Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Exp Ther Med ; 22(6): 1435, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34707716

RESUMO

Flavonoids which are extracted from citrus peel and pulp have been reported to have multiple beneficial effects on human health. Isosinensetin (ISO) is a type of flavonoid compound, which has several protective effects including anticancer, antioxidant, antiviral, anti-inflammatory and bacteriostatic. However, the molecular mechanism of its antioxidant and anti-inflammatory effects remain unclear. The present study aimed to investigate the intervention effect and possible mechanism of ISO on human bronchial epithelial cells injured by fine particular matter ≤2.5 µm in diameter (PM2.5). In the present study, the cell viability was detected by Cell Counting Kit-8 method. The levels of pro-inflammatory cytokines were analyzed by ELISA. The level of reactive oxygen species (ROS) was detected by fluorescence probe. The expression levels of proliferating cell nuclear antigen (PCNA), nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor ÐºΒ (NF-кB) proteins were detected by western blotting. The results revealed that ISO evidently increased the viability of 16-HBE cells and sharply decreased the levels of pro-inflammatory factors in cell culture supernatant. ISO significantly inhibited ROS release caused by PM2.5. Moreover, the expression levels of PCNA, Nrf2 and NF-кB proteins were downregulated after ISO incubation. These results indicated that ISO alleviated 16-HBE-cell injury by PM2.5 through the ROS-Nrf2/NF-кB signaling pathway.

2.
Cell Rep ; 36(8): 109596, 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433060

RESUMO

Germline alterations of the NF2 gene cause neurofibromatosis type 2, a syndrome manifested with benign tumors, and Nf2 deletion in mice also results in slow tumorigenesis. As a regulator of the Hippo signaling pathway, NF2 induces LATS1/2 kinases and consequently represses YAP/TAZ. YAP/TAZ oncoproteins are also inhibited by motin family proteins (Motins). Here, we show that the Hippo signaling is fine-tuned by Motins in a NF2-dependent manner, in which NF2 recruits E3 ligase RNF146 to facilitate ubiquitination and subsequent degradation of Motins. In the absence of NF2, Motins robustly accumulate to restrict full activation of YAP/TAZ and prevent rapid tumorigenesis. Hence, NF2 deficiency not only activates YAP/TAZ by inhibiting LATS1/2 but also stabilizes Motins to keep YAP/TAZ activity in check. The upregulation of Motins upon NF2 deletion serves as a strategy for avoiding uncontrolled perturbation of the Hippo signaling and may contribute to the benign nature of most NF2-mutated tumors.

3.
Angew Chem Int Ed Engl ; 60(41): 22276-22282, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34427019

RESUMO

Designing definite metal-support interfacial bond is an effective strategy for optimizing the intrinsic activity of noble metals, but rather challenging. Herein, a series of quantum-sized metal nanoparticles (NPs) anchored on nickel metal-organic framework nanohybrids (M@Ni-MOF, M=Ru, Ir, Pd) are rationally developed through a spontaneous redox strategy. The metal-oxygen bonds between the NPs and Ni-MOF guarantee structural stability and sufficient exposure of the surface active sites. More importantly, such precise interfacial feature can effectively modulate the electronic structure of hybrids through the charge transfer of the formed Ni-O-M bridge and then improves the reaction kinetics. As a result, the representative Ru@Ni-MOF exhibits excellent hydrogen evolution reaction (HER) activity at all pH values, even superior to commercial Pt/C and recent noble-metal catalysts. Theoretical calculations deepen the mechanism understanding of the superior HER performance of Ru@Ni-MOF through the optimized adsorption free energies of water and hydrogen due to the interfacial-bond-induced electron redistribution.

