RESUMO
Liver fibrosis is a significant health concern globally due to its association with severe liver conditions like cirrhosis and liver cancer. Histone lactylation has been implicated in the progression of hepatic fibrosis, but its specific role in liver fibrosis, particularly regarding H3K18 lactylation, remained unclear. To investigate this, we established in vivo and in vitro models of liver fibrosis using carbon tetrachloride (CCl4) injection in rats and stimulation of hepatic stellate cells (HSCs) with TGF-ß1, respectively. We found that histone lactylation, particularly H3K18 lactylation, was upregulated in both CCl4-induced rats and TGF-ß1-activated HSCs, indicating its potential involvement in liver fibrosis. Further experiments revealed that lactate dehydrogenase A (LDHA) knockdown inhibited H3K18 lactylation and had a beneficial effect on liver fibrosis by suppressing HSC proliferation, migration, and extracellular matrix (ECM) deposition. This suggests that H3K18 lactylation promotes liver fibrosis progression. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that H3K18 lactylation facilitated the transcription of SOX9, a transcription factor associated with fibrosis. Importantly, overexpression of SOX9 counteracted the effects of LDHA silencing on activated HSCs, indicating that SOX9 is downstream of H3K18 lactylation in promoting liver fibrosis. In summary, this study uncovers a novel mechanism by which H3K18 lactylation contributes to liver fibrosis by activating SOX9 transcription. This finding opens avenues for exploring new therapeutic strategies for hepatic fibrosis targeting histone lactylation pathways.
Assuntos
Progressão da Doença , Células Estreladas do Fígado , Histonas , Cirrose Hepática , Ratos Sprague-Dawley , Fatores de Transcrição SOX9 , Animais , Humanos , Masculino , Ratos , Tetracloreto de Carbono , Movimento Celular/genética , Proliferação de Células , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Histonas/metabolismo , Histonas/genética , L-Lactato Desidrogenase/metabolismo , L-Lactato Desidrogenase/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/genética , Cirrose Hepática/induzido quimicamente , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição SOX9/genética , Transcrição Gênica , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Semiconductor photocatalysis holds significant promise in addressing both environmental and energy challenges. However, a major hurdle in photocatalytic processes remains the efficient separation of photoinduced charge carriers. In this study, TiO2nanorod arrays were employed by glancing angle deposition technique, onto which Ti3C2TxMXene was deposited through a spin-coating process. This hybrid approach aims to amplify the photocatalytic efficacy of TiO2nanorod arrays. Through photocurrent efficiency characterization testing, an optimal loading of TiO2/Ti3C2Txcomposites is identified. Remarkably, this composite exhibits a 40% increase in photocurrent density in comparison to pristine TiO2. This enhancement is attributed to the exceptional electrical conductivity and expansive specific surface area inherent to Ti3C2TxMXene. These attributes facilitate swift transport of photoinduced electrons, consequently refining the separation and migration of electron-hole pairs. The synergistic TiO2/Ti3C2Txcomposite showcases its potential across various domains including photoelectrochemical water splitting and diverse photocatalytic devices. As such, this composite material stands as a novel and promising entity for advancing photocatalytic applications. This study can offer an innovative approach for designing simple and efficient photocatalytic materials composed of MXene co-catalysts and TiO2for efficient water electrolysis on semiconductors.
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Amylose content (AC) is the main factor determining the palatability, viscosity, transparency, and digestibility of rice (Oryza sativa) grains. AC in rice grains is mainly controlled by different alleles of the Waxy (Wx) gene. The AP2/EREBP transcription factor OsEBP89 interacts with the MYC-like protein OsBP5 to synergistically regulate the expression of Wx. Here, we determined that the GLYCOGEN SYNTHASE KINASE 5 (OsGSK5, also named SHAGGY-like kinase 41 [OsSK41]) inhibits the transcriptional activation activity of OsEBP89 in rice grains during amylose biosynthesis. The loss of OsSK41 function enhanced Wx expression and increased AC in rice grains. By contrast, the loss of function of OsEBP89 reduced Wx expression and decreased AC in rice grains. OsSK41 interacts with OsEBP89 and phosphorylates four of its sites (Thr-28, Thr-30, Ser-238, and Thr-257), which makes OsEBP89 unstable and attenuates its interaction with OsBP5. Wx promoter activity was relatively weak when regulated by the phosphomimic variant OsEBP89E -OsBP5 but relatively strong when regulated by the nonphosphorylatable variant OsEBP89A -OsBP5. Therefore, OsSK41-mediated phosphorylation of OsEBP89 represents an additional layer of complexity in the regulation of amylose biosynthesis during rice grain development. In addition, our findings provide four possible sites for regulating rice grain AC via precise gene editing.
