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1.
Anticancer Drugs ; 32(9): 950-961, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34016832

RESUMO

This study aims to explore the biological actions of circular RNA (circRNA) ArfGAP with SH3 domain, ankyrin repeat and PH domain 2 (circ_ASAP2, circ_0006089) in cisplatin (DDP) resistance of gastric cancer. Circ_ASAP2, ecto-5'-nucleotidase (NT5E) and miR-330-3p were quantified by quantitative real-time PCR or western blot. The measurements of the IC50 value and cell proliferation were done using 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay. Cell colony formation, cell cycle distribution, apoptosis, migration and invasion were evaluated by the colony formation, flow cytometry and transwell assays. Dual-luciferase reporter assay was performed to confirm the targeted relationship between different molecules. The role of circ_ASAP2 in tumor growth was gauged by in vivo animal studies. Circ_ASAP2 and NT5E were overexpressed in DDP-resistant gastric cancer tissues and cells. Knockdown of circ_ASAP2 promoted DDP sensitivity, apoptosis and repressed proliferation, migration and invasion of DDP-resistant gastric cancer cells in vitro and diminished tumor growth in vivo. Moreover, NT5E was a downstream effector of circ_ASAP2 in regulating cell DDP sensitivity and functional behaviors. Mechanistically, circ_ASAP2 directly bound to miR-330-3p to promote NT5E expression. Furthermore, circ_ASAP2 modulated cell DDP sensitivity and functional behaviors by targeting miR-330-3p. Knockdown of circ_ASAP2 promoted DDP sensitivity and suppressed malignant behaviors of DDP-resistant gastric cancer cells through targeting the miR-330-3p/NT5E axis.

2.
Neuron ; 107(5): 909-923.e6, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32649865

RESUMO

The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the spinoparabrachial pathway underlying its functional role in nociceptive information processing remains elusive. Here, we report that the PBN directly relays nociceptive signals from the spinal cord to the intralaminar thalamic nuclei (ILN). We demonstrate that the spinal cord connects with the PBN in a bilateral manner and that the ipsilateral spinoparabrachial pathway is critical for nocifensive behavior. We identify Tacr1-expressing neurons as the major neuronal subtype in the PBN that receives direct spinal input and show that these neurons are critical for processing nociceptive information. Furthermore, PBN neurons receiving spinal input form functional monosynaptic excitatory connections with neurons in the ILN, but not the amygdala. Together, our results delineate the neural circuit underlying nocifensive behavior, providing crucial insight into the circuit mechanism underlying nociceptive information processing.


Assuntos
Vias Aferentes , Lateralidade Funcional/fisiologia , Núcleos Intralaminares do Tálamo , Nociceptividade/fisiologia , Núcleos Parabraquiais , Vias Aferentes/citologia , Vias Aferentes/fisiologia , Tonsila do Cerebelo , Animais , Núcleos Intralaminares do Tálamo/citologia , Núcleos Intralaminares do Tálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/fisiologia , Núcleos Parabraquiais/citologia , Núcleos Parabraquiais/fisiologia , Medula Espinal/citologia , Medula Espinal/fisiologia
3.
J Hazard Mater ; 398: 122936, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-32512450

RESUMO

Lead pipe has been banned in the drinking water distribution system in most countries since 1980s. Although water authorities around the world have attempted to replace all remaining lead pipes in service, pipe replacement was often hindered by high cost and lack of access to private premises. Hence, partial replacement has become a common scenario where portions of lead pipes remain in the system. When the lead pipe is connected to two other different metallic materials at both ends, two different galvanic couples can form simultaneously in this three-metal system. The release of lead resulting from galvanic corrosion in such three-metal systems consisting of lead (Pb), copper (Cu) and stainless steel (SS) with three different configurations, namely Cu-SS-Pb, SS-Cu-Pb and Cu-Pb-SS was investigated in this study. The results showed that when the materials are arranged in order of reduction potential as in SS-Cu-Pb configuration, lead release was the highest. A more fluent electron transport across the system was proposed based on the direction and magnitude of galvanic currents measured at each galvanic couple.


