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1.
Clin Case Rep ; 12(4): e8680, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38571902

RESUMO

Key Clinical Message: In a patient with metastatic breast cancer, an acquired BRCA mutation in the BRCA gene was detected, resulting in benefits from olaparib treatment. This underscores the importance of ongoing genetic phenotype testing after paclitaxel chemotherapy. Abstract: Triple-negative breast cancer (TNBC) is associated with a poor prognosis and elevated mortality risk. BRCA mutations are commonly regarded as prevalent mutations in TNBC patients, strongly associated with congenital familial heredity. Dynamic changes in mutation sites, however, are rarely reported. In this case report, we report a 59-year-old TNBC patient who developed pulmonary metastases post-chemoradiotherapy. No BRCA mutations were detected through NGS. After 7.6 months of nab-paclitaxel treatment, the patient experienced progression of lung metastases, and BRCA mutations were detected through NGS testing. Subsequent administration of olaparib resulted in a reduction in lung metastasis, demonstrating significant therapeutic efficacy. This case underscores the infrequent occurrence of treatment-induced BRCA mutations and emphasizes the significance of dynamic NGS genetic testing for real-time assessment of a patient's mutational status.

2.
Heliyon ; 10(7): e28458, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38601543

RESUMO

In managing unique complexities associated with Chinese medicinal quality assessment, metabolomics serves as an innovative tool. This study proposes an analytical approach to assess differing qualities of Scrophularia ningpoensis (S. ningpoensis)Hemsl by identifying potential biomarker metabolites and their activity with the corresponding secondary metabolites. The methodology includes four steps; first, a GC-MS based metabolomics exploration of the Scrophularia ningpoensis Hemsl. Second, a multivariate statistical analysis (PCA, PLS-DA, OPLS-DA) for quality assessment and biomarker identification. Third, the application of ROC analysis and pathway analysis based on identified biomarkers. Finally, validation of the associated active ingredients by HPLC. The analysis showed distinct metabolite profiles across varying grades of S. ningpoensis Hemsl, establishing a grading dependency relationship. Select biomarkers (gluconic Acid, d-xylulose, sucrose, etc.) demonstrated robust grading performances. Further, the Pentose Phosphate Pathway, deemed as most influential in grading, was tied to the synthesis of key constituents (iridoids, phenylpropanoids). HPLC validation tests affirm a decreasing trend in harpagoside and cinnamic acid levels between first and third-grade samples. In conclusion, this GC-MS based metabolomics combined HPLC method offers a sound approach to assess and distinguish quality variations in S. ningpoensis Hemsl samples.

3.
Org Lett ; 26(15): 3037-3042, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38557076

RESUMO

A synthetic method for the enantioselective and regiodivergent synthesis of hexahydro-2H-2,4a-methanonaphthalen-4-yl and octahydro-2,4-methanoazulen-1-yl esters that relies on the gold(I)- and chiral Brønsted acid-catalyzed cycloisomerization/Diels-Alder (CDA) reaction of (E)-1,10-dien-4-yn-3-yl acetates is described.

4.
Nat Commun ; 15(1): 1908, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459023

RESUMO

Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.


Assuntos
Acetaminofen , Fígado , Animais , Humanos , Masculino , Camundongos , Acetaminofen/toxicidade , Receptor de Asialoglicoproteína/genética , Receptor de Asialoglicoproteína/metabolismo , Estresse do Retículo Endoplasmático , Fibrose , Fígado/metabolismo , Cirrose Hepática/patologia
5.
Nature ; 626(8001): 1042-1048, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38418917

RESUMO

The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'1-3, with a proposed role in contributing to human bipedalism4-6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans10. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.


