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Ischemic stroke is one of the main causes of disability and death. However, recanalization of occluded cerebral arteries is effective only within a very narrow time window. Therefore, it is particularly important to find neuroprotective biological targets for cerebral artery recanalization. Here, gene expression profiles of datasets GSE160500 and GSE97537 were downloaded from the GEO database, which were related to ischemic stroke in rats. Olfactory receptor 78 (Olfr78) was screened, and which highly associated with Calcium signalling pathway and MAPK pathway. Interacting protein of Olfr78, Prkaca, was predicted by STRING, and their interaction was validated by Co-IP analysis. Then, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a neuronal cell model stimulated by oxygen-glucose deprivation/reoxygenation (OGD/R) were constructed, and the results showed that expression of Olfr78 and Prkaca was downregulated in MCAO rats and OGD/R-stimulated neurons. Overexpression of Olfr78 or Prkaca inhibited the secretion of inflammatory factors, Ca2+ overload, and OGD/R-induced neuronal apoptosis. Moreover, Overexpression of Prkaca increased protein levels of cAMP, PKA and phosphorylated p38 in OGD/R-stimulated neurons, while SB203580, a p38 inhibitor, treatment inhibited activation of the cAMP/PKA-MAPK pathway and counteracted the effect of Olfr78 overexpression on improvement of neuronal functions. Meanwhile, overexpression of Olfr78 or Prkaca markedly inhibited neuronal apoptosis and improved brain injury in MCAO/R rats. In conclusion, overexpression of Olfr78 inhibited Ca2+ overload and reduced neuronal apoptosis in MCAO/R rats by promoting Prkaca-mediated activation of the cAMP/PKA-MAPK pathway, thereby improving brain injury in cerebral ischaemia-reperfusion.
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Apoptose , AMP Cíclico , Ratos Sprague-Dawley , Receptores Odorantes , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/genética , Ratos , Masculino , AMP Cíclico/metabolismo , Receptores Odorantes/metabolismo , Receptores Odorantes/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Lesões Encefálicas/metabolismo , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Neurônios/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Transdução de SinaisRESUMO
Burn injury is a serious traumatic injury that leads to severe physical and psychosocial impairment. Wound healing after burn injury is a substantial challenge in medical community. This study investigated the biological effects of the demethylase fat mass and obesity-associated protein (FTO) on burn injury. FTO protein level in burn skin tissues of patients was measured with Western blot assay. Keratinocytes (HaCaT cells) were given heat stimulation to induce an in vitro burn injury model, and then transfected with overexpression plasmids of FTO (pcDNA-FTO) or small interfering RNA against FTO (si-FTO). Cell proliferation, migration, and angiogenesis in keratinocytes were evaluated with CCK-8, Transwell, and tube formation assays, respectively. Tissue factor pathway inhibitor-2 (TFPI-2) m6A methylation level was detected with MeRIPqPCR assay. Then rescue experiments were conducted to explore the effects of FTO/TFPI-2 axis on keratinocyte functions. Lentivirus carrying FTO overexpression plasmids was injected into a burn rat model to detect its effects on wound healing and depressive-like behaviors in burn rats. FTO was downregulated in burn skin and heat-stimulated keratinocytes. FTO prominently augmented proliferation, migration and angiogenesis in heat-stimulated keratinocytes, while FTO knockdown showed the opposite results. FTO inhibited TFPI-2 expression by FTO-mediated m6A methylation modification. TFPI-2 overexpression abrogated FTO mediated enhancement of proliferation, migration and angiogenesis in keratinocytes. Additionally, FTO overexpression accelerated wound healing and improved depressive-like behaviors in burn rat model. FTO prominently augmented proliferation, migration and angiogenesis in heat-stimulated keratinocytes though inhibiting TFPI-2, and then improved wound healing and depressive-like behaviors.