Assuntos
Água Potável , Poluentes Químicos da Água , Cobre/análise , Corrosão , Chumbo , Aço Inoxidável , Poluentes Químicos da Água/análise , Abastecimento de Água
4.
Neurobiol Dis ; 130: 104486, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31150793

RESUMO

Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that the male Cntnap3-null mice exhibited deficits in social interaction, spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing mechanistic insights into ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/genética , Comportamento Social , Animais , Comportamento Animal , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Sinapses
5.
J Neurosci ; 39(3): 456-471, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30459220

RESUMO

AGRP (agouti-related neuropeptide) expressing inhibitory neurons sense caloric needs of an animal to coordinate homeostatic feeding. Recent evidence suggests that AGRP neurons also suppress competing actions and motivations to mediate adaptive behavioral selection during starvation. Here, in adult mice of both sexes we show that AGRP neurons form inhibitory synapses onto ∼30% neurons in the medial preoptic area (mPOA), a region critical for maternal care. Remarkably, optogenetically stimulating AGRP neurons decreases maternal nest-building while minimally affecting pup retrieval, partly recapitulating suppression of maternal behaviors during food restriction. In parallel, optogenetically stimulating AGRP projections to the mPOA or to the paraventricular nucleus of hypothalamus but not to the LHA (lateral hypothalamus area) similarly decreases maternal nest-building. Chemogenetic inhibition of mPOA neurons that express Vgat (vesicular GABA transporter), the population targeted by AGRP terminals, also decreases maternal nest-building. In comparison, chemogenetic inhibition of neurons in the LHA that express vesicular glutamate transporter 2, another hypothalamic neuronal population critical for feeding and innate drives, is ineffective. Importantly, nest-building during low temperature thermal challenge is not affected by optogenetic stimulation of AGRP→mPOA projections. Finally, via optogenetic activation and inhibition we show that distinctive subsets of mPOA Vgat+ neurons likely underlie pup retrieval and maternal nest-building. Together, these results show that AGRP neurons can modulate maternal nest-building, in part through direct projections to the mPOA. This study corroborates other recent discoveries and underscores the broad functions that AGRP neurons play in antagonizing rivalry motivations to modulate behavioral outputs during hunger.SIGNIFICANCE STATEMENT In order for animals to initiate ethologically appropriate behaviors, they must typically decide between behavioral repertoires driven by multiple and often conflicting internal states. How neural pathways underlying individual behaviors interact to coherently modulate behavioral outputs, in particular to achieve a proper balance between behaviors that serve immediate individual needs versus those that benefit the propagation of the species, remains poorly understood. Here, by investigating projections from a neuronal population known to drive hunger behaviors to a brain region critical for maternal care, we show that activation of AGRP→mPOA projections in females dramatically inhibits maternal nest-building while leaving mostly intact pup retrieval behavior. Our findings shed new light on neural organization of behaviors and neural mechanisms that coordinate behavioral selection.


Assuntos
Proteína Relacionada com Agouti/fisiologia , Comportamento Materno/fisiologia , Rede Nervosa/fisiologia , Comportamento de Nidação/fisiologia , Neurônios/fisiologia , Área Pré-Óptica/fisiologia , Proteína Relacionada com Agouti/genética , Animais , Temperatura Baixa , Feminino , Privação de Alimentos , Região Hipotalâmica Lateral/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Optogenética , Núcleo Hipotalâmico Paraventricular/fisiologia , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo
6.
Neuron ; 101(1): 45-59.e9, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30554781

RESUMO

Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.