4.
Cell Prolif ; 54(9): e13107, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34346124

RESUMO

OBJECTIVES: In recent years, cellular senescence has attracted a lot of interest in researchers due to its involvement in non-alcoholic fatty liver disease (NAFLD). However, the mechanism of cellular senescence is not clear. The purpose of this study was to investigate the effect of curcumol on hepatocyte senescence in NAFLD and the molecular mechanisms implicated. MATERIALS AND METHODS: LVG Golden Syrian hamsters, C57BL/6J mice and human hepatocyte cell line LO2 were used. Cellular senescence was assessed by analyses of senescence marker SA-ß-gal, p16 and p21, H3K9me3, γ-H2AX and telomerase activity. RESULTS: The results showed that curcumol could inhibit hepatocyte senescence in both in vivo and in vitro NAFLD models, and the mechanism might be related to its regulation of ferritinophagy and subsequent alleviation of iron overload. Moreover, overexpression of nuclear receptor coactivator 4 (NCOA4) weakened the effect of curcumol on ferritinophagy-mediated iron overload and cellular senescence. Furthermore, we demonstrated that curcumol reduced the expression of NCOA4 by Yes-associated protein (YAP). In addition, depression of YAP could impair the effect of curcumol on iron overload and cellular senescence. CONCLUSION: Our results clarified the mechanism of curcumol inhibition of hepatocyte senescence through YAP/NCOA4 regulation of ferritinophagy in NAFLD. These findings provided a promising option of curcumol to regulate cellular senescence by target YAP/NCOA4 for the treatment of NAFLD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Ferritinas/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Coativadores de Receptor Nuclear/metabolismo , Sesquiterpenos/farmacologia , Animais , Linhagem Celular , Hepatócitos/metabolismo , Humanos , Ferro/metabolismo , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo
5.
J Cell Mol Med ; 25(15): 7354-7366, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34190396

RESUMO

Although recent evidence has shown that hepatocyte senescence plays a crucial role in the pathogenesis and development of non-alcoholic fatty liver disease (NAFLD), the mechanism is still not clear. The purpose of this study was to investigate the signal transduction pathways involved in the senescence of hepatocyte, in order to provide a potential strategy for blocking the process of NAFLD. The results confirmed that hepatocyte senescence occurred in HFD-fed Golden hamsters and PA-treated LO2 cells as manifested by increased levels of senescence marker SA-ß-gal, p16 and p21, heterochromatin marker H3K9me3, DNA damage marker γ-H2AX and decreased activity of telomerase. Further studies demonstrated that iron overload could promote the senescence of hepatocyte, whereas the overexpression of Yes-associated protein (YAP) could blunt iron overload and alleviate the senescence of hepatocyte. Of importance, depression of lncRNA MAYA (MAYA) reduced iron overload and cellular senescence via promotion of YAP in PA-treated hepatocytes. These effects were further supported by in vivo experiments. In conclusion, these data suggested that inhibition of MAYA could up-regulate YAP, which might repress hepatocyte senescence through modulating iron overload. In addition, these findings provided a promising option for heading off the development of NAFLD by abrogating hepatocyte senescence.

6.
Front Neurosci ; 15: 671280, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935644

RESUMO

Cervical discogenic pain (CDP) is mainly induced by cervical disc degeneration. However, how CDP modulates the functional interactions within the pain network remains unclear. In the current study, we studied the changed resting-state functional connectivities of pain network with 40 CDP patients and 40 age-, gender-matched healthy controls. We first defined the pain network with the seeds of the posterior insula (PI). Then, whole brain and seed-to-target functional connectivity analyses were performed to identify the differences in functional connectivity between CDP and healthy controls. Finally, correlation analyses were applied to reveal the associations between functional connectivities and clinical measures. Whole-brain functional connectivity analyses of PI identified increased functional connectivity between PI and thalamus (THA) and decreased functional connectivity between PI and middle cingulate cortex (MCC) in CDP patients. Functional connectivity analyses within the pain network further revealed increased functional connectivities between bilateral PI and bilateral THA, and decreased functional connectivities between left PI and MCC, between left postcentral gyrus (PoCG) and MCC in CDP patients. Moreover, we found that the functional connectivities between right PI and left THA, between left PoCG and MCC were negatively and positively correlated with the visual analog scale, respectively. Our findings provide direct evidence of how CDP modulates the pain network, which may facilitate understanding of the neural basis of CDP.

7.
Mol Cancer Ther ; 20(6): 986-998, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33850002

RESUMO

Mutations in the neurofibromatosis type 2 (NF2) gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit NF2-deficient mesothelioma cell proliferation in vitro and growth of subcutaneous tumor xenografts in vivo These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.

8.
Cell Biol Toxicol ; 37(3): 367-378, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32656717

RESUMO

CD8+T cells play an important role in controlling infections and tumorigenesis in vivo. naïve CD8+T cells exponentially expand and exert effector functions in response to TCR ligation. After antigen clearance, most effector CD8+T cells (Teff) experience activation-induced cell death, only a small portion becomes long-lived memory T cells (Tmem). The cell-intrinsic mechanisms driving the differentiation need further understanding. Here we used combined transposase-accessible chromatin (ATAC-seq) technology and RNA-seq analysis to explore chromatin accessibility in CD8+T cell subsets (naïve T cells, Teff, and Tmem). The data demonstrates different chromatin openness of CD8+T cell states is associated with metabolic regulation and the high accessibility of upstream binding site SP1 emerged as critical transcription factor for both Teff and Tmem in fatty acid oxidation (FAO) and glycolysis. The different presence of accessible regions in CD8+T cell subsets provides a novel perspective for understanding epigenetic mechanisms underlying T cell differentiation and related immune response.

