RESUMO
This article introduces a Combined .symmetrical and complementary Input Pairs (CIP) of a Differential Difference Amplifier (DDA), to boost the total Common-Mode Rejection Ratio (CMRR) for multi-channel neural signal recording. The proposed CIP-DDA employs three input pairs (transconductors). The dc-coupled input neural signal connection, via the gate terminal of the first transconductor, yields a high input impedance. The high-pass corner frequency and dc quiescent operation point are stabilized by the second transconductor. The calibration path of differential-mode gain and Common-Mode Feedback (CMFB) is provided by the proposed third transconductor. The parallel connection has no need for extra voltage headroom of input and output. The proposed CIP-DDA is targeted at integrated circuit realization and designed in a 0.18-µm CMOS technology. The proposed CIP-DDAs with system CMFB achieve an average CMRR of 103 dB, and each channel consumes circa 3.6 µW power consumption.
Assuntos
Ácido Aminossalicílico , Amplificadores Eletrônicos , Desenho de Equipamento , Retroalimentação , TecnologiaRESUMO
Cadmium (Cd) is a ubiquitous heavy metal with neurotoxicity. Our previous study reported that Cd could inhibit the proliferation of mouse neural stem cells (mNSCs). However, the underlying mechanisms are obscure. In recent years, the rapid growth of multi-omics techniques enables us to explore the cellular responses that occurred after toxicant exposure at the molecular level. In this study, we used a combination of metabolomics and transcriptomics approaches to investigate the effects of exposure to Cd on mNSCs. After treatment with Cd, the metabolites and transcripts in mNSCs changed significantly with 110 differentially expressed metabolites and 2135 differentially expressed genes identified, respectively. The altered metabolites were mainly involved in glycerophospholipid metabolism, arginine and proline metabolism, arginine biosynthesis, glyoxylate and dicarboxylate metabolism. Meanwhile, the transcriptomic data demonstrated perturbed membrane function and signal transduction. Furthermore, integrated analysis of metabolomic and transcriptomic data suggested that glycerophospholipid metabolism might be the major metabolic pathway affected by Cd in mNSCs. More interestingly, the supplementation of lysophosphatidylethanolamine (LPE) attenuated Cd-induced mitochondrial impairment and the inhibition of cell proliferation and differentiation in mNSCs, further supporting our analysis. Overall, the study provides new insights into the mechanisms of Cd-induced neurotoxicity.
Assuntos
Cádmio , Síndromes Neurotóxicas , Animais , Camundongos , Cádmio/toxicidade , Transcriptoma , Metabolômica , Arginina , GlicerofosfolipídeosRESUMO
RNA-binding proteins (RBPs) play essential roles in tumorigenesis and progression, but their functions in gastric cancer (GC) remain largely elusive. Here, it is reported that Pumilio 1 (PUM1), an RBP, induces metabolic reprogramming through post-transcriptional regulation of DEP domain-containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) in GC. In clinical samples, elevated expression of PUM1 is associated with recurrence, metastasis, and poor survival. In vitro and in vivo experiments demonstrate that knockdown of PUM1 inhibits the proliferation and metastasis of GC cells. In addition, RNA-sequencing and bioinformatics analyses show that PUM1 is enriched in the glycolysis gene signature. Metabolomics studies confirm that PUM1 deficiency suppresses glycolytic metabolism. Mechanistically, PUM1 binds directly to DEPTOR mRNA pumilio response element to maintain the stability of the transcript and prevent DEPTOR degradation through post-transcriptional pathway. PUM1-mediated DEPTOR upregulation inhibits mTORC1 and alleviates the inhibitory feedback signal transmitted from mTORC1 to PI3K under normal conditions, thus activating the PI3K-Akt signal and glycolysis continuously. Collectively, these results reveal the critical epigenetic role of PUM1 in modulating DEPTOR-dependent GC progression. These conclusions support further clinical investigation of PUM1 inhibitors as a metabolic-targeting treatment strategy for GC.
Assuntos
Transdução de Sinais , Neoplasias Gástricas , Humanos , Fosfatidilinositol 3-Quinases , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Gástricas/genética , Serina-Treonina Quinases TOR/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
Complete tumor regression is a great challenge faced by single therapy of near-infrared (NIR)-triggered hyperthermia or vascular disrupting agents. An injectable nanocomposite (NC) hydrogel is rationally designed for combined anticancer therapy based on NIR-triggered hyperthermia and vascular disruption. The NC hydrogel, codelivered with Prussian blue (PB) nanoparticles and combretastatin A4 (CA4), has good shear-thinning, self-recovery, and excellent photothermal properties. Because of the remarkable tumor-site retention and sustained release of CA4 (about 10% over 12 days), the NC hydrogel has a tumor suppression rate of 99.6%. The programmed combinational therapy conveys the concept of "attack + guard", where PB-based NIR irradiation imposes intensive attack on most of cancer cells, and CA4 serves as a guard against the tumor growth by cutting off the energy supply. Moreover, the biosafety and eco-friendliness of the hydrogel platform pave the way toward clinical applications.