Assuntos
Neurocinina A/biossíntese , Neurônios/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Prurido/metabolismo , Tratos Piramidais/metabolismo , Receptores da Neurocinina-1/biossíntese , Animais , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurocinina A/genética , Neurônios/química , Substância Cinzenta Periaquedutal/química , Prurido/patologia , Tratos Piramidais/química , Distribuição Aleatória , Receptores da Neurocinina-1/genética , Taquicininas/biossíntese , Taquicininas/genética
7.
Oncol Res ; 27(2): 139-146, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29471888

RESUMO

Inhibition of tumor metastasis is one of the most important purposes in colorectal cancer (CRC) treatment. This study aimed to explore the effects of liquiritigenin, a flavonoid extracted from the roots of Glycyrrhiza uralensis Fisch, on HCT116 cell proliferation, invasion, and epithelial-to-mesenchymal transition (EMT). We found that liquiritigenin significantly inhibited HCT116 cell proliferation, invasion, and the EMT process, but had no influence on cell apoptosis. Moreover, liquiritigenin remarkably reduced the expression of runt-related transcription factor 2 (Runx2) in HCT116 cells. Overexpression of Runx2 obviously reversed the liquiritigenin-induced invasion and EMT inhibition. Furthermore, liquiritigenin inactivated the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway in HCT116 cells. Upregulation of Runx2 reversed the liquiritigenin-induced PI3K/AKT pathway inactivation. In conclusion, our research verified that liquiritigenin exerted significant inhibitory effects on CRC invasion and EMT process by downregulating the expression of Runx2 and inactivating the PI3K/AKT signaling pathway. Liquiritigenin could be an effective therapeutic and preventative medicine for CRC treatment.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Subunidade alfa 1 de Fator de Ligação ao Core/antagonistas & inibidores , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Flavanonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Subunidade alfa 1 de Fator de Ligação ao Core/fisiologia , Células HCT116 , Humanos , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/fisiologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/efeitos dos fármacos
8.
Nat Commun ; 9(1): 279, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29348568

RESUMO

The medial preoptic area (mPOA) differs between males and females in nearly all species examined to date, including humans. Here, using fiber photometry recordings of Ca2+ transients in freely behaving mice, we show ramping activities in the mPOA that precede and correlate with sexually dimorphic display of male-typical mounting and female-typical pup retrieval. Strikingly, optogenetic stimulation of the mPOA elicits similar display of mounting and pup retrieval in both males and females. Furthermore, by means of recording, ablation, optogenetic activation, and inhibition, we show mPOA neurons expressing estrogen receptor alpha (Esr1) are essential for the sexually biased display of these behaviors. Together, these results underscore the shared layout of the brain that can mediate sex-specific behaviors in both male and female mice and provide an important functional frame to decode neural mechanisms governing sexually dimorphic behaviors in the future.


Assuntos
Encéfalo/fisiologia , Neurônios/fisiologia , Área Pré-Óptica/fisiologia , Comportamento Sexual Animal , Animais , Encéfalo/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Optogenética/métodos , Área Pré-Óptica/metabolismo , Fatores Sexuais
9.
Proc Natl Acad Sci U S A ; 114(8): 2042-2047, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28053227

RESUMO

The homeostatic control of body temperature is essential for survival in mammals and is known to be regulated in part by temperature-sensitive neurons in the hypothalamus. However, the specific neural pathways and corresponding neural populations have not been fully elucidated. To identify these pathways, we used cFos staining to identify neurons that are activated by a thermal challenge and found induced expression in subsets of neurons within the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial hypothalamus (DMD). Activation of GABAergic neurons in the vLPO using optogenetics reduced body temperature, along with a decrease in physical activity. Optogenetic inhibition of these neurons resulted in fever-level hyperthermia. These GABAergic neurons project from the vLPO to the DMD and optogenetic stimulation of the nerve terminals in the DMD also reduced body temperature and activity. Electrophysiological recording revealed that the vLPO GABAergic neurons suppressed neural activity in DMD neurons, and fiber photometry of calcium transients revealed that DMD neurons were activated by cold. Accordingly, activation of DMD neurons using designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics increased body temperature with a strong increase in energy expenditure and activity. Finally, optogenetic inhibition of DMD neurons triggered hypothermia, similar to stimulation of the GABAergic neurons in the vLPO. Thus, vLPO GABAergic neurons suppressed the thermogenic effect of DMD neurons. In aggregate, our data identify vLPO→DMD neural pathways that reduce core temperature in response to a thermal challenge, and we show that outputs from the DMD can induce activity-induced thermogenesis.