9.
Front Cell Dev Biol ; 8: 586581, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195240

RESUMO

Mutations in the enzyme isocitrate dehydrogenase 1/2 (IDH1/2) are the most common somatic mutations in low-grade glioma (LGG). The Hippo signaling pathway is known to play a key role in organ size control, and its dysregulation is involved in the development of diverse cancers. Large tumor suppressor 1/2 (LATS1/2) are core Hippo pathway components that phosphorylate and inactivate Yes-associated protein (YAP), a transcriptional co-activator that regulates expression of genes involved in tumorigenesis. A recent report from The Cancer Genome Atlas (TCGA) has highlighted a frequent hypermethylation of LATS2 in IDH-mutant LGG. However, it is unclear if LATS2 hypermethylation is associated with YAP activation and prognosis of LGG patients. Here, we performed a network analysis of the status of the Hippo pathway in IDH-mutant LGG samples and determined its association with cancer prognosis. Combining TCGA data with our biochemical assays, we found hypermethylation of LATS2 promoter in IDH-mutant LGG. LATS2 hypermethylation, however, did not translate into YAP activation but highly correlated with IDH mutation. LATS2 hypermethylation may thus serve as an alternative for IDH mutation in diagnosis and a favorable prognostic factor for LGG patients.

10.
Biochem Biophys Res Commun ; 531(2): 96-104, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32773110

RESUMO

Yes-associated protein (YAP) is a key downstream effector of the highly conserved Hippo signaling pathway, which regulates organ size, regeneration and tumorigenesis. Known classically to function as a transcriptional co-activator, YAP interacts with TEA domain transcription factors (TEAD1-4) to induce expression of target genes. However, a number of genes are repressed upon YAP activation, suggesting a transcriptional repressor role of YAP. Here, we report that TP73 is a direct target gene of YAP, and its transcription is repressed by YAP in a TEAD-independent manner. On the other hand, WW domains of YAP are indispensable for the regulation of TP73 expression, which may recruit YAP to TP73 gene though interaction with ZEB1 and/or RUNX2, two transcriptional repressors. Moreover, YAP-mediated repression of TP73 promotes cancer cell survival in the presence of chemotherapeutic agents, suggesting YAP-TP73 signaling as a mechanism for cancer cell resistance to chemotherapies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Transcrição Genética , Proteína Tumoral p73/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Bases , Linhagem Celular Tumoral , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Domínios Proteicos , Proteínas Repressoras/metabolismo , Fatores de Transcrição/química , Proteína Tumoral p73/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
11.
Front Neurosci ; 14: 733, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760245

RESUMO

Cervical discogenic pain (CDP) is a clinically common pain syndrome caused by cervical disk degeneration. A large number of studies have reported that CDP results in brain functional impairments. However, the detailed dynamic brain functional abnormalities in CDP are still unclear. In this study, using resting-state functional magnetic resonance imaging, we explored the neural basis of CDP with 40 CDP patients and 40 age-, gender-matched healthy controls to delineate the changes of the voxel-level static and dynamic amplitude of low frequency fluctuations (ALFF). We found increased static ALFF in left insula (INS) and posterior precuneus (PCu), and decreased static ALFF in left precentral/postcentral gyrus (PreCG/PoCG), thalamus (THA), and subgenual anterior cingulate cortex in CPD patients compared to healthy controls. We also found decreased dynamic ALFF in left PreCG/PoCG, right posterior middle temporal gyrus, and bilateral THA. Moreover, we found that static ALFF in left PreCG/PoCG and dynamic ALFF in THA were significantly negatively correlated with visual analog scale and disease duration, respectively. Our findings provide the neurophysiological basis for CDP and facilitate understanding the neuropathology of CDP.