Assuntos
Endosperma , Oryza , Endosperma/metabolismo , Amilose/metabolismo , Oryza/metabolismo , Regiões Promotoras Genéticas , Grão Comestível/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
Auxin is an important phytohormone in plants, and auxin signaling pathways in rice play key roles in regulating its growth, development, and productivity. To investigate how rice grain yield traits are regulated by auxin signaling pathways and to facilitate their application in rice improvement, we validated the functional relationships among regulatory genes such as OsIAA10, OsSK41, and OsARF21 that are involved in one of the auxin (OsIAA10) signaling pathways. We assessed the phenotypic effects of these genes on several grain yield traits across two environments using knockout and/or overexpression transgenic lines. Based on the results, we constructed a model that showed how grain yield traits were regulated by OsIAA10 and OsTIR1, OsAFB2, and OsSK41 and OsmiR393 in the OsSK41-OsIAA10-OsARF module and by OsARF21 in the transcriptional regulation of downstream auxin response genes in the OsSK41-OsIAA10-OsARF module. The population genomic analyses revealed rich genetic diversity and the presence of major functional alleles at most of these loci in rice populations. The strong differentiation of many major alleles between Xian/indica and Geng/japonica subspecies and/or among modern varieties and landraces suggested that they contributed to improved productivity during evolution and breeding. We identified several important aspects associated with the genetic and molecular bases of rice grain and yield traits that were regulated by auxin signaling pathways. We also suggested rice auxin response factor (OsARF) activators as candidate target genes for improving specific target traits by overexpression and/or editing subspecies-specific alleles and by searching and pyramiding the 'best' gene allelic combinations at multiple regulatory genes in auxin signaling pathways in rice breeding programs.
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Oryza , Oryza/metabolismo , Melhoramento Vegetal , Fenótipo , Ácidos Indolacéticos/metabolismo , Grão Comestível/genética , Grão Comestível/metabolismoRESUMO
BACKGROUND: Rice eating quality largely dictates consumer preference, and the demand for new rice varieties with excellent eating quality from farmers is increasing. Identification of factors contributing to eating quality is helpful for developing high-quality rice varieties. RESULTS: Two groups of rice with different apparent amylose content (AACs) were used in this study. One group contained four varieties with low AACs (8.8-9.4%), whereas the other contained four traditional varieties with medium AACs (17.2-17.5%). The physicochemical properties, starch fine structure and crystallinity and storage protein composition of the two groups were analyzed. We found that, in both groups, the rice varieties with high eating quality had more short-chain amylopectin, lower glutelin and prolamin content, and a higher albumin content. In addition, the low-AAC varieties produced opaque endosperms, which may result from an increased number of pores in the center of starch granules. CONCLUSIONS: Both the fine structure of starch and the storage protein composition were closely related to rice eating quality. In both groups, short branch-chain amylopectin, short-chain amylopectin [degree of polymerization (DP) 6-12], and albumin had positive effects on eating quality. By contrast, long branch-chain amylopectin, long-chain amylopectin (DP 35-60), glutelin and prolamin had adverse effects on eating quality of rice. © 2020 Society of Chemical Industry.
Assuntos
Oryza/química , Proteínas de Armazenamento de Sementes/química , Amido/química , Amilopectina/química , Amilopectina/metabolismo , Amilose/química , Amilose/metabolismo , Análise de Alimentos , Humanos , Oryza/classificação , Oryza/metabolismo , Sementes/química , Sementes/classificação , Sementes/metabolismo , Amido/metabolismoRESUMO
Plants maintain a dynamic balance between plant growth and stress tolerance to optimise their fitness and ensure survival. Here, we investigated the roles of a clade A type 2C protein phosphatase (PP2C)-encoding gene, OsPP2C09, in regulating the trade-off between plant growth and drought tolerance in rice (Oryza sativa L.). The OsPP2C09 protein interacted with the core components of abscisic acid (ABA) signalling and showed PP2C phosphatase activity in vitro. OsPP2C09 positively affected plant growth but acted as a negative regulator of drought tolerance through ABA signalling. Transcript and protein levels of OsPP2C09 were rapidly induced by exogenous ABA treatments, which suppressed excessive ABA signalling and plant growth arrest. OsPP2C09 transcript levels in roots were much higher than those in shoots under normal conditions. After ABA, polyethylene glycol and dehydration treatments, the accumulation rate of OsPP2C09 transcripts in roots was more rapid and greater than that in shoots. This differential expression between the roots and shoots may increase the plant's root-to-shoot ratio under drought-stress conditions. This study sheds new light on the roles of OsPP2C09 in coordinating plant growth and drought tolerance. In particular, we propose that OsPP2C09-mediated ABA desensitisation contributes to root elongation under drought-stress conditions in rice.
