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1.
Mol Cell ; 83(23): 4386-4397.e9, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-37995686

RESUMO

The multi-pass transmembrane protein ACCELERATED CELL DEATH 6 (ACD6) is an immune regulator in Arabidopsis thaliana with an unclear biochemical mode of action. We have identified two loci, MODULATOR OF HYPERACTIVE ACD6 1 (MHA1) and its paralog MHA1-LIKE (MHA1L), that code for ∼7 kDa proteins, which differentially interact with specific ACD6 variants. MHA1L enhances the accumulation of an ACD6 complex, thereby increasing the activity of the ACD6 standard allele for regulating plant growth and defenses. The intracellular ankyrin repeats of ACD6 are structurally similar to those found in mammalian ion channels. Several lines of evidence link increased ACD6 activity to enhanced calcium influx, with MHA1L as a direct regulator of ACD6, indicating that peptide-regulated ion channels are not restricted to animals.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Anquirinas/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Morte Celular , Canais Iônicos/genética , Canais Iônicos/metabolismo , Imunidade Vegetal/genética
2.
J Immunol ; 210(6): 699-707, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36881905

RESUMO

C-reactive protein (CRP) is a highly conserved pentraxin with pattern recognition receptor-like activities. However, despite being used widely as a clinical marker of inflammation, the in vivo functions of CRP and its roles in health and disease remain largely unestablished. This is, to certain extent, due to the drastically different expression patterns of CRP in mice and rats, raising concerns about whether the functions of CRP are essential and conserved across species and how these model animals should be manipulated to examine the in vivo actions of human CRP. In this review, we discuss recent advances highlighting the essential and conserved functions of CRP across species, and propose that appropriately designed animal models can be used to understand the origin-, conformation-, and localization-dependent actions of human CRP in vivo. The improved model design will contribute to establishing the pathophysiological roles of CRP and facilitate the development of novel CRP-targeting strategies.


Assuntos
Proteína C-Reativa , Inflamação , Humanos , Animais , Camundongos , Ratos , Modelos Animais
3.
Plant Biotechnol J ; 22(4): 1017-1032, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38012865

RESUMO

Maize is one of the most important crops for food, cattle feed and energy production. However, maize is frequently attacked by various pathogens and pests, which pose a significant threat to maize yield and quality. Identification of quantitative trait loci and genes for resistance to pests will provide the basis for resistance breeding in maize. Here, a ß-glucosidase ZmBGLU17 was identified as a resistance gene against Pythium aphanidermatum, one of the causal agents of corn stalk rot, by genome-wide association analysis. Genetic analysis showed that both structural variations at the promoter and a single nucleotide polymorphism at the fifth intron distinguish the two ZmBGLU17 alleles. The causative polymorphism near the GT-AG splice site activates cryptic alternative splicing and intron retention of ZmBGLU17 mRNA, leading to the downregulation of functional ZmBGLU17 transcripts. ZmBGLU17 localizes in both the extracellular matrix and vacuole and contribute to the accumulation of two defence metabolites lignin and DIMBOA. Silencing of ZmBGLU17 reduces maize resistance against P. aphanidermatum, while overexpression significantly enhances resistance of maize against both the oomycete pathogen P. aphanidermatum and the Asian corn borer Ostrinia furnacalis. Notably, ZmBGLU17 overexpression lines exhibited normal growth and yield phenotype in the field. Taken together, our findings reveal that the apoplastic and vacuolar localized ZmBGLU17 confers resistance to both pathogens and insect pests in maize without a yield penalty, by fine-tuning the accumulation of lignin and DIMBOA.