12.
Clin Transl Med ; 10(3): e133, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32659053

RESUMO

BACKGROUND: Exhausted T cells and regulatory T cells (Tregs) comprise diverse subsets of tumor immunosuppressive microenvironment that play key roles in tumor progress. Understanding subset diversity in T cells is a critical question for developing cancer immunotherapy. METHODS: A total of 235 specimens from surgical resections of hepatocellular carcinoma (HCC) patients were examined for infiltration of exhausted T cell (Tex) in tumor and adjacent tissue. We conducted deep single-cell targeted immune profiling on CD3+ cells collected from tumor tissues, adjacent normal tissues (ANTs) and peripheral blood of HCC patients. Total 10 cell clusters were identified with distinct distributions and characteristics. RESULTS: We observed transitional differentiation of exhausted CD8+ T cells and Tregs increasingly enriched in tumor tissue. The accumulation and location of Tex were related to the differences in the long-term clinical outcome of HCC. Furthermore, data of single-cell RNA-seq showed that (1) cells transforming from effector CD8+ T cells to exhausted CD8+ T cells simultaneously expressed upregulated effector molecules and inhibitory receptors, (2) indicated alteration of gene expression related to stress response and cell cycle at early exhaustion stage, and (3) immunosuppressive Treg had profound activation in comparison to resting Tregs. CONCLUSIONS: T cell exhaustion is a progressive process, and the gene-expression profiling displayed T cell exhaustion and anergy are different. Accordingly, it is possible that functional exhaustion is caused by the combination effects of passive defects and overactivation in stress response. The results help to understand the dynamic framework of T cells function in cancer which is important for designing rational cancer immunotherapies.

13.
Environ Pollut ; 266(Pt 1): 115055, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32629208

RESUMO

Bisphenol A (BPA), can lead to learning and memory impairment, but the underlying mechanism is poorly understood. Researchers have indicated that the N-methyl-D-aspartate receptor (NMDAR)/postsynaptic density protein 95 (PSD-95)/neuronal nitric oxide synthase (nNOS)-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway greatly contributes to learning and memory process. Pregnant rats were exposed to 0, 0.05, 0.5, 5 and 50 mg/kg/day BPA via oral gavage from gestational day (GD) 5 to GD 19. Morris water maze, transmission electron microscope, western blot, real time PCR, biochemical analysis and ELISA were used to analyze the changes in behavior, synaptic ultrastructure, protein and gene expression of NMDAR, PSD-95, nNOS, together with nNOS activity, NO (Nitrate reductase method) and cGMP levels of the rat pups at different growth stages. Results of this research displayed that exposure to 0.5 mg/kg/day BPA could damage the spatial learning ability of rats at postnatal day (PND) 56. However, spatial memory ability could be affected by exposure to BPA at doses up to 5 mg/kg/day. Moreover, the thickness of the postsynaptic density decreased after exposure to BPA at doses of 5 and 50 mg/kg/day. Levels of NR1, NR2A, PSD-95 protein and mRNA were downregulated to some extent after exposure to BPA, whereas the expression of NR2B increased at GD 20 but decreased at PND 21 and 56. Contrarily, the nNOS expression along with the enzyme activity were promoted after exposure to BPA. Meanwhile, the NO and cGMP levels were suppressed at GD 20 but promoted at PND 21 and 56. In conclusion, these results demonstrated that NMDAR/PSD-95/nNOS-NO-cGMP pathway could be affected by embryonic exposure to BPA, which may involve in the spatial learning and memory dysfunction of rats in later life.


Assuntos
Hipocampo , Receptores de N-Metil-D-Aspartato , Animais , Compostos Benzidrílicos , Proteína 4 Homóloga a Disks-Large , Feminino , Óxido Nítrico Sintase Tipo I , Fenóis , Gravidez , Ratos
14.
Environ Sci Pollut Res Int ; 27(14): 17290-17302, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32157532

RESUMO

The effect of prenatal bisphenol A (BPA) exposure is increasingly concerned. We investigated the effect of maternal BPA exposure during pregnancy on male offspring and its potential mechanism. Thirty pregnant Sprague Dawley (SD) rats were randomly divided into exposed and control groups. At PND56, the number of sperm, luteinizing hormone, and testosterone in the BPA-exposed group decreased, and testicular tissue structure was damaged in offsprings. At GD20, the miRNA profile in the testis of male offspring was examined and the expression levels of 28 deregulated miRNAs were validated by qRT-PCR. We found that miR-361-5p, miR-203a-3p, and miR-19b-2-5p had significantly different expression levels in the testis. These results suggest that maternal exposure to BPA can lead to differential changes in progeny miRNAs, which will provide direction for future in-depth mechanisms of reproductive injury.