Assuntos
Processamento Alternativo , Evolução Molecular , Hominidae , Proteínas com Domínio T , Cauda , Animais , Humanos , Camundongos , Processamento Alternativo/genética , Elementos Alu/genética , Modelos Animais de Doenças , Genoma/genética , Hominidae/anatomia & histologia , Hominidae/genética , Íntrons/genética , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Fenótipo , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Cauda/anatomia & histologia , Cauda/embriologia , Éxons/genética
7.
Biochem Genet ; 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38280152

RESUMO

The feather growth rate in chickens included early and late feathering. We attempted to characterize the genes and pathways associated with the feather growth rate in chickens that are not in agreement with Mendelian inheritance. Gene expression profiles in the hair follicle tissues of late-feathering cocks (LC), early-feathering cocks (EC), late-feathering hens (LH), and early-feathering hens (EH) were acquired using RNA sequencing (RNA-seq), mass spectrometry (MS), and quantitative reverse transcription PCR (qRT­PCR). A total of 188 differentially expressed genes (DEGs) were ascertained in EC vs. LC and 538 DEGs were identified in EH vs. LH. We observed that 14 up-regulated genes and 9 down-regulated genes were screened both in EC vs. LC and EH vs. LH. MS revealed that 41 and 138 differentially expressed proteins (DEPs) were screened out in EC vs. LC and EH vs. LH, respectively. Moreover, these DEGs and DEPs were enriched in multiple feather-related pathways, including JAK-STAT, MAPK, WNT, TGF-ß, and calcium signaling pathways. qRT-PCR assay showed that the expression of WNT8A was decreased in LC compared with EC, while ALK and GRM4 expression were significantly up-regulated in EH relative to LH. This study helps to elucidate the potential mechanism of the feather growth rate in chickens that do not conform to genetic law.

8.
J Cell Mol Med ; 28(3): e18097, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38164738

RESUMO

Current studies have indicated that insufficient trophoblast epithelial-mesenchymal transition (EMT), migration and invasion are crucial for spontaneous abortion (SA) occurrence and development. Exosomal miRNAs play significant roles in embryonic development and cellular communication. Hereon, we explored the roles of serum exosomes derived from SA patients on trophoblast EMT, migration and invasion. Exosomes were isolated from normal control (NC) patients with abortion for unplanned pregnancy and SA patients, then characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting. Exosomal miRNA profiles were identified by miRNA sequencing. The effects of serum exosomes on trophoblast migration and invasion were detected by scratch wound healing and transwell assays, and other potential mechanisms were revealed by quantitative real-time PCR (RT-PCR), western blotting and dual-luciferase reporter assay. Finally, animal experiments were used to explore the effects of exosomal miR-410-3p on embryo absorption in mice. The serum exosomes from SA patients inhibited trophoblast EMT and reduced their migration and invasion ability in vitro. The miRNA sequencing showed that miR-410-3p was upregulated in SA serum exosomes. The functional experiments showed that SA serum exosomes restrained trophoblast EMT, migration and invasion by releasing miR-410-3p. Mechanistically, SA serum exosomal miR-410-3p inhibited trophoblast cell EMT, migration and invasion by targeting TNF receptor-associated factor 6 (TRAF6) at the post-transcriptional level. Besides, SA serum exosomal miR-410-3p inhibited the p38 MAPK signalling pathway by targeting TRAF6 in trophoblasts. Moreover, milk exosomes loaded with miR-410-3p mimic reached the maternal-fetal interface and aggravated embryo absorption in female mice. Clinically, miR-410-3p and TRAF6 expression were abnormal and negatively correlated in the placental villi of SA patients. Our findings indicated that exosome-derived miR-410-3p plays an important role between SA serum and trophoblasts in intercellular communication, suggesting a novel mechanism by which serum exosomal miRNA regulates trophoblasts in SA patients.