Assuntos
Zea mays , beta-Glucosidase , Animais , Bovinos , Zea mays/genética , Zea mays/química , beta-Glucosidase/genética , Estudo de Associação Genômica Ampla , Lignina , Melhoramento Vegetal , Insetos
4.
Eur Radiol ; 34(2): 899-913, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37597033

RESUMO

OBJECTIVE: This study aimed to establish a MRI-based deep learning radiomics (DLR) signature to predict the human epidermal growth factor receptor 2 (HER2)-low-positive status and further verified the difference in prognosis by the DLR model. METHODS: A total of 481 patients with breast cancer who underwent preoperative MRI were retrospectively recruited from two institutions. Traditional radiomics features and deep semantic segmentation feature-based radiomics (DSFR) features were extracted from segmented tumors to construct models separately. Then, the DLR model was constructed to assess the HER2 status by averaging the output probabilities of the two models. Finally, a Kaplan‒Meier survival analysis was conducted to explore the disease-free survival (DFS) in patients with HER2-low-positive status. The multivariate Cox proportional hazard model was constructed to further determine the factors associated with DFS. RESULTS: First, the DLR model distinguished between HER2-negative and HER2-overexpressing patients with AUCs of 0.868 and 0.763 in the training and validation cohorts, respectively. Furthermore, the DLR model distinguished between HER2-low-positive and HER2-zero patients with AUCs of 0.855 and 0.750, respectively. Cox regression analysis showed that the prediction score obtained using the DLR model (HR, 0.175; p = 0.024) and lesion size (HR, 1.043; p = 0.009) were significant, independent predictors of DFS. CONCLUSIONS: We successfully constructed a DLR model based on MRI to noninvasively evaluate the HER2 status and further revealed prospects for predicting the DFS of patients with HER2-low-positive status. CLINICAL RELEVANCE STATEMENT: The MRI-based DLR model could noninvasively identify HER2-low-positive status, which is considered a novel prognostic predictor and therapeutic target. KEY POINTS: • The DLR model effectively distinguished the HER2 status of breast cancer patients, especially the HER2-low-positive status. • The DLR model was better than the traditional radiomics model or DSFR model in distinguishing HER2 expression. • The prediction score obtained using the model and lesion size were significant independent predictors of DFS.


Assuntos
Neoplasias da Mama , Aprendizado Profundo , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Intervalo Livre de Doença , Estudos Retrospectivos , Radiômica , Imageamento por Ressonância Magnética
5.
Skin Res Technol ; 30(5): e13719, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38696230

RESUMO

BACKGROUND: The assessment of skin aging through skin measurements faces limitations, making perceived age evaluation a more valuable and direct tool for assessing skin aging. Given that the aging process markedly affects the appearance of the eye contour, characterizing the eye region could be beneficial for perceived age assessment. This study aimed to analyze age-correlated changes in the eye contour within the Chinese Han female population and to develop, validate, and apply a multiple linear regression model for predicting perceived age. MATERIALS AND METHODS: A naïve panel of 107 Chinese women assessed the perceived ages of 212 Chinese Han women. Instrumental analysis evaluated periorbital parameters, including palpebral fissure width (PFW), palpebral fissure height (PFH), acclivity of palpebral fissure (AX), angle of inner canthal (AEN), and angle of outer canthal (AEX). These parameters were used to construct a multiple linear regression model for predicting the perceived ages of Chinese Han women. A combined treatment using Fotona 4D and an anti-aging eye cream, formulated with plant extracts, peptides, and antioxidants, was conducted to verify the cream's anti-aging efficacy and safety. This eye cream was then tested in a large-scale clinical trial involving 101 participants. The prediction model was employed in this trial to assess the perceived ages of the women after an 8-week application of the eye cream. RESULTS: All parameters were observed to decrease with age. An intergroup comparison indicated that eyelid aging in Chinese Han women accelerates beyond the age of 50. Consequently, a linear regression model was constructed and validated, with the perceived age being calculated as 183.159 - 1.078 * AEN - 4.487 * PFW + 6.061 * PFH - 1.003 * AX - 0.328 * AEX. The anti-aging efficacy and safety of the eye cream were confirmed through combined treatment with Fotona 4D, showing improvements in wrinkles, elasticity, and dark circles under the eyes. In a large-scale clinical evaluation using this eye cream, a perceived age prediction model was applied, suggesting that 8 weeks of use made participants appear 2.25 years younger. CONCLUSION: Our study developed and validated a multiple linear regression model to predict the perceived age of Chinese Han women. This model was successfully utilized in a large-scale clinical evaluation of anti-aging eye cream, revealing that 8 weeks of usage made participants appear 2.25 years younger. This method effectively bridges the gap between clinical research and consumer perceptions, explores the complex factors influencing perceived age, and aims to improve anti-aging formulations.