Assuntos
Núcleo Hipotalâmico Dorsomedial/fisiologia , Neurônios GABAérgicos/fisiologia , Vias Neurais/fisiologia , Área Pré-Óptica/fisiologia , Termogênese/fisiologia , Animais , Cálcio/metabolismo , Temperatura Baixa , Fenômenos Eletrofisiológicos , Temperatura Alta , Hipotermia/fisiopatologia , Imuno-Histoquímica , Camundongos , Fotometria , Proteínas Proto-Oncogênicas c-fos/metabolismo
10.
J Biol Chem ; 288(15): 10361-73, 2013 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-23430746

RESUMO

Pro-opiomelanocortin (POMC) is a common precursor of melanocortin-related peptides in the pituitary and primarily regulated by corticotropin- releasing factor (CRF). Our results show that miR-375 is highly expressed in the mouse pituitary gland and located specifically in the intermediate lobe of pituitary. The functional studies show that the forced inhibition of endogenous miR-375 in AtT-20 mouse pituitary tumor cells and in the intermediate lobe of the pituitary gland significantly increases POMC expression, whereas miR-375 overexpression down-regulates POMC expression and ACTH secretion stimulated by CRF. This function of miR-375 is accomplished by its binding to the 3'-UTR of mitogen-activated protein kinase kinase kinase-8. Our results here have demonstrated that miR-375 acts as a negative regulating molecule mediating the signaling pathway of CRF and affecting POMC expression by targeting mitogen-activated protein kinase kinase kinase-8, which subsequently down-regulates ERK1/2 phosphorylation and nerve growth factor-induced clone B (NGFI-B) transcription activity. Taken together, our results show that miR-375 is a novel negative regulator of POMC expression and related hormone secretion.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Regulação da Expressão Gênica/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , MicroRNAs/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Hipófise/metabolismo , Pró-Opiomelanocortina/biossíntese , Animais , Linhagem Celular Tumoral , Hormônio Liberador da Corticotropina/genética , Feminino , Masculino , Camundongos , MicroRNAs/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fosforilação/fisiologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Pró-Opiomelanocortina/genética
11.
Front Biosci (Landmark Ed) ; 18: 588-97, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23276944

RESUMO

Although microRNAs (miRNAs) have been implicated in fine-tuning gene networks, the roles of mmu-mir-143 (miR-143) in mammalian ovary development have not been studied in vitro. We investigated the expression and function of miR-143 in the mouse ovary during primordial follicle formation. Real-time polymerase chain reaction analysis showed that miR-143 expression increased during primordial follicle formation from 15.5 days post-coitus to 4 days post-partum. miR-143 was located in pregranulosa cells by in situ hybridization. To study the function of miR-143 in primordial follicle formation we established an electroporation transfection model in vitro that allowed miR-143 expression to be efficiently upregulated and inhibited in cultured ovaries. Further studies showed that miR-143 inhibited the formation of primordial follicles by suppressing pregranulosa cell proliferation and downregulating the expression of genes related to the cell cycle. These findings suggest that miR-143 is critical for the formation of primordial follicles and regulates ovarian development and function.


Assuntos
MicroRNAs/fisiologia , Folículo Ovariano/fisiologia , Animais , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/efeitos dos fármacos , Feminino , Masculino , Camundongos , MicroRNAs/biossíntese , Folículo Ovariano/efeitos dos fármacos , Ovário/crescimento & desenvolvimento
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