Assuntos
Hidrogéis/química , Nanocompostos/química , Animais , Linhagem Celular Tumoral , Feminino , Ferrocianetos/química , Humanos , Hipertermia Induzida , Camundongos Endogâmicos BALB C , Nanopartículas/química , Estilbenos/químicaRESUMO
Injectable nanocomposite hydrogels containing small copper sulfide nanoparticles (6-8 nm) with a 54.6% photothermal conversion efficiency have been facilely prepared by applying an upper critical solution temperature (UCST)-type biopolymer gellan. This minimally invasive formulation ablates cancer completely in vivo after NIR-triggered chemo-photothermal therapy.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/terapia , Cobre/uso terapêutico , Doxorrubicina/uso terapêutico , Hidrogéis/uso terapêutico , Nanocompostos/uso terapêutico , Polissacarídeos Bacterianos/uso terapêutico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Terapia Combinada/métodos , Cobre/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Hidrogéis/administração & dosagem , Hipertermia Induzida/métodos , Injeções , Camundongos , Nanocompostos/administração & dosagem , Fototerapia/métodos , Polissacarídeos Bacterianos/administração & dosagem , TemperaturaRESUMO
OBJECTIVE: To study the 1-bromopropane (1-BP)-induced altered gene expression profiles in rat gonad, and explore its male reproductive toxicity-related mRNA changes. METHODS: Twelve F344/NSIc male rats were randomly divided into two groups of 6 each. Rats were exposed to either fresh air or 5030 mg/m3 1-BP through inhalation for 8 h. Rats were sacrificed and testes were removed at 16 h after exposure. Global changes in gene expression were determined by microarray analysis using rat genital chip followed by Real-time PCR validation. RESULTS: Among the 5082 genes and ESTs in the genital chip, 62 genes were down-regulated and 3 genes were up-regulated by 1-BP, which include synthetic sex hormone-related genes cytochrome P450 aromatase (CYP19a), glutathione S-transferase (GSTT1), creatine kinase (Ckb), myelin and lymphocyte protein (Mal) and S100 calcium-binding protein (S100a4). Classification analysis revealed that the majority of gene changes was involved protein/lipid metabolism, followed by the stress-associated defense response. Real-time PCR confirmed the down-regulation of CYP19a, GSTT1, Mal and S100a4 genes. CONCLUSION: Acute high-dose exposure to 1-BP causes the down-regulation of testicular CYP19a, S100a4, GSTT1 and Mal. This altered gene profiles might reflect the toxic mechanism which suggested that 1-BP disrupt the metabolics and endocrine balance.
Assuntos
Exposição Ambiental/efeitos adversos , Perfilação da Expressão Gênica , Testículo/metabolismo , Animais , Aromatase/genética , Aromatase/metabolismo , Regulação para Baixo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Hidrocarbonetos Bromados/toxicidade , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase em Tempo RealRESUMO
The changes of N-methyl-D-aspartate (NMDA) receptor and protective efficacy of memantine (MEM) in rats poisoned with dichlorvos were studied. Dichlorvos evoked down-regulation of the affinity and density of [(3)H]MK-801 binding to NMDA receptor in the brain of rats receiving dichlorvos (15 and 25 mg/kg bw, i.p.). The binding capacity of NMDA receptor and acetylcholinesterase activity were determined at 4 h, 8 h, 16 h, 24 h and 48 h after treatment. When rats were given a different doses of MEM (5, 15 and 45 mg/kg bw) after poisoning (dichlorvos 25 mg/kg bw), the latency of onset of signs was postponed and the magnitude of muscular fasciculation was alleviated as the dose of MEM increased. The lower doses of MEM (5 and 15 mg/kg bw) could antagonize the dichlorvos-evoked down-regulation of NMDA receptor, while the highest dose (45 mg/kg bw) decreased the Bmax and Kd values of NMDA receptors. These results show the dichlorvos-evoked down-regulation of NMDA receptor might be self-regulation by the body to protect the central nervous system. MEM could antagonize the down-regulation of NMDA receptors, and alleviated signs of poisoning, especially reducing the magnitude of muscular fasciculation. We suggest that the role of NMDA receptor in organophosphates (OP) poisoning should receive more attention, and, that MEM treatment in acute OP poisoning, as a supplement to atropine and oxime, should be considered.