits potential antidepressant properties, with its action potentially tied to the modulation of synaptic functions and mitochondrial activities.
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Conducta Animal , Depresión , Modelos Animales de Enfermedad , Lanosterol , Ratones Endogámicos C57BL , Corteza Prefrontal , Proteómica , Derrota Social , Estrés Psicológico , Animales , Ratones , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Masculino , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Lanosterol/análogos & derivados , Lanosterol/farmacología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Imipramina/farmacología , Proteína Doblecortina , Ácidos HeptanoicosRESUMEN
Natural organic materials such as protein and carbohydrates are abundant in nature, renewable, and biodegradable, desirable for the construction of artificial synaptic devices for emerging neuromorphic computing systems with energy efficient operation and environmentally friendly disposal. These artificial synaptic devices are based on memristors or transistors with the memristive layer or gate dielectric formed by natural organic materials. The fundamental requirement for these synaptic devices is the ability to mimic the memory and learning behaviors of biological synapses. This paper reviews the synaptic functions emulated by a variety of artificial synaptic devices based on natural organic materials and provides a useful guidance for testing and investigating more of such devices.
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Memristors with nonvolatile storage performance and simulated synaptic functions are regarded as one of the critical devices to overcome the bottleneck in traditional von Neumann computer architecture. 2D van der Waals heterostructures have paved a new way for the development of advanced memristors by integrating the intriguing features of different materials and offering additional controllability over their optoelectronic properties. Herein, planar memristors with both electrical and optical tunability based on ReS2 /WS2 van der Waals heterostructure are demonstrated. The devices show unique unipolar nonvolatile behavior with high Roff /Ron ratio of up to 106 , desirable endurance, and retention, which are superior to pure ReS2 and WS2 devices. When decreasing the channel length, the set voltage can be notably reduced while the high Roff /Ron ratios are retained. By introducing electrostatic doping through the gate control, the set voltage can be tailored in a wide range from 4.50 to 0.40 V. Furthermore, biological synaptic functions and plasticity, including spike rate-dependent plasticity and paired-pulse facilitation, are successfully realized. By employing optical illumination, resistive switching can also be modulated, which is dependent on the illumination energy and power. A mechanism related to the interlayer charge transfer controlled by optical excitation is revealed.
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Alzheimer's disease (AD), a neurodegenerative disease, is characterized by the presence of extracellular amyloid-ß (Aß) aggregates and intracellular neurofibrillary tangles formed by hyperphosphorylated tau as pathological features and the cognitive decline as main clinical features. An important cellular correlation of cognitive decline in AD is synapse loss. Soluble Aß oligomer has been proposed to be a crucial early event leading to synapse dysfunction in AD. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function have been suggested in the pathogenesis of AD. Astrocytes may contribute to synapse dysfunction at an early stage of AD by participating in Aß metabolism, brain inflammatory response, and synaptic regulation. While mesenchymal stem cells can inhibit astrogliosis, and promote non-reactive astrocytes. They can also induce direct regeneration of neurons and synapses. This review describes the role of mesenchymal stem cells and underlying mechanisms in regulating astrocytes-related Aß metabolism, neuroinflammation, and synapse dysfunction in early AD, exploring the open questions in this field.
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Tremendous progress has been achieved on organic transistor-based photodetectors; however, because of the nonpositive correlation relationship between the photo/dark current ratio (P) and the gate voltage, the claimed best P, R (photoresponsivity), and D* (detectivity) can hardly be obtained simultaneously at a given gate voltage, which severely compromises the device performance. Here, a light and voltage dually gated transistor based on an organic semiconducting single crystal of 2,6-dithienylanthracene (DTAnt) is developed. Attributing to its very low on/off ratio in the dark and the remarkable increment of mobilities under illumination, this phototransistor shows good performance with a P of 3.83 × 103, R of 1.32 A W-1, and D* of 1.94 × 1012 Jones achieved simultaneously at Vg = -100 V. Besides, the good reversibility and repeatability of its light-responsive behavior allows for the construction of an artificial photonic neuromorphic device with demonstrated synaptic functions, including excitatory postsynaptic current, short/long-term memory , and pair-pulse facilitation/depression.
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Transient receptor potential melastatin-like 7 (TRPM7) has a unique dual protein structure. It is an ion channel that has biophysical characteristics enabling divalent cations transport and a kinase domain involved in molecular events starting from modulating signaling pathways to inducing chromatin remodeling. Over the past 15 years, significant progress in the molecular and functional characterization of TRPM7 has been made in peripheral tissue and/or cell lines. TRPM7 appears to be involved in a plethora of physiological and pathological processes including embryonic development, organogenesis, cell proliferation and survival, and cell death following certain triggers. In the post-mitotic neuronal cells, however, the functional role of TRPM7 remains unclear. Majority of the progress in this area of research has focused on the potential role of TRPM7 in mediating neuronal death following ischemia-like and neuronal injuries-like conditions. Here, we summarize major progress on the biological roles of the TRPM7 during development and in mitotic systems (cell lines). Then, we address the recent developments made in neuronal systems. Besides its role in neuronal death, we emphasize on direct and indirect evidences that could link TRPM7 to fundamental neurobiological processes such as synaptic transmission, synapse remodeling, plasticity, cognitive functions as well as to some mental disorders. Therefore, we propose that an equivalent effort is demanded to systematically characterize the role of TRPM7 in healthy neural system before presenting it as a potential molecular target to treat neurodegenerative disorders or to prevent neuronal death following ischemia and/or neuronal injuries.
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Encéfalo/metabolismo , Neuronas/metabolismo , Canales Catiónicos TRPM/metabolismo , Animales , Encéfalo/crecimiento & desarrollo , HumanosRESUMEN
Alzheimer's disease (AD) is the most common age-dependent disease of dementia, and there is currently no cure available. This hallmark pathologies of AD are the presence of amyloid plaques and neurofibrillary tangles. Although the exact etiology of AD remains a mystery, studies over the past 30 have shown that abnormal generation or accumulation of ß-amyloid peptides (Aß) is likely to be a predominant early event in AD pathological development. Aß is generated from amyloid precursor protein (APP) via proteolytic cleavage by ß-site APP cleaving enzyme 1 (BACE1). Chemical inhibition of BACE1 has been shown to reduce Aß in animal studies and in human trials. While BACE1 inhibitors are currently being tested in clinical trials to treat AD patients, it is highly important to understand whether BACE1 inhibition will significantly impact cognitive functions in AD patients. This review summarizes the recent studies on BACE1 synaptic functions. This knowledge will help to guide the proper use of BACE1 inhibitors in AD therapy.
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Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene account for approximately 95 % of all RTT cases. To model RTT in vitro, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of two RTT patients with different mutations (MECP2 (R306C) and MECP2 (1155Δ32)) in their MECP2 gene. We found that these iPSCs were capable of differentiating into functional neurons. Compared to control neurons, the RTT iPSC-derived cells had reduced soma size and a decreased amount of synaptic input, evident both as fewer Synapsin 1-positive puncta and a lower frequency of spontaneous excitatory postsynaptic currents. Supplementation of the culture media with choline rescued all of these defects. Choline supplementation may act through changes in the expression of choline acetyltransferase, an important enzyme in cholinergic signaling, and also through alterations in the lipid metabolite profiles of the RTT neurons. Our study elucidates the possible mechanistic pathways for the effect of choline on human RTT cell models, thereby illustrating the potential for using choline as a nutraceutical to treat RTT.