Assuntos
Aborto Espontâneo , Exossomos , MicroRNAs , Humanos , Feminino , Gravidez , Camundongos , Animais , Exossomos/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Placenta/metabolismo , MicroRNAs/genética , Trofoblastos/metabolismo , Transição Epitelial-Mesenquimal/genética , Proliferação de Células , Movimento Celular/genética
9.
Mol Nutr Food Res ; 68(1): e2300283, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37888838

RESUMO

SCOPE: Propolis has been found to decrease glucose levels and increase insulin sensitivity in type 2 diabetes. However, the active ingredient responsible for these effects and its regulating mechanism are not fully understood. METHODS AND RESULTS: To address this, molecular docking screening is used to screen the effective hypoglycemic ingredient in propolis and found that tectochrysin (TEC) has a high affinity to the insulin receptor (IR), highlighting its potential for glycemic control. In vivo tests show that TEC decreases glucose levels and enhances insulin sensitivity in db/db mice. By hyperinsulinemic euglycemic clamp test, this study further finds that TEC promotes glucose uptake in adipose tissue and skeletal muscle, as well as inhibits hepatic gluconeogenesis. Moreover, it finds that TEC promotes glucose uptake and adipocytes differentiation in 3T3-L1 cells like insulin, suggesting that TEC exerts an insulin mimetic effect. Mechanistically, pharmacology inhibition of IRß abolishes the effects of TEC on glucose uptake and the phosphorylation of IR. The study further demonstrates that TEC binds to and activates IRß by targeting its E1077 and M1079. CONCLUSION: Therefore, this study sheds light on the mechanism underlying propolis' potential for ameliorating type 2 diabetes, offering a natural food-derived compound as a promising therapeutic option.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Própole , Camundongos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptor de Insulina/metabolismo , Própole/farmacologia , Simulação de Acoplamento Molecular , Insulina/metabolismo , Glucose/metabolismo , Células 3T3-L1
10.
Eur Radiol ; 34(3): 1524-1533, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37644150

RESUMO

OBJECTIVES: To develop a mediastinal shift angle (MSA) measurement method applicable to right-sided congenital diaphragmatic hernia (RCDH) in fetal MRI and to validate the predictive value of MSA in RCDH. METHODS: Twenty-seven fetuses with isolated RCDH and 53 controls were included in our study. MSA was measured on MRI axial image at the level of four-chamber view of the fetal heart. The angle between the sagittal midline landmark line and the left boundary landmark line touching tangentially the lateral wall of the left ventricle was used to quantify MSA for RCDH. Appropriate statistical analyses were performed to determine whether MSA can be regarded as a valid predictive tool for postnatal outcomes. Furthermore, predictive performance of MSA was compared with that of lung area to head circumference ratio (LHR), observed/expected LHR (O/E LHR), total fetal lung volume (TFLV), and observed/expected TFLV (O/E TFLV). RESULTS: MSA was significantly higher in the RCDH group than in the control group. MSA, LHR, O/E LHR, TFLV, and O/E TFLV were all correlated with postnatal survival, pulmonary hypertension (PH), and extracorporeal membrane oxygenation (ECMO) therapy (p < 0.05). Value of the AUC demonstrated good predictive performance of MSA for postnatal survival (0.901, 95%CI: (0.781-1.000)), PH (0.828, 95%CI: (0.661-0.994)), and ECMO therapy (0.813, 95%CI: (0.645-0.980)), which was similar to O/E TFLV but slightly better than TFLV, O/E LHR, and LHR. CONCLUSIONS: We developed a measurement method of MSA for RCDH for the first time and demonstrated that MSA could be used to predict postnatal survival, PH, and ECMO therapy in RCDH. CLINICAL RELEVANCE STATEMENT: Newly developed MRI assessment method of fetal MSA in RCDH offers a simple and effective risk stratification tool for patients with RCDH. KEY POINTS: • We developed a measurement method of mediastinal shift angle for right-sided congenital diaphragmatic hernia for the first time and demonstrated its feasibility and reproducibility. • Mediastinal shift angle can predict more prognostic information other than survival in right-sided congenital diaphragmatic hernia with good performance. • Mediastinal shift angle can be used as a simple and effective risk stratification tool in right-sided congenital diaphragmatic hernia to improve planning of postnatal management.