Assuntos
Oryza , Ácido Abscísico , Secas , Regulação da Expressão Gênica de Plantas , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Estresse Fisiológico/genéticaRESUMO
The aim of this study was to access whether microsurgical subinguinal varicocelectomy (MSV) with testicular delivery has a better therapeutic effect than MSV without testicular delivery, including semen quality, serum testosterone (T) level and International Index of Erectile Function (IIEF)-5 score in infertility male patients with varicocele. In this prospective study, 181 patients were included and they chose the treatment by themselves. A total of 114 patients who received MSV without testicular delivery (TD) and 67 patients who received MSV with TD were followed-up 6 months after the operation. Semen parameters, serum T level and IIEF-5 scores were recorded before and 6 months after the operation. Results showed that MSV with or without TD could improve semen quality, serum T level and IIEF-5 score. For semen quality 6 months after the operation, there was no significant difference between patients received MSV with or without TD. But in patients with varicocele of grade III, MSV without testicular delivery improved the sperm concentration and motility more. And patients received MSV without TD have a higher T level 6 months after the operation, especially in patients ≤27 years. MSV with TD is not superior to that without, but this should be verified in more samples and a better designed randomised controlled study in the future.
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Infertilidade Masculina/cirurgia , Microcirurgia/métodos , Testículo/irrigação sanguínea , Procedimentos Cirúrgicos Urológicos Masculinos/métodos , Varicocele/cirurgia , Veias/cirurgia , Adulto , Humanos , Infertilidade Masculina/etiologia , Canal Inguinal , Ligadura , Masculino , Ereção Peniana , Estudos Prospectivos , Análise do Sêmen , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Testosterona/metabolismo , Resultado do Tratamento , Varicocele/complicações , Varicocele/metabolismo , Procedimentos Cirúrgicos Vasculares/métodos , Adulto JovemRESUMO
Heterotrimeric G proteins, which consist of Gα , Gß and Gγ subunits, function as molecular switches that regulate a wide range of developmental processes in plants. In this study, we characterised the function of rice RGG2, which encodes a type B Gγ subunit, in regulating grain size and yield production. The expression levels of RGG2 were significantly higher than those of other rice Gγ -encoding genes in all tissues tested, suggesting that RGG2 plays essential roles in rice growth and development. By regulating cell expansion, overexpression of RGG2 in Nipponbare (NIP) led to reduced plant height and decreased grain size. By contrast, two mutants generated by the clustered, regularly interspaced, short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system in the Zhenshan 97 (ZS97) background, zrgg2-1 and zrgg2-2, exhibited enhanced growth, including elongated internodes, increased 1000-grain weight and plant biomass and enhanced grain yield per plant (+11.8% and 16.0%, respectively). These results demonstrate that RGG2 acts as a negative regulator of plant growth and organ size in rice. By measuring the length of the second leaf sheath after gibberellin (GA3 ) treatment and the GA-induced α-amylase activity of seeds, we found that RGG2 is also involved in GA signalling. In summary, we propose that RGG2 may regulate grain and organ size via the GA pathway and that manipulation of RGG2 may provide a novel strategy for rice grain yield enhancement.