Assuntos
Povo Asiático , Envelhecimento da Pele , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , China/etnologia , População do Leste Asiático , Olho , Modelos Lineares , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/fisiologia , Envelhecimento da Pele/etnologia , Creme para a Pele/administração & dosagem
6.
Alzheimers Dement ; 20(4): 2516-2525, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38329281

RESUMO

INTRODUCTION: The objective of this study is to investigate the incremental value of amyloid positron emission tomography (Aß-PET) in a tertiary memory clinic setting in China. METHODS: A total of 1073 patients were offered Aß-PET using 18F-florbetapir. The neurologists determined a suspected etiology (Alzheimer's disease [AD] or non-AD) with a percentage estimate of their confidence and medication prescription both before and after receiving the Aß-PET results. RESULTS: After disclosure of the Aß-PET results, etiological diagnoses changed in 19.3% of patients, and diagnostic confidence increased from 69.3% to 85.6%. Amyloid PET results led to a change of treatment plan in 36.5% of patients. Compared to the late-onset group, the early-onset group had a more frequent change in diagnoses and a higher increase in diagnostic confidence. DISCUSSION: Aß-PET has significant impacts on the changes of diagnoses and management in Chinese population. Early-onset cases are more likely to benefit from Aß-PET than late-onset cases. HIGHLIGHTS: Amyloid PET contributes to diagnostic changes and its confidence in Chinese patients. Amyloid PET leads to a change of treatment plans in Chinese patients. Early-onset cases are more likely to benefit from amyloid PET than late-onset cases.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Amiloide , Doença de Alzheimer/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Proteínas Amiloidogênicas , Compostos de Anilina , China , Peptídeos beta-Amiloides , Disfunção Cognitiva/diagnóstico
7.
Int J Mol Sci ; 25(11)2024 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-38891975

RESUMO

Saline and alkaline stresses limit plant growth and reduce crop yield. Soil salinization and alkalization seriously threaten the sustainable development of agriculture and the virtuous cycle of ecology. Biofertilizers made from plant growth-promoting rhizobacteria (PGPR) not only enhance plant growth and stress tolerance, but also are environmentally friendly and cost-effective. There have been many studies on the mechanisms underlying PGPRs enhancing plant salt resistance. However, there is limited knowledge about the interaction between PGPR and plants under alkaline-sodic stress. To clarify the mechanisms underlying PGPR's improvement of plants' tolerance to alkaline-sodic stress, we screened PGPR from the rhizosphere microorganisms of local plants growing in alkaline-sodic land and selected an efficient strain, Bacillus altitudinis AD13-4, as the research object. Our results indicate that the strain AD13-4 can produce various growth-promoting substances to regulate plant endogenous hormone levels, cell division and differentiation, photosynthesis, antioxidant capacity, etc. Transcriptome analysis revealed that the strain AD13-4 significantly affected metabolism and secondary metabolism, signal transduction, photosynthesis, redox processes, and plant-pathogen interactions. Under alkaline-sodic conditions, inoculation of the strain AD13-4 significantly improved plant biomass and the contents of metabolites (e.g., soluble proteins and sugars) as well as secondary metabolites (e.g., phenols, flavonoids, and terpenoids). The 16S rRNA gene sequencing results indicated that the strain AD13-4 significantly affected the abundance and composition of the rhizospheric microbiota and improved soil activities and physiochemical properties. Our study provides theoretical support for the optimization of saline-alkali-tolerant PGPR and valuable information for elucidating the mechanism of plant alkaline-sodic tolerance.


Assuntos
Bacillus , Medicago sativa , Rizosfera , Microbiologia do Solo , Medicago sativa/microbiologia , Medicago sativa/crescimento & desenvolvimento , Bacillus/genética , Bacillus/fisiologia , Álcalis , Microbiota , Estresse Fisiológico , Tolerância ao Sal , Solo/química
8.
J Environ Manage ; 356: 120729, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38537464