Assuntos
MicroRNAs , Testículo , Animais , Compostos Benzidrílicos , Feminino , Humanos , Masculino , Exposição Materna , Fenóis , Gravidez , Ratos , Ratos Sprague-Dawley
15.
Plant Cell Environ ; 43(5): 1175-1191, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31990075

RESUMO

Photorespiratory hydrogen peroxide (H2 O2 ) plays key roles in pathogenesis responses by triggering the salicylic acid (SA) pathway in Arabidopsis. However, factors linking intracellular H2 O2 to activation of the SA pathway remain elusive. In this work, the catalase-deficient Arabidopsis mutant, cat2, was exploited to elucidate the impact of S-nitrosoglutathione reductase 1 (GSNOR1) on H2 O2 -dependent signalling pathways. Introducing the gsnor1-3 mutation into the cat2 background increased S-nitrosothiol levels and abolished cat2-triggered cell death, SA accumulation, and associated gene expression but had little additional effect on the major components of the ascorbate-glutathione system or glycolate oxidase activities. Differential transcriptome profiles between gsnor1-3 and cat2 gsnor1-3 together with damped ROS-triggered gene expression in cat2 gsnor1-3 further indicated that GSNOR1 acts to mediate the SA pathway downstream of H2 O2 . Up-regulation of GSNOR activity was compromised in cat2 cad2 and cat2 pad2 mutants in which glutathione accumulation was genetically prevented. Experiments with purified recombinant GSNOR revealed that the enzyme is posttranslationally regulated by direct denitrosation in a glutathione-dependent manner. Together, our findings identify GSNOR1-controlled nitrosation as a key factor in activation of the SA pathway by H2 O2 and reveal that glutathione is required to maintain this biological function.


Assuntos
Proteínas de Arabidopsis/metabolismo , Glutationa Redutase/metabolismo , Glutationa/metabolismo , Peróxido de Hidrogênio/metabolismo , Oxirredução , Transdução de Sinais , Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Microscopia Confocal , Nitrosação , Estresse Oxidativo , Reguladores de Crescimento de Plantas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Ácido Salicílico/metabolismo
16.
Environ Sci Pollut Res Int ; 27(1): 1131-1143, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31820230

RESUMO

Environmental contamination by perfluorooctanoic acid (PFOA) has raised concerns for years. Yet, little information on its phytotoxic effects and underlying mechanisms in higher plants is available. To this end, comparative analyses of the responses to PFOA exposure between shoots and roots in the model plant species Arabidopsis thaliana were performed at the physiological and molecular levels. Our results showed that PFOA exposure reduced Arabidopsis biomass in a dose-related manner, and shoot growth was more sensitive to PFOA than root growth. Consistently, PFOA accumulation and the levels of several metal elements, including Zn, Ca, Cu, and K, in addition to Fe, were more substantially affected in the shoots than in the roots. Transcriptomic analysis further showed that the shoot transcriptional profile was distinguishable from that of roots upon PFOA exposure. Nevertheless, some overlapping genes were present between the shoots and roots, mainly including transporter genes, Fe-deficiency-responsive genes, and oxidative stress-related genes. More importantly, a comparative analysis of ROS-associated genes in combination with other oxidative stress assays pointed out that PFOA triggered certain oxidative stress-associated events more strongly in shoots than in roots. Overall, the results demonstrated that PFOA exposure caused alterations in PFOA distribution, metal element balance, reconfiguration of transcriptomes, and induction of oxidative stress in a tissue-dependent manner in Arabidopsis thaliana.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Caprilatos/toxicidade , Fluorcarbonetos/toxicidade , Metais/metabolismo , Arabidopsis/química , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Caprilatos/química , Fluorcarbonetos/química , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Metais/química , Transcriptoma
17.
Biomolecules ; 9(12)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31861226