Assuntos
Grão Comestível/crescimento & desenvolvimento , Subunidades gama da Proteína de Ligação ao GTP/genética , Oryza/genética , Proteínas de Plantas/genética , Sistemas CRISPR-Cas , Grão Comestível/genética , Subunidades gama da Proteína de Ligação ao GTP/fisiologia , Edição de Genes/métodos , Regulação da Expressão Gênica de Plantas , Mutação/genética , Oryza/crescimento & desenvolvimento , Proteínas de Plantas/fisiologia , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/crescimento & desenvolvimentoRESUMO
Polyamines, including putrescine, spermidine, and spermine, play essential roles in a wide variety of prokaryotic and eukaryotic organisms. Rice (Oryza sativa) contains four putative spermidine/spermine synthase (SPMS)-encoding genes (OsSPMS1, OsSPMS2, OsSPMS3, and OsACAULIS5), but none have been functionally characterized. In this study, we used a reverse genetic strategy to investigate the biological function of OsSPMS1 We generated several homozygous RNA interference (RNAi) and overexpression (OE) lines of OsSPMS1 Phenotypic analysis indicated that OsSPMS1 negatively regulates seed germination, grain size, and grain yield per plant. The ratio of spermine to spermidine was significantly lower in the RNAi lines and considerably higher in the OE lines than in the wild type, suggesting that OsSPMS1 may function as a SPMS. S-Adenosyl-l-methionine is a common precursor of polyamines and ethylene biosynthesis. The 1-aminocyclopropane-1-carboxylic acid (ACC) and ethylene contents in seeds increased significantly in RNAi lines and decreased in OE lines, respectively, compared with the wild type. Additionally, the reduced germination rates and growth defects of OE lines could be rescued with ACC treatment. These data suggest that OsSPMS1 affects ethylene synthesis and may regulate seed germination and plant growth by affecting the ACC and ethylene pathways. Most importantly, an OsSPMS1 knockout mutant showed an increase in grain yield per plant in a high-yield variety, Suken118, suggesting that OsSPMS1 is an important target for yield enhancement in rice.
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Germinação/fisiologia , Oryza/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Sementes/crescimento & desenvolvimento , Espermina Sintase/metabolismo , Aminoácidos Cíclicos/metabolismo , Etilenos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Homeostase , Oryza/enzimologia , Oryza/genética , Filogenia , Proteínas de Plantas/genética , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Brotos de Planta/genética , Brotos de Planta/crescimento & desenvolvimento , Plantas Geneticamente Modificadas , Sementes/genética , Sementes/metabolismo , Espermina Sintase/genéticaRESUMO
As the most common histological subtype of lung cancer, lung adenocarcinoma remains a tremendous risk to public health, which requires ceaseless efforts to elucidate the potential diagnostic and therapeutic strategies. Circular RNAs (circRNAs) have been identified with emerging roles in tumorigenesis and development. Our preliminary work noticed that hsa_circ_0025036 was significantly upregulated in lung adenocarcinoma tissues. However, its specific roles in lung adenocarcinoma remain unclear. The results in this study revealed that hsa_circ_0025036 existed as a circular form and was aberrantly upregulated in lung adenocarcinoma tissues via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Its expression level exhibited a close link with aggressive clinicopathological parameters including cancer differentiation, TNM stage and lymph node metastasis. hsa_circ_0025036 knockdown significantly suppressed cell proliferation and promoted cell apoptosis in A549 and Calu-3 cells. Moreover, hsa_circ_0025036/miR-198/SHMT1&TGF-α axis was identified via bioinformatics analysis and Dual-Luciferase Reporter assays. miR-198 inhibitors reversed the function of hsa_circ_0025036 knockdown. hsa_circ_0025036 knockdown exerted similar effects with miR-198 upregulation on cell proliferation and apoptosis. In conclusion, we demonstrate that hsa_circ_0025036 regulates cell proliferation and apoptosis in lung adenocarcinoma cells probably via hsa_circ_0025036/miR-198/SHMT1&TGF-α axis. hsa_circ_0025036 may serve as a potential prognostic biomarker and a therapeutic target for lung adenocarcinoma.