RESUMO

The recovery of valuable metals from spent lithium-ion batteries (LIBs) is crucial for environmental protection and resource optimization. In the traditional recovery process of spent LIBs, the leaching of high-valence metals has the problems of high cost and limited reagent utilization, and some valuable metals are lost in the subsequent purification process of the leaching solution. To reduce the cost of reagents, this study proposes the use of low-cost SO2 as a reagent combined with pressure leaching to efficiently recover high-valence metals from delithiated materials of spent LIBs, while selective solvent extraction is used to remove trace impurities in the leaching solution to avoid the loss of valuable metals. Experimental results demonstrated that by optimizing the conditions to 0.25 MPa SO2 partial pressure and 60 min reaction time at 70 °C, the leaching efficiencies for Ni, Co, and Mn reached 99.6%, 99.3%, and 99.6%, respectively. The kinetic study indicated that the leaching process was diffusion-controlled. Furthermore, the delithiated materials were used to completely utilize the residual SO2 in the solution to obtain a high concentration Ni-Co-Mn rich solution. Subsequently, Fe and Al impurities were deeply removed through a synergistic extraction of Di-2-ethylhexyl phosphoric acid (D2EHPA) and tributyl phosphate (TBP) without loss of valuable metals, achieving a high-purity Ni-Co-Mn solution. The process developed based on this work has the characteristics of environmental friendliness, high valuable metal recovery, and high product purity, providing a reference technical method for the synergistic treatment of waste SO2 flue gas with spent LIBs and the deep purification of impurities in spent LIBs.


Assuntos
Lítio , Reciclagem , Reciclagem/métodos , Metais , Fontes de Energia Elétrica , Cinética
9.
J Environ Manage ; 356: 120612, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38537465

RESUMO

In this study, we synthesized a high removal efficiency catalyst using biochar-supported nanoscale zero-valent iron and g-C3N4, denoted as g-C3N4/nZVI@SBC, to activate persulfate (PS) for the degradation of total petroleum hydrocarbon (TPH) in groundwater. We characterized the morphology and physiochemical properties of g-C3N4/nZVI@SBC with scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR), BET surface area analysis, and X-ray photoelectron spectroscopy (XPS). To assess the performance of the g-C3N4/nZVI@SBC catalyst, we investigated various reaction parameters, such as the mass ratio of g-C3N4 to nZVI@SBC, PS concentration, initial pH, initial TPH concentration, and the presence of coexisting ions in the system. The results from batch experiments and repeated use trials indicate that g-C3N4/nZVI@SBC exhibited both excellent catalytic activation capability and impressive durability, making it a promising choice for TPH degradation. Specifically, when the PS concentration reached 1 mM, the catalyst dosage was 0.3 g/L, and the g-C3N4 to nZVI@SBC mass ratio was 2, we achieved a remarkable TPH removal efficiency of 93.8%. Through electron paramagnetic resonance (EPR) testing and quenching experiments, we identified sulfate radicals, hydroxyl radicals, and superoxide radicals as the primary active substance involved in the TPH degradation process. Moreover, the g-C3N4/nZVI@SBC composite proved highly effective for in-situ TPH removal from groundwater and displayed an 86% removal rate, making it a valuable candidate for applications in permeable reactive barriers (PRB) aimed at enhancing environmental remediation. In summary, by skillfully utilizing g-C3N4/nZVI@SBC, this study has made notable advancements in synthesis and characterization, presenting a feasible and innovative approach to addressing TPH pollution in groundwater.


Assuntos
Água Subterrânea , Poluentes Químicos da Água , Poluentes Químicos da Água/química , Ferro/química , Microscopia Eletrônica de Varredura , Hidrocarbonetos , Água Subterrânea/química
10.
J Sci Food Agric ; 104(5): 2888-2896, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38018275

RESUMO

BACKGROUND: The effect of bamboo leaf extract (BLE) on controlling the browning of fresh-cut apple stored at 4 °C was investigated. Browning index, H2 O2 content, O2 - production rate, malondialdehyde (MDA) contents, total phenolic content (TPC) and soluble quinone content (SQC), the activities of polyphenol oxidase (PPO), peroxidase (POD), lipoxygenase (LOX), superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX), DPPH (2,2-diphenyl-2-picryl-hydrazyl) and ABTS [2,2-azinobis(3-ethylbenzothiazoline- 6-sulfonic acid)] radical scavenging activities, and the expression of genes related to browning were all investigated. RESULTS: BLE effectively alleviated the surface browning of fresh-cut apple, accompanied by a reduction in SQC, LOX activity, H2 O2 , O2 - production rate and MDA accumulation. Furthermore, BLE treatment enhanced the TPC, enzymatic (SOD, CAT, APX and POD) and non-enzymatic antioxidant activities. Principal component analysis and Pearson correlation analysis found the browning inhibition by BLE is not through the reduction of phenolic substrates and PPO activity. CONCLUSION: BLE controls the browning of fresh-cut apple by increasing the antioxidant capacity to scavenge ROS, which could alleviate oxidative damage and maintain the membrane integrity. © 2023 Society of Chemical Industry.