Assuntos
Hérnias Diafragmáticas Congênitas , Hipertensão Pulmonar , Gravidez , Feminino , Humanos , Hérnias Diafragmáticas Congênitas/diagnóstico por imagem , Hérnias Diafragmáticas Congênitas/terapia , Pulmão/diagnóstico por imagem , Medidas de Volume Pulmonar/métodos , Reprodutibilidade dos Testes , Imageamento por Ressonância Magnética , Medição de Risco , Ultrassonografia Pré-Natal , Estudos Retrospectivos
11.
Cell Metab ; 35(12): 2165-2182.e7, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38056430

RESUMO

A ketogenic diet (KD) has been promoted as an obesity management diet, yet its underlying mechanism remains elusive. Here we show that KD reduces energy intake and body weight in humans, pigs, and mice, accompanied by elevated circulating growth differentiation factor 15 (GDF15). In GDF15- or its receptor GFRAL-deficient mice, these effects of KD disappeared, demonstrating an essential role of GDF15-GFRAL signaling in KD-mediated weight loss. Gdf15 mRNA level increases in hepatocytes upon KD feeding, and knockdown of Gdf15 by AAV8 abrogated the obesity management effect of KD in mice, corroborating a hepatic origin of GDF15 production. We show that KD activates hepatic PPARγ, which directly binds to the regulatory region of Gdf15, increasing its transcription and production. Hepatic Pparγ-knockout mice show low levels of plasma GDF15 and significantly diminished obesity management effects of KD, which could be restored by either hepatic Gdf15 overexpression or recombinant GDF15 administration. Collectively, our study reveals a previously unexplored GDF15-dependent mechanism underlying KD-mediated obesity management.


Assuntos
Dieta Cetogênica , Obesidade , Animais , Humanos , Camundongos , Fator 15 de Diferenciação de Crescimento/metabolismo , Camundongos Knockout , Obesidade/metabolismo , PPAR gama , Suínos , Redução de Peso
12.
BMC Pulm Med ; 23(1): 503, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38087209

RESUMO

OBJECTIVE: The purpose of this study was to examine the feasibility of using a combination of diaphragmatic ultrasound and muscle relaxation monitoring in predicting adverse respiratory events after extubation among elderly patients in an anesthetic intensive care unit (AICU). METHODS: The study participants were 120 elderly patients who were in the AICU after laparoscopic radical resection for colorectal cancer. Based on whether there were critical respiratory events (CREs) after extubation, they were divided into the adverse event group and the non-adverse event group. We used logistic regression to identify factors influencing the occurrence of CREs post-extubation in elderly patients. Using the receiver operating characteristic (ROC) curve, we analyzed the value of each indicator in predicting CREs post-extubation. RESULTS: We included 109 patients in the final analysis. In the adverse event group (n = 19), the age, proportion of females, and proportion of preoperative respiratory diseases were higher than in the non-adverse event group (n = 90). The muscle relaxation value, quiet breathing diaphragmatic excursion during extubation (DE-QB), deep breathing diaphragmatic excursion during extubation (DE-DB), and deep breathing diaphragmatic thickening fraction during extubation (DTF-DB) of patients in the adverse event group were significantly lower than those in the non-adverse event group (P < 0.05). Using binary logistic regression analysis, we identified muscle relaxation value, DE-DB, and DTF-DB during extubation as significant predictors of CREs post-extubation in elderly patients (P < 0.05). The area under the curve (AUC) of the combination of the muscle relaxation value, DE-DB, and DTF-DB during extubation for predicting CREs after extubation in elderly patients was 0.949, which was higher than that of any single indicator. CONCLUSION: The combination of diaphragmatic ultrasound and muscle relaxation monitoring was more accurate in predicting CREs post-extubation among elderly patients in the AICU.