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Angiogênese , Queimaduras , Glicoproteínas , Animais , Humanos , Ratos , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Queimaduras/genética , Proliferação de Células , Desmetilação , Depressão/genética , Queratinócitos , CicatrizaçãoRESUMO
BACKGROUND: Pseudostellaria heterophylla is a Chinese medicine and healthy edible that is widely used to for its immunomodulatory, antioxidant, antidiabetic and antitussive properties. However, the potential function of P. heterophylla in intestinal microecology remains unclear. In this study, we investigated the impact of P. heterophylla on immune functions and evaluated its potential to regulate the gut microbiota and metabolome. RESULTS: The results showed that P. heterophylla significantly increased the content of red blood cells, total antioxidant capacity and expression of immune factors, and decreased platelet counts when compared to the control under cyclophosphamide injury. In addition, P. heterophylla altered the diversity and composition of the gut bacterial community; increased the abundance of potentially beneficial Akkermansia, Roseburia, unclassified Clostridiaceae, Mucispirillum, Anaeroplasma and Parabacteroides; and decreased the relative abundance of pathogenic Cupriavidus and Staphylococcus in healthy mice. Metabolomic analyses showed that P. heterophylla significantly increased the content of functional oligosaccharides, common oligosaccharides, vitamins and functional substances. Probiotics and pathogens were regulated by metabolites across 11 pathways in the bacterial-host co-metabolism network. CONCLUSION: We demonstrated that P. heterophylla increased the abundance of probiotics and decreased pathogens, and further stimulated host microbes to produce beneficial secondary metabolites for host health. Our studies highlight the role of P. heterophylla in gut health and provide new insights for the development of traditional Chinese medicine in the diet. © 2024 Society of Chemical Industry.
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Bactérias , Microbioma Gastrointestinal , Animais , Camundongos , Bactérias/classificação , Bactérias/metabolismo , Bactérias/genética , Bactérias/isolamento & purificação , Intestinos/microbiologia , Masculino , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/metabolismo , Metaboloma , HumanosRESUMO
Hole-transporting materials (HTMs) are crucial for obtaining the stability and high efficiency of perovskite solar cells (PSCs). However, the current state-of-the-art n-i-p PSCs relied on the use of 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro-OMeTAD) exhibit inferior intrinsic and ambient stability due to the p-dopant and hydrophilic Li-TFSI additive. In this study, a new spiro-type HTM with a critical quasi-planar core (Z-W-03) is developed to improve both the thermal and ambient stability of PSCs. The results suggest that the planar carbazole structure effectively passivates the trap states compared to the triphenylamine with a propeller-like conformation in spiro-OMeTAD. This passivation effect leads to the shallower trap states when the quasi-planar HTMs interact with the Pb-dimer. Consequently, the device using Z-W-03 achieves a higher Voc of 1.178 V compared to the spiro-OMeTAD's 1.155 V, resulting in an enhanced efficiency of 24.02%. In addition, the double-column π-π stacking of Z-W-03 results in high hole mobility (~10-4 cm2 V-1 s-1) even without p-dopant. Moreover, when the surface interface is modified, the undoped Z-W-03 device can achieve an efficiency of nearly 23%. Compared to the PSCs using spiro-OMeTAD, those with Z-W-03 exhibit enhanced stability under N2 and ambient conditions.