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Adenocarcinoma de Pulmão/metabolismo , Apoptose/genética , Neoplasias Pulmonares/metabolismo , RNA/metabolismo , Adenocarcinoma de Pulmão/patologia , Proliferação de Células/genética , Biologia Computacional , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , MicroRNAs/farmacologia , Pessoa de Meia-Idade , RNA/antagonistas & inibidores , RNA/genética , RNA Circular , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
MAIN CONCLUSION: The acetohydroxy acid synthase S627N mutation confers herbicide tolerance in rice, and the rice variety containing this mutation produces good yields. This variety is commercially viable at Shanghai and Jiangsu regions in China. Weedy rice is a type of rice that produces lower yields and poorer quality grains than cultivated rice. It plagues commercial rice fields in many countries. One strategy to control its proliferation is to develop rice varieties that are tolerant to specific herbicides. Acetohydroxy acid synthase (AHAS) mutations have been found to confer herbicide tolerance to rice. Here, we identified a single mutation (S627N) in AHAS from an indica rice variety that conferred tolerance against imidazolinone herbicides, including imazethapyr and imazamox. A japonica rice variety (JD164) was developed to obtain herbicide tolerance by introducing the mutated indica ahas gene. Imidazolinone application was sufficient to efficiently control weedy rice in the JD164 field. Although the imazethapyr treatment caused dwarfing in the JD164 plants, it did not significantly reduce yields. To determine whether the decrease of the ahas mRNA expression caused the dwarfism of JD164 after imazethapyr application, we detected the ahas mRNA level in plants. The abundance of the ahas mRNA in JD164 increased after imidazolinone application, thus excluding the mRNA expression level as a possible cause of dwarfism. Activity assays showed that the mutated AHAS was tolerant to imidazolinone but the catalytic efficiency of the mutated AHAS decreased in its presence. Moreover, the activity of the mutated AHAS decreased more in the presence of imazethapyr than in the presence of imazamox. We observed no difference in the AHAS secondary structures, but homology modeling suggested that the S627N mutation enabled the substrate to access the active site channel in AHAS, resulting in imidazolinone tolerance. Our work combined herbicides with a rice variety to control weedy rice and showed the mechanism of herbicide tolerance in this rice variety.
Assuntos
Acetolactato Sintase/genética , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Imidazolinas/farmacologia , Oryza/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Acetolactato Sintase/metabolismo , China , Produção Agrícola , Oryza/enzimologiaRESUMO
MiR-198 is involved in tumorigenesis, migration, invasion, and metastasis of various malignant cancers. However, the exact expression levels of miR-198 and the molecular mechanism underlying its role in lung adenocarcinoma require further exploration. In this study, quantitative real-time PCR was applied to study miR-198 and serine hydroxymethyltransferase 1 (SHMT1) expression in 47 paired lung adenocarcinoma tissues and adjacent nontumor lung tissues. Clinicopathological characters were analyzed. Pearson's correlation analysis was used to detect the relationship between miR-198 and SHMT1 expression. The function of miR-198 was explored by measuring cell proliferation, cell apoptosis, and the cell-cycle in vitro and in vivo. The target gene of miR-198 was certified using dual luciferase report assay. We found that in lung adenocarcinoma, miR-198 was significantly downregulated and SHMT1 was inversely upregulated. A strong negative correlation was noticed between miR-198 and SHMT1 expression. Further analysis revealed that miR-198 expression was associated with TNM stage and lymph node metastasis. Upregulated miR-198 could inhibit cell proliferation, enhance cell apoptosis, and lead to cell-cycle arrest in lung adenocarcinoma, which showed a more effective alteration than SHMT1 siRNA. Moreover, we identified SHMT1 as a target gene of miR-198. In conclusion, miR-198 suppressed proliferation of lung adenocarcinoma cells both in vitro and in vivo by directly targeting SHMT1. miR-198 may be a potential therapeutic target for lung adenocarcinoma in the near future.
Assuntos
Adenocarcinoma/genética , Carcinogênese/genética , Glicina Hidroximetiltransferase/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , MicroRNAs/biossíntese , Pessoa de Meia-IdadeRESUMO
Currently, lung cancer is still a main cause of malignancy-associated death worldwide. Even though various methods for prevention and treatment of lung cancer have been improved in recent decades, the 5-year survival rate has remained very low. Insights into the anticancer function of small-molecule anticancer compounds have opened our visual field about cancer therapy. α-Solanine has been well studied for its antitumor properties, but its effect in lung cancer and associated molecular mechanisms have not yet been evaluated. To explore the anticancer function of α-solanine, we performed an MTT assay, Transwell arrays, colony-forming survival assay, quantitative reverse transcription PCR (qRT-PCR), Western blotting, and dual luciferase reporter assays in A549 and H1299 cells. We found that α-solanine not only inhibited cell migration and invasion ability but also enhanced the chemosensitivity and radiosensitivity of A549 and H1299 cells. Moreover, we discovered that α-solanine could affect the expression of miR-138 and focal adhesion kinase (FAK), both of which were also found to affect the chemosensitivity and radiosensitivity of A549 and H1299 cells. In conclusion, α-solanine could affect miR-138 and FAK expression to restrict cell migration and invasion and enhance the chemosensitivity and radiosensitivity of A549 and H1299 cells. The α-solanine/miR-138/FAK cascade can probably be a potential therapy target against lung adenocarcinoma.