Assuntos
Anestesia , Desmame do Respirador , Feminino , Humanos , Idoso , Extubação/efeitos adversos , Estudos Prospectivos , Valor Preditivo dos Testes , Ultrassonografia , Diafragma/diagnóstico por imagem , Unidades de Terapia Intensiva , Respiração Artificial
13.
Environ Sci Pollut Res Int ; 30(58): 122304-122321, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37966638

RESUMO

Identifying the regional differences and drivers for carbon reduction of construction and demolition waste (C&DW) recycling is essential to combat climate change. This study aims to calculate the carbon reduction potential for C&DW recycling from 2006 to 2021 in China and investigates the spatial differences and driving factors of carbon reduction potential for C&DW waste by combining the Theil index, Gini coefficient, and geographic detector methods. The carbon reduction potential for C&DW recycling in China was "high in the east and low in the west" overall level, with an average annual growth rate of 6.27%. The overall differences in carbon reduction potential for C&DW recycling are decreasing, mainly due to intraregional differences and inter-provincial differences in Northeast China. The population size, urbanization rate, and technological effect are the key factors influencing carbon reduction potential for C&DW recycling. There are two types of interactions between influencing factor pairs: nonlinear enhancement and two-factor enhancement. This study's results can guide policymakers to devise relevant, regionally specific policies.


Assuntos
Indústria da Construção , Gerenciamento de Resíduos , Gerenciamento de Resíduos/métodos , Materiais de Construção , Reciclagem , China , Urbanização , Carbono , Resíduos Industriais
14.
Plant Physiol Biochem ; 204: 108098, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37879128

RESUMO

Research of lactic acid bacteria and its metabolites on biological preservatives becomes a hot topic. Lactobacillus plantarum O2, with good inhibition on Phytophthora capsici (P. capsici), was isolated from the pickle. In this study, the effects of L. plantarum O2 fermentation supernatant (FS) on pepper postharvest preservation and its induced resistance to P. capsici were studied. Results showed that weight loss rate, rot index, respiration rate, relative electrical conductivity, loss of chlorophyll content and VC of pepper in FS treatment group were decreased by 18 %, 64 %, 15 %, 26 %, 33 % and 20 % compared with blank control (BC) after 20 d storage. L* and b*-value of pepper in FS group were lower than those in the BC group. In addition, the damage-induced resistance test found that the infection rate in the FS group was reduced by 39 %, compared with CK2 after 12 d storage. Moreover, phenylalanine ammonia-lyase activity, peroxidase activity, polyphenol oxidase activity, proline content, total phenol content and flavonoid content increased by 14 %, 9 %, 30 %, 8 %, 8 % and 9 %, respectively, while malondialdehyde content decreased by 13 %. These results indicated that FS treatment showed good fresh-keeping effects on postharvest pepper. It could enhance the tolerance of pepper under stress by improving defensive enzyme activities, slowing down the damage caused by P. capsici, and inducing pepper resistance to P. capsici. Therefore, FS can be used as a microbial source bio-preservative for postharvest pepper.


Assuntos
Capsicum , Lactobacillus plantarum , Phytophthora , Phytophthora/fisiologia , Fermentação , Antioxidantes , Doenças das Plantas/microbiologia
15.
Sci Total Environ ; 905: 167114, 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-37717751