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OBJECTIVES: We systematically reviewed published clinical trials to evaluate the effectiveness of virtual reality (VR) technology on functional improvement, pain relief, and reduction of mental distress among burn patients undergoing rehabilitation. DATA SOURCES: Systematic searches were conducted in 4 databases, including PubMed, the Cochrane Library, Embase, and Web of Science, from inception to August 2021. STUDY SELECTION: Randomized controlled trials (RCTs) evaluating any type of VR for the rehabilitation in burn patients with dysfunction were included. DATA EXTRACTION: Two reviewers evaluated the eligibility, and another 2 reviewers used the Cochrane risk of bias assessment tool to assess the risk of bias. The extracted data included the main results of rehabilitation evaluation (quality of life [QOL], work performance, range of motion [ROM] of joints, hand grip and pinch strength, pain, fun, anxiety), the application performance of VR (realness and presence), adverse effects (fatigue and nausea), and characteristics of the included studies. Heterogeneity was evaluated using the chi-square tests and I2 statistics. Random- or fixed-effects models were conducted to pool the effect sizes expressed as standardized mean differences (SMDs). DATA SYNTHESIS: Sixteen RCTs with 535 burn patients were included. VR-based interventions were superior to usual rehabilitation in QOL and work performance of burn patients and produced positive effect on the average gain of ROM (SMD=0.72) as well. VR was not associated with improved hand grip and pinch strength (SMD=0.50, 1.22, respectively) but was associated with reduced intensity, affective, and cognitive components of pain (SMD=-1.26, -0.71, -1.01, respectively) compared with control conditions. Ratings of fun in rehabilitation therapy were higher (SMD=2.38), and anxiety scores were lower (SMD=-0.73) than in control conditions. CONCLUSIONS: VR-based burn rehabilitation significantly improves the QOL and work performance of burn patients, increases the ROM gain in the joints, reduces the intensity and unpleasantness of pain and the time spent thinking about pain, increases the fun in the rehabilitation therapy, reduces the anxiety caused by the treatment, and has no obvious adverse effects. However, it did not significantly improve hand grip or pinch strength.
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Queimaduras , Realidade Virtual , Humanos , Queimaduras/reabilitação , Dor , Manejo da Dor/métodos , Qualidade de VidaRESUMO
BACKGROUND: BRCA1 associated protein (BRAP) participates in the regulation of myocardial infarction and atherosclerosis. But the function of BRAP in cerebral ischemia-reperfusion (CIR) injury has not been elucidated yet. METHODS: BRAP expression in PC12 cells in response to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment was examined with Western blot assay. PC12 cells underwent OGD/R-treatment and were subsequently transfected with pcDNA-BRAP or sh-BRAP, followed by determination of viability, lactate dehydrogenase (LDH) production, apoptosis, inflammatory cytokine secretion, and oxidative stress marker protein levels. Paraoxonase 1 (PON1) promoter methylation was evaluated with methylation-specific PCR assay. the effect of BRAP/PON1 axis on CIR injury was investigated by rescue experiments. Additionally, sh-BRAP was injected into a middle cerebral artery occlusion (MCAO) rat model, and the changes of neurological damage were evaluated. RESULTS: BRAP overexpression exacerbated OGD/R-induced viability reduction, LDH production, apoptosis, inflammatory cytokine secretion and oxidative stress in PC12 neuronal cells. In contrast, BRAP silencing showed the opposite results. Mechanistically, BRAP reduced PON1 expression by promoting DNA methyl transferase1 (DNMT1)-mediated PON1 promoter methylation. PON1 silencing reversed BRAP-mediated neuroprotection. Additionally, BRAP silencing alleviated CIR-induced neurological damage in MCAO rats. CONCLUSION: BRAP silencing suppressed OGD/R-induced neuronal apoptosis, inflammation, and oxidative stress, and alleviated CIR-induced neurological damage in MCAO rats through facilitating PON1 expression.