Assuntos
Adenocarcinoma/genética , Antineoplásicos Fitogênicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/genética , MicroRNAs/genética , Solanina/farmacologia , Regiões 3' não Traduzidas , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão , Antineoplásicos Fitogênicos/química , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Interferência de RNA , Tolerância a Radiação/efeitos dos fármacos , Solanina/químicaRESUMO
OBJECTIVE: To investigate the changes in expression of the ACE2/Ang(1-7)/Mas receptor axis' components that occur during progression of liver fibrosis using a rat model system. METHODS: Thirty-six adult male Wistar rats, were randomly assigned to groups of normal control (n = 6; no manipulation) and liver fibrosis (n = 30; given a subcutaneous injection of 40% chronic carbon tetrachloride (CCl4)). At post-injection days 15, 30, 45, 60 and 75, 1 control rat and 6 modeled rats were sacrificed for analysis. Histopathological analysis of liver tissue was performed with hematoxylin-eosin and rapid Masson staining. Protein expression level of Ang(1-7) was determined by enzyme-linked immunosorbent assay, and of ACE2 and Mas receptor was evaluated by immunohistochemistry. Real-time PCR was used to measure the mRNA expression levels of ACE2 and Mas receptor. RESULTS: The expression levels of ACE2, Ang(1-7) and Mas receptor showed a statistically significant upward trend that followed the progression of fibrosis up to post-injection day 60 (P less than 0.01), but the significant increase was not seen from day 60 to day 75. CONCLUSION: Each component of the ACE2/Ang(1-7)/Mas receptor axis shows differential expression during the development of liver fibrosis and may contribute to disease progression.
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Puerarin (Pue), a flavonoid compound, possesses cytoprotective effects and LPS has been reported to induce renal inflammatory injury in bovine. However, whether Pue inhibits lipopolysaccharide (LPS)-induced inflammatory damage of bovine kidney cells remains unknown. Based on an in vitro model with Madin-Darby bovine kidney (MDBK) cell line, it has found that Pue attenuated LPS-induced damage of MDBK cells, as evidenced by cell viability and lactic dehydrogenase (LDH) release rescued by Pue (P < 0.05). Additionally, the real-time quantitative PCR (qPCR) and enzyme linked immunosorbent assay (ELISA) showed that LPS elevated the levels of pro-inflammatory factors interleukin (IL)-1ß, IL-8 and tumor necrosis factor (TNF)-α, which was reversed by pretreatment of Pue (P < 0.05). Besides, Pue reduced the expression of Toll like receptor 4 (TLR4) and phosphorylated nuclear factor kappa B (p-NF-κB) of LPS-exposed MDBK cells (P < 0.05). Collectively, these results showed that Pue suppresses LPS-evoked inflammatory damage of bovine kidney cells, suggesting Pue a potential compound for intervention of bovine inflammation.
Assuntos
Isoflavonas , Rim , Lipopolissacarídeos , Animais , Bovinos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Interleucina-8/genética , Isoflavonas/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Rim/citologia , L-Lactato Desidrogenase/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Gefitinib (GR), a representative drug of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is a key pillar in the treatment of lung adenocarcinoma (LUAD), but drug resistance is universal. Identifying the potential factors of drug resistance to GR is essential to treat patients with EGFR mutant LUAD. METHODS: The GR-resistant LUAD cells were established and confirmed by MTT assay. The effects of PC4 and SRSF1 interacting protein 1 (PSIP1) on GR-resistant cell proliferation and apoptosis in vitro and in vivo were detected by colony formation, flow cytometry, tumor-bearing animal model, immunohistochemistry, and TUNEL staining. Western blotting and qPCR were used to determine the expression of relevant markers. The effect of PSIP1 on the promoter region of Wiskott-Aldrich syndrome protein family member 3 (WASF3) was detected by the dual-luciferase assay. The interaction between PSIP1 and RNA polymerase II was evaluated using ChIP-qPCR and Co-IP assays. RESULTS: PSIP1 was highly enriched in GR-resistant LUAD cells. Downregulation of PSIP1 expression significantly inhibited the proliferation of LUAD-resistant cells and promoted apoptosis. WASF3 was shown to have similar effects as PSIP1 in promoting drug resistance in LUAD cells. PSIP1 promoted the transcriptional activity of WASF3, which was achieved by increasing RNA polymerase II recruitment on the WASF3 promoter. Furthermore, PSIP1 positively regulated the expression of the pro-EGFR-TKI resistance factor integrin subunit beta 3 (ITGB3). CONCLUSION: Our work suggests that PSIP1 promotes resistance to GR in LUAD cells by inducing the expression of WASF3 and its downstream regulator ITGB3.