RESUMO

Copper (Cu) is an important micronutrient for animals and plants, but it is toxic at high concentrations in soil. Soils adjacent to industrial areas would be subjected to severe Cu pollution. Identifying Cu sources in the surface environment is crucial for understanding their pollution level and fate. This study investigated Cu content, isotope composition of topsoils, and two soil profiles with varying levels of Cu contamination and related potential Cu sources in southwest China. The difference in Cu isotope compositions of tailing (1.29 ± 0.08 ‰), smelting fly ash (0.04 ± 0.03 ‰), coal (2.44 ± 0.09 ‰), coal-burning fly ash (0.34 ± 0.03 ‰), and geogenic soil (0.10 ± 0.03 ‰) enabled us to distinguish anthropogenic Cu from geogenic Cu. The plot of δ65Cu and 1/Cu demonstrates that Cu of the polluted soils was from three end-members: the smelting fly ash, the vehicle exhaust, and the background soils. Based on the mass balance model, we calculated that the fly ash from smelting was the major anthropogenic source, contributing approximately 29 % of Cu contamination in soils, and the diesel exhaust was another important source, with a contribution rate of approximately 25 %. Additionally, soil profile results suggest that anthropogenic Cu could transport through soil profiles and influence Cu content and isotope signatures of subsurface soils, at least to a depth of ∼60 cm. Finally, our research indicates that Cu isotopes could be a promising tool for tracing industrial pollution, as significant Cu isotope fractionation would occur during the smelting process. Our research highlights the contribution of smelting and diesel exhaust to Cu contamination in the soils in a representative mining area. These findings serve as a scientific foundation for the development of policy for pollution control in industrial-affected regions.

16.
Adv Sci (Weinh) ; 10(29): e2302298, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37551034

RESUMO

Sepsis-induced muscle atrophy often increases morbidity and mortality in intensive care unit (ICU) patients, yet neither therapeutic target nor optimal animal model is available for this disease. Here, by modifying the surgical strategy of cecal ligation and puncture (CLP), a novel sepsis pig model is created that for the first time recapitulates the whole course of sepsis in humans. With this model and sepsis patients, increased levels of the transcription factor zinc finger BED-type containing 6 (ZBED6) in skeletal muscle are shown. Protection against sepsis-induced muscle wasting in ZBED6-deficient pigs is further demonstrated. Mechanistically, integrated analysis of RNA-seq and ChIP-seq reveals dedicator of cytokinesis 3 (DOCK3) as the direct target of ZBED6. In septic ZBED6-deficient pigs, DOCK3 expression is increased in skeletal muscle and myocytes, activating the RAC1/PI3K/AKT pathway and protecting against sepsis-induced muscle wasting. Conversely, opposite gene expression patterns and exacerbated muscle wasting are observed in septic ZBED6-overexpressing myotubes. Notably, sepsis patients show increased ZBED6 expression along with reduced DOCK3 and downregulated RAC1/PI3K/AKT pathway. These findings suggest that ZBED6 is a potential therapeutic target for sepsis-induced muscle atrophy, and the established sepsis pig model is a valuable tool for understanding sepsis pathogenesis and developing its therapeutics.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Sepse , Animais , Humanos , Suínos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases , Transdução de Sinais , Atrofia Muscular/etiologia , Atrofia Muscular/prevenção & controle , Sepse/complicações , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas do Tecido Nervoso/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo
17.
Nucleic Acids Res ; 51(12): 6020-6038, 2023 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-37125636

RESUMO

Cell identity genes are distinct from other genes with respect to the epigenetic mechanisms to activate their transcription, e.g. by super-enhancers and broad H3K4me3 domains. However, it remains unclear whether their post-transcriptional regulation is also unique. We performed a systematic analysis of transcriptome-wide RNA stability in nine cell types and found that unstable transcripts were enriched in cell identity-related pathways while stable transcripts were enriched in housekeeping pathways. Joint analyses of RNA stability and chromatin state revealed significant enrichment of super-enhancers and broad H3K4me3 domains at the gene loci of unstable transcripts. Intriguingly, the RNA m6A methyltransferase, METTL3, preferentially binds to chromatin at super-enhancers, broad H3K4me3 domains and their associated genes. METTL3 binding intensity is positively correlated with RNA m6A methylation and negatively correlated with RNA stability of cell identity genes, probably due to co-transcriptional m6A modifications promoting RNA decay. Nanopore direct RNA-sequencing showed that METTL3 knockdown has a stronger effect on RNA m6A and mRNA stability for cell identity genes. Our data suggest a run-and-brake model, where cell identity genes undergo both frequent transcription and fast RNA decay to achieve precise regulation of RNA expression.