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Arildialquilfosfatase , Traumatismo por Reperfusão , Ubiquitina-Proteína Ligases , Animais , Ratos , Apoptose/genética , Arildialquilfosfatase/genética , Arildialquilfosfatase/metabolismo , Citocinas/metabolismo , Glucose/farmacologia , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/genética , Estresse Oxidativo , Oxigênio/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
OBJECTIVE: To explore the optimal cut-off value of serum procalcitonin (PCT) level in predicting bacterial infection in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: 204 hospitalized patients with AECOPD were enrolled in this study. Their diagnoses and treatments followed routine protocols in Fu-Xing Hospital affiliated to Capital Medical University, Beijing, China. Extra blood samples were taken for serum PCT level testing and the results were blinded to the treating physicians. On discharge, clinical data were collected and the treating physicians made comprehensive analyses to determine whether the AECOPD were triggered by respiratory tract bacterial infection or non-bacterial causes according to the "new diagnostic criteria" defined in this study. In the AECOPD patients with bacterial infection, treating physicians decided whether they had bacterial pneumonia based on imaging studies. Receiver operating characteristic curve (ROC) was used to analyze the accuracy of serum PCT level in predicting bacterial infection. RESULTS: In the 173 AECOPD patients who did not have pneumonia, 115 had evidences of bacterial infection while 58 did not. The median PCT levels were 0.1(0.08, 0.18) ng/ml and 0.07 (0.05, 0.08) ng/ml for each group, which were statistically different. The proposed optimal cut-off value of serum PCT level in predicting bacterial infection was 0.08 ng/mL according to this study, with a sensitivity of 81%, specificity of 67% and area under the ROC curve (AUC) of 0.794. There were 31 AECOPD patients diagnosed with pneumonia, their median PCT level was 0.23 ng/mL. CONCLUSIONS: The serum PCT levels slightly increased in the majority of hospitalized patients with AECOPD compared with reference range. When PCT level was ≥0.08 ng/mL, AECOPD was more likely to be caused by bacterial infection. A significantly elevated PCT levels may indicate combination of AECOPD and bacterial pneumonia.
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Pneumonia Bacteriana , Pró-Calcitonina , Doença Pulmonar Obstrutiva Crônica , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Humanos , Pneumonia Bacteriana/sangue , Pneumonia Bacteriana/diagnóstico , Pró-Calcitonina/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Curva ROCRESUMO
Glucose is an essential source of energy production for animal cells. The importance of glucose metabolism in oocyte maturation has been studied extensively in mammals. However, such roles in non-mammalian species are still largely unknown. Here, we used zebrafish as a model, which is phylogenetically distant from mammals, and analyzed the role of glucose metabolism in oocyte maturation. Major glucose transporters (GLUT/Slc2A) were analyzed in zebrafish, two Slc2a1 (Slc2a1a and Slc2a1b), one Slc2a2, and two Slc2a3 (Slc2a3a and Slc2a3b) were identified. Among these five Slc2a genes, slc2a1b exhibited the highest expression level in fully grown follicles. The expression of slc2a1b gradually increased during folliculogenesis, and also significantly increases during the oocyte maturation process. Consistently, the glucose concentration increases during natural oocyte maturation. By using a fluorescent glucose derivative (6-NBDG) to trace glucose transport, the uptake of glucose by ovarian follicles in a time-dependent manner could be observed. Intriguingly, by treatment of glucose in vitro, oocyte maturation could be induced in a time-, dose- and stage-dependent manner. Glucose can be metabolized by glycolysis, the pentose phosphate pathway (PPP), the hexosamine biosynthesis pathway (HBP), and the polyol pathway. Using the inhibitors for these pathways, we found only PPP but not glycolysis, HBP or polyol pathway is essential for oocyte maturation. All these results clearly demonstrate for the first time that the glucose metabolism is required for oocyte maturation of zebrafish, suggesting the highly conserved role of glucose metabolism in control of oocyte maturation between fish and mammals.
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Diferenciação Celular , Glucose/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Animais , Feminino , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Folículo Ovariano/citologia , Folículo Ovariano/metabolismo , Via de Pentose Fosfato , Peixe-ZebraRESUMO
As in other vertebrates, fish reproduction is tightly controlled by gonadotropin signaling. One of the most perplexing aspects of gonadotropin action on germ cell biology is the restricted expression of gonadotropin receptors in somatic cells of the gonads. Therefore, the identification of factors conveying the action of gonadotropins on germ cells is particularly important for understanding the mechanism of reproduction. Insulin-like growth factors (Igfs) are recognized as key factors in regulating reproduction by triggering a series of physiological processes in vertebrates. Recently, a novel member of Igfs called Igf3 has been identified in teleost. Different from the conventional Igf1 and Igf2 that are ubiquitously expressed in a majority of tissues, Igf3 is solely or highly expressed in the fish gonads. The role of Igf3 in mediating the action of gonadotropin through Igf type 1 receptor on several aspects of oogenesis and spermatogenesis have been demonstrated in several fish species. In this review, we will summarize existing data on Igf3. This new information obtained from Igf3 provides insight into elucidating the molecular mechanism of fish reproduction, and also highlights the importance of Igf system in mediating the action of gonadotropin signaling on animal reproduction.