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Approximation ability is one of the most important topics in the field of neural networks (NNs). Feedforward NNs, activated by rectified linear units and some of their specific smoothed versions, provide universal approximators to convex as well as continuous functions. However, most of these networks are investigated empirically, or their characteristics are analyzed based on specific operation rules. Moreover, an adequate level of interpretability of the networks is missing as well. In this work, we propose a class of new network architecture, built with reusable neural modules (functional blocks), to supply differentiable and interpretable approximators for convex and continuous target functions. Specifically, first, we introduce a concrete model construction mechanism with particular blocks based on differentiable programming and the composition essence of the max operator, extending the scope of existing activation functions. Moreover, explicit block diagrams are provided for a clear understanding of the external architecture and the internal processing mechanism. Subsequently, the approximation behavior of the proposed network to convex functions and continuous functions is rigorously proved as well, by virtue of mathematical induction. Finally, plenty of numerical experiments are conducted on a wide variety of problems, which exhibit the effectiveness and the superiority of the proposed model over some existing ones.
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The extracellular matrix plays a crucial role in the growth of human neural stem cells (hNSCs) by forming a stem cell niche, bothin vitroandin vivo. The demand for defined synthetic substrates has been increasing recently in stem cell research, reflecting the requirements for precise functions and safety concerns in potential clinical approaches. In this study, we tested the adhesion and expansion of one of the most representative hNSC lines, the ReNcell VM Human Neural Progenitor Cell Line, in a pure-synthesized short peptide-basedin vitroniche using a previously established integrin-binding peptide array. Spontaneous cell differentiation was then induced using two differentin vitroapproaches to further confirm the multipotent features of cells treated with the peptides. Twelve different integrin-binding peptides were capable of supporting hNSC adhesion and expansion at varied proliferation rates. In the ReNcell medium-based differentiation approach, cells detached in almost all peptide-based groups, except integrinα5ß1 binding peptide. In an altered differentiation process induced by retinoic acid containing neural differentiation medium, cell adhesion was retained in all 12 peptide groups. These peptides also appeared to have varied effects on the differentiation potential of hNSCs towards neurons and astrocytes. Our findings provide abundant options for the development ofin vitroneural stem cell niches and will help develop promising tools for disease modeling and future stem cell therapies for neurological diseases.
Assuntos
Adesão Celular , Diferenciação Celular , Proliferação de Células , Integrinas , Células-Tronco Neurais , Peptídeos , Humanos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Diferenciação Celular/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , Integrinas/metabolismo , Proliferação de Células/efeitos dos fármacos , Linhagem Celular , Matriz Extracelular/metabolismo , Neurônios/metabolismo , Neurônios/citologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Tretinoína/farmacologia , Propriedades de Superfície , Astrócitos/metabolismo , Astrócitos/citologiaRESUMO
Based on the core hysteresis features, the RTD-fluxgate core, while working, is repeatedly saturated with excitation field. When the fluxgate simulates, the accurate characteristic model of the core may provide a precise simulation result. As the shape of the ideal hysteresis loop model is fixed, it cannot accurately reflect the actual dynamic changing rules of the hysteresis loop. In order to improve the fluxgate simulation accuracy, a dynamic hysteresis loop model containing the parameters which have actual physical meanings is proposed based on the changing rule of the permeability parameter when the fluxgate is working. Compared with the ideal hysteresis loop model, this model has considered the dynamic features of the hysteresis loop, which makes the simulation results closer to the actual output. In addition, other hysteresis loops of different magnetic materials can be explained utilizing the described model for an example of amorphous magnetic material in this manuscript. The model has been validated by the output response comparison between experiment results and fitting results using the model.