Assuntos
Cromatina , Regulação da Expressão Gênica , Estabilidade de RNA , Cromatina/genética , Epigênese Genética , Metiltransferases/metabolismo , RNA/química
18.
Nat Commun ; 14(1): 2390, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37185814

RESUMO

A comprehensive understanding of endothelial cell lineage specification will advance cardiovascular regenerative medicine. Recent studies found that unique epigenetic signatures preferentially regulate cell identity genes. We thus systematically investigate the epigenetic landscape of endothelial cell lineage and identify MECOM to be the leading candidate as an endothelial cell lineage regulator. Single-cell RNA-Seq analysis verifies that MECOM-positive cells are exclusively enriched in the cell cluster of bona fide endothelial cells derived from induced pluripotent stem cells. Our experiments demonstrate that MECOM depletion impairs human endothelial cell differentiation, functions, and Zebrafish angiogenesis. Through integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, and RNA-Seq data, we find MECOM binds enhancers that form chromatin loops to regulate endothelial cell identity genes. Further, we identify and verify the VEGF signaling pathway to be a key target of MECOM. Our work provides important insights into epigenetic regulation of cell identity and uncovered MECOM as an endothelial cell lineage regulator.


Assuntos
Células Endoteliais , Epigênese Genética , Animais , Humanos , Diferenciação Celular/genética , Linhagem da Célula/genética , Células Endoteliais/metabolismo , Proteína do Locus do Complexo MDS1 e EVI1/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
20.
Zhongguo Zhong Yao Za Zhi ; 48(5): 1280-1288, 2023 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-37005812

RESUMO

This paper compared the differences between two kinds of Bufonis Venenum produced by Bufo gargarizans gargarizans and B. gararizans andrewsi, and verified the rationality of the market value orientation of Bufonis Venenum based on the zebrafish mo-del. Twenty batches of Bufonis Venenum from Jiangsu province, Hebei province, Liaoning province, Jilin province, and Liangshan, Sichuan province, including B. gargarizans gargarizans and B. gararizans andrewsi, were collected. The UHPLC-LTQ-Orbitrap-MS combined with principal component analysis was used to compare the differences between two kinds of Bufonis Venenum. According to the limiting conditions of VIP>1, FC<0.5 or FC>2.0, and peak total area ratio>1%, 9 differential markers were determined, which were cinobufagin, cinobufotalin, arenobufagin, resibufogenin, scillaredin A, resibufagin, 3-(N-suberoylargininyl)-arenobufagin, 3-(N-suberoylargininyl)-marinobufagin, and 3-(N-suberoylargininyl)-resibufogenin. The content of 20 batches of Bufonis Venenum was determined according to the Chinese Pharmacopoeia(2020 edition) by high-performance liquid chromatography, and the 2 batches of Bufonis Venenum, CS7(8.99% of total content) and CS9(5.03% of total content), with the largest difference in the total content of the three quality control indexes of the Chinese Pharmacopoeia(bufalin, cinobufagin, and resibufogenin) were selected to evaluate their anti-liver tumor activity based on the zebrafish model. The tumor inhibition rates of the 2 batches were 38.06% and 45.29%, respectively, proving that only using the quality control indexes of the Chinese Pharmacopoeia as the value orientation of Bufonis Venenum market circulation was unreasonable. This research provides data support for the effective utilization of Bufonis Venenum resources and the establishment of a rational quality evaluation system of Bufonis Venenum.


Assuntos
Bufanolídeos , Peixe-Zebra , Animais , Bufanolídeos/análise , Bufonidae , Cromatografia Líquida de Alta Pressão , Controle de Qualidade , Linhagem Celular Tumoral
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