RESUMO

Misfolding and aggregation of transthyretin (TTR) is widely known to be responsible for a progressive systemic disorder called amyloid transthyretin (ATTR) amyloidosis. Studies suggest that TTR aggregation is initiated by a rate-limiting dissociation of the homo-tetramer into its monomers, which can rapidly misfold and self-assemble into amyloid fibril. Thus, exploring conformational change involved in TTR monomer misfolding is of vital importance for understanding the pathogenesis of ATTR amyloidosis. In this work, microsecond timescale hybrid-resolution molecular dynamics (MD) simulations combined with Markov state model (MSM) analysis were performed to investigate the misfolding mechanism of the TTR monomer. The results indicate that a macrostate with partially unfolded conformations may serve as the misfolded state of the TTR monomer. This misfolded state was extremely stable with a very large equilibrium probability of about 85.28%. With secondary structure analysis, we found the DAGH sheet in this state to be significantly destroyed. The CBEF sheet was relatively stable and sheet structure was maintained. However, the F-strand in this sheet was likely to move away from E-strand and reform a new ß-sheet with the H-strand. This observation is consistent with experimental finding that F and H strands in the outer edge drive the misfolding of TTR. Finally, transition pathways from a near native state to this misfolded macrostate showed that the conformational transition can occur either through a native-like ß-sheet intermediates or through partially unfolded intermediates, while the later appears to be the main pathway. As a whole, we identified a potential misfolded state of the TTR monomer and elucidated the misfolding pathway for its conformational transition. This work can provide a valuable theoretical basis for understanding of TTR aggregation and the pathogenesis of ATTR amyloidosis at the atomic level.


Assuntos
Cadeias de Markov , Simulação de Dinâmica Molecular , Pré-Albumina/química , Humanos , Dobramento de Proteína
18.
Plant Cell Environ ; 42(12): 3182-3196, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31369162

RESUMO

A biological clock activated by oscillating signals, known as root clock, has been linked to lateral root (LR) formation and is essential for regular LR spacing along the primary root. However, it remains unclear how this internal mechanism is influenced by environmental factors known to affect the LR pattern. Here, we report that excessive cadmium (Cd) inhibits LR formation by disrupting the lateral root cap (LRC)-programmed cell death (PCD)-regulated root clock. Cd restricts the frequency of the oscillating signal rather than its amplitude. This could be attributed to the inhibition on meristematic activity by Cd, which resulted in decreased LRC cell number and LRC-PCD frequency. Genetic evidence further showed that LRC cell number is positively correlated with root resistance to Cd. Our study reveals root cap dynamics as a novel mechanism mediating root responses to Cd, providing insight into the signalling pathways of the root clock responding to environmental cues.


Assuntos
Relógios Biológicos , Cádmio/toxicidade , Raízes de Plantas/crescimento & desenvolvimento , Estresse Fisiológico/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Meristema/efeitos dos fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Plantas/efeitos dos fármacos , Plantas/genética , Especificidade da Espécie , Estresse Fisiológico/genética
19.
Environ Sci Pollut Res Int ; 26(21): 22040-22050, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31144181

RESUMO

Exposure to fine particulate matter (PM2.5) could induce lung impairment aggravation. Moreover, endogenous substances are known to play a significant role in lung impairment. Therefore, the research objectives was to investigate the influence of PM2.5-induced lung impairment on the levels of the eight endogenous substances, γ-aminobutyric acid (GABA), acetylcholine (ACh), glutamate (Glu), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA), noradrenaline (NE), dopamine (DA), and 3, 4-dihydroxyphenylacetic acid (DOPAC). A sensitive UPLC-MS/MS method for the simultaneous determination of these endogenous substances in rat plasma and lung tissues was developed. The validated method was successfully applied for comparing profiles of analytes in rat plasma and lung tissues. The results indicated that five endogenous substances, namely, GABA, Ach, Glu, DA, and DOPAC, had a significant change in the rats with PM2.5-induced lung impairment.


Assuntos
Pulmão/metabolismo , Material Particulado/toxicidade , Animais , Cromatografia Líquida , Dopamina , Ácido Glutâmico , Masculino , Neurotransmissores , Ratos , Serotonina , Espectrometria de Massas em Tandem/métodos , Ácido gama-Aminobutírico
20.
Phys Chem Chem Phys ; 21(21): 11004-11010, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31089593

RESUMO

Benzoquinone (BQ)-based macrocyclic compounds have shown great potential as cathode materials for lithium-ion batteries (LIBs) owing to their high redox potential and specific capacity. However, such materials usually have complex structures, which impede the investigation of lithiation mechanisms. Herein, we take Calix[4]quinone (C4Q) molecule as an example to develop a viable mechanism investigation method for such materials. The lithiation profile of C4Q is determined by condensed Fukui function which provides the reaction sites and orders. A correction of redox potential is proposed by leaving out the ion-transfer effect during the redox reaction based on Gibbs free energy change. The redox potential obtained by this approach shows high consistency with the experimental results. Moreover, this method can also be well extended to study the lithiation mechanism of another BQ-based macrocyclic compound (Pillar[5]quinone). Our results are promising to more deeply understand the reaction mechanism and predict the redox potential of new BQ-based macrocyclic compounds for LIBs.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...