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Gônadas , Reprodução , Animais , Peixes , Masculino , Oogênese , EspermatogêneseRESUMO
We explored the functions and mechanisms of N-myc downstream-regulated gene 4 (NDRG4) in an amyloid beta 1-40 induced Alzheimer's disease cell model. The levels of total and phosphorylated Tau protein were significantly up-regulated and cell activity was decreased with increasing Aß1-40 treatment in SH-SY5Y cells. The expression of NDRG4 mRNA and protein levels were significantly decreased that induced by Aß1-40 in these cells. NDRG4 overexpression significantly alleviated Aß1-40-induced SH-SY5Y apoptosis rates and caspases-3/7 activities. Equally, Reactive oxygen species, Mitochondrial membrane potential and Microscale malondialdehyde levels were significantly down-regulated, and Superoxide dismutase activity was increased by NDRG4 overexpression. BDNF protein level and phosphorylation levels of AKT and ERK1/2 were enhanced by NDRG4 overexpression. We also determined that the inhibitory effects of NDRG4 on cell apoptosis and Reactive oxygen species release were partially reversed by BDNF silencing, and by application of the PI3K specific inhibitor (LY294002) or ERK inhibitor (PD98059). These data indicate that NDRG4 attenuates Aß1-40-induced cell apoptosis and Reactive oxygen species release release, as well as oxidative stress injury. These effects may be mediated through BDNF-induced PI3K/AKT and MEK/ERK pathways.
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Peptídeos beta-Amiloides/toxicidade , Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Proteínas Musculares/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Fragmentos de Peptídeos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVES: Noroviruses (NoVs) are major cause of acute viral gastroenteritis in worldwide, and the lack of a cell culture system that must be considered the virus like particles (VLPs) are used as an effective vaccine development. MATERIALS AND METHODS: In the present study, we investigated the expression of the major capsid protein (VP1) of the Genogroup II, genotype 17 (GII.17) NoV, using recombinant baculovirus system in insect cells, as well as a saliva binding blockade assay to detect their protective potency. RESULTS: Our results showed that GII.17 VLPs could be successfully generated in sf9 insect cells, and electron microscopic revealed that GII.17 VLPs appeared as spherical particles with a - 35 nm diameter. Immunized mice with purified VLPs produced GII.17 specific sera and could efficiently block GII.17 VLPs binding to the saliva histo-blood group antigens (HBGAs). CONCLUSIONS: Together, these results suggested that GII.17 VLPs represent a promising vaccine candidate against NoV GII.17 infection and strongly support further preclinical and clinical studies.
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Anticorpos Antivirais/imunologia , Infecções por Caliciviridae/imunologia , Norovirus/imunologia , Proteínas Recombinantes/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/metabolismo , Antígenos de Grupos Sanguíneos/metabolismo , Infecções por Caliciviridae/prevenção & controle , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Norovirus/genética , Coelhos , Proteínas Recombinantes/genética , Saliva/química , Células Sf9 , Vacinas de Partículas Semelhantes a Vírus/genética , Proteínas do Core Viral/genética , Proteínas do Core Viral/imunologiaRESUMO
Fragment splicing is a primary strategy in the design and optimization of leading compound toward new skeleton with target bioactivity. Herein a series of novel substituted phenyl oxazole derivatives were designed via fragment analysis and coupling strategy that led to highly potent and bio-selective herbicide safener. The biological tests showed that most of the compounds could enhance the maize growth index, glutathione content and anti-reverse enzyme glutathione S-transferase activity in vivo. The molecular docking model exhibited that the novel compound could compete with chlorsulfuron binding to the herbicide target enzyme, which consequently attained the herbicide detoxification. Especially compound I-f displayed the best activities than commercial safener isoxadifen-ethyl and other compounds. The present work demonstrates that the synthesized compounds could be developed as potential candidates for the discovery of novel herbicide safeners in the future.
Assuntos
Desenho de Fármacos , Oxazóis/química , Oxazóis/farmacologia , Cristalografia por Raios X , Glutationa Transferase/metabolismo , Herbicidas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxazóis/síntese química , Análise Espectral/métodos , Sulfonamidas/metabolismo , Triazinas/metabolismo , Zea mays/crescimento & desenvolvimentoRESUMO
The metal ion-DNA interaction is key to biochemical processes and has applications in areas such as metal ion sensors and DNA nanomachines. For example, the formation of the T-Hg2+-T structure has been used in technologies such as DNA-based mercuric ion sensors. Though the interaction is widely used for practical purposes, the underlying mechanism has not been fully understood. In the present study, we used magnetic tweezers to explore the interactions between λ-DNA and two metal ions, Hg2+ and Cd2+, at the single-molecule level. Both metal ions caused considerable DNA conformational changes. The resulting DNA compaction dynamics were related to the ion concentration and the exerted force. The increase in the ion concentration promoted DNA compaction, whereas exerting greater forces inhibited this process. Application of a high force generated two-stage dynamics of the Hg2+-DNA interaction. However, at a sufficiently high Hg2+ concentration, a lower force led to a three-stage process. In contrast, the curves of the binding of Cd2+ ions to DNA had a stepwise pattern. Both the AFM scanning results and the single-molecule measurements confirmed that Hg2+ influences the DNA conformation in a more pronounced manner than Cd2+. The multistage Hg2+-DNA interaction was considered to be a result of the different binding mechanisms, including the mismatched base-pair formation. A model was then proposed to explain the peculiar dynamics.
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DNA/química , Mercúrio/química , Pareamento Incorreto de Bases , Cádmio/química , Cádmio/metabolismo , DNA/metabolismo , Íons/química , Mercúrio/metabolismo , Microscopia de Força Atômica , Conformação de Ácido Nucleico , Timina/química , Timina/metabolismoRESUMO
The function of insulin-like growth factor (Igf) system in ovary has attracted much attention, but the role of Igf binding proteins (Igfbps) in ovary is still largely unknown. In this study, the role of Igfbps in oocyte maturation was investigated in zebrafish. The expression of all eight identified Igfbps except Igfbp6b could be detected in the adult ovary and exhibited differential expression profiles during folliculogenesis. The expression of several Igfbps is dynamically changed during oocyte maturation induced by human chorionic gonadotropin (hCG). By treatment of an Igfbps inhibitor NBI-31772 in vitro, the oocyte maturation could be stimulated in a clear dose-, time- and stage-dependent manner. Such effects were also observed by administration of NBI-31772 in vivo. Igfbps are differentially expressed in both follicular cells and oocytes, but the effect of NBI-31772 could only be found in intact follicles and not in the denuded oocytes. Previous studies have demonstrated that Igf3 is the major Igf member in regulating oocyte maturation of zebrafish. Interestingly, NBI-31772 could increase the effect of Igf3 on oocyte maturation. Furthermore, we found the effect of NBI-31772 on oocyte maturation could be blocked by an Igf type 1 receptor inhibitor BMS-536924 in vitro, suggesting the Igfbps can inhibit the oocyte maturation via Igf/Igf1r pathway. Together, we provided the first evidence in fish that Igfbps inhibit oocyte maturation of zebrafish.
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Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Oócitos/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Catecóis/farmacologia , Gonadotropina Coriônica/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like I/metabolismo , Isoquinolinas/farmacologia , Oócitos/metabolismo , Oogênese/efeitos dos fármacos , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
A series of novel substituted oxazole isoxazole carboxamides derivatives were designed on the basis of active subunit combination. Forty-four novel compounds were synthesized by an efficient one-pot procedure under microwave irradiation. The bioactivity was evaluated as herbicide safener against the injury of chlorsulfuron. It was found that most of the synthesized compounds displayed remarkable protection against chlorsulfuron via enhanced glutathione content and glutathione S transferase activity. Especially compound I-11 exhibited better bioactivity than the safeners isoxadifen-ethyl and R-28725. Molecular docking simulations suggested that the target compounds could compete with chlorsulfuron in the active site of acetolactate synthase, which could explain the protective effects of safeners. The present work demonstrates that the target compounds containing oxazole isoxazole groups could be considered as potential candidates for developing novel safeners in the future.
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Herbicidas/química , Herbicidas/farmacologia , Isoxazóis/química , Oxazóis/química , Sulfonamidas/farmacologia , Triazinas/farmacologia , Acetolactato Sintase/genética , Acetolactato Sintase/metabolismo , Ativação Enzimática/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Relação Estrutura-Atividade , Zea mays/enzimologiaRESUMO
BACKGROUND Multivariate models with a combination of variables can predict disease more accurately than a single variable employed alone. We developed a logistic regression model with a combination of variables and evaluated its ability to predict lung cancer. MATERIAL AND METHODS The exhaled breath from 57 patients with lung cancer and 72 healthy controls without cancer was collected. The VOCs of exhaled breath were examined qualitatively and quantitatively by a novel electronic nose (Z-nose4200 equipment). The VOCs in the 2 groups were compared using the Mann-Whitney U test, and the baseline data were compared between the 2 groups using the chi-square test or ANOVA. Variables from VOCs and baseline data were selected by stepwise logistic regression and subjected to a prediction model for the diagnosis of lung cancer as combined factors. The receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of this prediction model. RESULTS Nine VOCs in exhaled breath of lung cancer patients differed significantly from those of healthy controls. Four variables - age, hexane, 2,2,4,6,6-pentamethylheptane, and 1,2,6-trimethylnaphthalene - were entered into the prediction model, which could effectively separate the lung cancer samples from the control samples with an accuracy of 82.8%, a sensitivity of 76.0%, and a speciï¬city of 94.0%. CONCLUSIONS The profile of VOCs in exhaled breath contained distinguishable biomarkers in the patients with lung cancers. The prediction model with 4 variables appears to provide a new technique for lung cancer detection.
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Testes Respiratórios/instrumentação , Testes Respiratórios/métodos , Neoplasias Pulmonares/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/análise , Expiração , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e EspecificidadeRESUMO
Dorsal premotor cortex (PMd) is considered to play a crucial role in motor preparation, yet how the variation of neuronal activity affects the generation of different circumstances dependent movements remains unclear. Here we trained two monkeys to perform a delayed reaching task instructed by two sets of cues, one for indicating the target locations and another for indicating a conditionally presented virtual obstacle in the reaching path, which required the monkey to make a bypassing instead of straight reaching. We recorded the activity of PMd neurons and investigated how they responded to the switching of intended hand path induced by obstacle bypassing. Comparing the neuronal activity between hand bypassing trials and straight reaching trials, we found 30% of the total 687 set-related neurons showed different overall discharging level, and another 24% showed different onset time during the delay period. We also found 16% of the neurons were modulated only by target location and 14% were modulated by both target location and path switching. Our results demonstrate PMd neurons not only represent the planning of reaching to different target locations, as many previous studies have shown, but also represent the switching of intended reaching path induced by hand bypassing, suggesting how PMd neurons coordinate for such circumstances dependent motor planning.
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Mãos/fisiologia , Atividade Motora/fisiologia , Córtex Motor/fisiologia , Neurônios/fisiologia , Potenciais de Ação , Análise de Variância , Animais , Fenômenos Biomecânicos , Macaca mulatta , Masculino , Microeletrodos , Testes Neuropsicológicos , Processamento de Sinais Assistido por Computador , Fatores de TempoRESUMO
The first series of nitric oxide donating derivatives of evodiamine were designed and prepared. NO releasing ability of all target derivatives was evaluated in BGC-823, Bel-7402 and L-02 cells. The cytotoxicity was evaluated against three human tumor cell lines (Bel-7402, A549 and BGC-823) and normal human liver cells L-02. The nitrate derivatives 11a and 11b only exhibited moderate activity and furoxan-based derivatives 13a-c, 14a and 14b showed promising activity. 13c showed good cytotoxic selectivity between tumor and normal liver cells and was further investigated for its apoptotic properties on human hepatocarcinoma Bel-7402 cells. The molecular mode of action revealed that 13c caused cell-cycle arrest at S phase and induced apoptosis in Bel-7402 cells through mitochondria-related caspase-dependent pathways.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Óxido Nítrico/química , Quinazolinas/química , Quinazolinas/farmacologia , Antineoplásicos/química , Antineoplásicos/toxicidade , Western Blotting , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Quinazolinas/toxicidadeRESUMO
BACKGROUND: Prediction of the functional outcome for patients with convulsive status epilepticus (CSE) has been a challenge. The aim of this study was to characterize the prognostic factors and functional outcomes of patients after CSE in order to develop a practicable scoring system for outcome prediction. METHODS: We performed a retrospective explorative analysis on consecutive patients diagnosed with CSE between March, 2008 and November, 2014 in a tertiary academic medical center in northwest China. The modified Rankin Scale (mRS) was used to measure the functional outcome at three months post discharge. RESULTS: A total of 132 CSE patients was included, with a median age of 25.5 years and 60.6% were male. Three months post discharge, an unfavorable outcome with mRS of 3-6 was seen in 62 (47.0%) patients, 25 (18.9%) of whom died. Logistic regression analysis revealed that encephalitis (p = 0.029), nonconvulsive SE (p = 0.018), diazepam resistance (p = 0.005), image abnormalities (unilateral lesions, p = 0.027; bilateral lesions or diffuse cerebral edema, p < 0.001) and tracheal intubation (p = 0.032) were significant independent predictors for unfavorable outcomes. Based on the coefficients in the model, these predictors were assigned a value of 1 point each, with the exception of the image, creating a 6-point scoring system, which we refer to as END-IT, for the outcome prediction of CSE. The area under the receiver operating characteristic curve for the END-IT score was 0.833 and using a cut-off point of 3 produced the highest sum sensitivity (83.9%) and specificity (68.6%). Compared with status epilepticus severity score (STESS) and Epidemiology-based Mortality score in SE (EMSE), END-IT score showed better discriminative power and predictive accuracy for the outcome prediction. CONCLUSIONS: We developed an END-IT score with a strong discriminative power for predicting the functional outcome of CSE patients. External prospective validation in different cohorts is needed for END-IT score.
Assuntos
Avaliação de Resultados da Assistência ao Paciente , Estado Epiléptico/mortalidade , Adolescente , Adulto , China , Feminino , Previsões/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do TratamentoRESUMO
In higher plants, the salt overly sensitive (SOS) signalling pathway plays a crucial role in maintaining ion homoeostasis and conferring salt tolerance under salinity condition. Previously, we functionally characterized the conserved SOS pathway in the woody plant Populus trichocarpa. In this study, we demonstrate that overexpression of the constitutively active form of PtSOS2 (PtSOS2TD), one of the key components of this pathway, significantly increased salt tolerance in aspen hybrid clone Shanxin Yang (Populus davidiana × Populus bolleana). Compared to the wild-type control, transgenic plants constitutively expressing PtSOS2TD exhibited more vigorous growth and produced greater biomass in the presence of high concentrations of NaCl. The improved salt tolerance was associated with a decreased Na(+) accumulation in the leaves of transgenic plants. Further analyses revealed that plasma membrane Na(+) /H(+) exchange activity and Na(+) efflux in transgenic plants were significantly higher than those in the wild-type plants. Moreover, transgenic plants showed improved capacity in scavenging reactive oxygen species (ROS) generated by salt stress. Taken together, our results suggest that PtSOS2 could serve as an ideal target gene to genetically engineer salt-tolerant trees.