Assuntos
Antioxidantes , Malus , Antioxidantes/análise , Malus/metabolismo , Metabolismo dos Lipídeos , Peroxidase/metabolismo , Peroxidases/metabolismo , Superóxido Dismutase/metabolismo , Fenóis/química , Ascorbato Peroxidases/metabolismo , Extratos Vegetais/farmacologia
11.
J Biol Chem ; 298(8): 102160, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35724961

RESUMO

C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression pattern of CRP have not been well defined. Here, we identify a constitutively active enhancer (E1) located 37.7 kb upstream of the promoter of human CRP in hepatocytes. By using chromatin immunoprecipitation, luciferase reporter assay, in situ genetic manipulation, CRISPRi, and CRISPRa, we show that E1 is enriched in binding sites for transcription factors STAT3 and C/EBP-ß and is essential for the full induction of human CRP during the acute phase. Moreover, we demonstrate that E1 orchestrates with the promoter of CRP to determine its varied expression across tissues and species through surveying activities of E1-promoter hybrids and the associated epigenetic modifications. These results thus suggest an intriguing mode of molecular evolution wherein expression-changing mutations in distal regulatory elements initiate subsequent functional selection involving coupling among distal/proximal regulatory mutations and activity-changing coding mutations.


Assuntos
Proteína C-Reativa , Elementos Facilitadores Genéticos , Sítios de Ligação , Proteína C-Reativa/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Regulação da Expressão Gênica , Hepatócitos , Humanos , Regiões Promotoras Genéticas , Fator de Transcrição STAT3/metabolismo , Transcrição Gênica
12.
Artigo em Inglês | MEDLINE | ID: mdl-33593833

RESUMO

Two novel ISCR1-associated dfr genes, dfrA42 and dfrA43, were identified from trimethoprim (TMP)-resistant Proteus strains and were shown to confer high level TMP resistance (MIC ≥ 1024 mg/L) when cloned into Escherichia coli These genes were hosted by complex class 1 integrons suggesting their potentials for dissemination. Analysis of enzymatic parameters and TMP affinity were performed, suggesting that the mechanism of TMP resistance for these novel DHFRs is the reduction of binding with TMP.

13.
Allergy ; 78(9): 2487-2496, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37203302

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) involves a chronic immune-mediated response to dietary antigens. Recent work identifies T-cell clonality in children with EoE, however, it is unknown whether this is true in adults or whether there is a restricted food-specific T-cell repertoire. We sought to confirm T-cell receptor (TCR) clonality in EoE and assess for differences with specific food triggers. METHODS: Bulk TCR sequencing was performed on mRNA isolated from esophageal biopsies obtained from adults and children with EoE (n = 15) who had food triggers confirmed by endoscopic evaluation. Non-EoE adult and pediatric controls (n = 10) were included. Differences in TCR clonality by disease and treatment status were assessed. Shared and similar V-J-CDR3s were assessed based on specific food triggers. RESULTS: Active EoE biopsies from children but not adults displayed decreased unique TCRα/ß clonotypes and increased relative abundance of TCRs comprising >1% of the total compared to non-EoE controls and paired inactive EoE samples. Among patients in which baseline, post diet elimination, and food trigger reintroduction samples (n = 6) were obtained, we observed ~1% of TCRs were shared only between pre-diet elimination and trigger reintroduction. Patients with a shared EoE trigger (milk) had a greater degree of shared and similar TCRs compared to patients with differing triggers (seafood, wheat, egg, soy). CONCLUSION: We confirmed relative clonality in children but not adults with active EoE and identified potential food-specific TCRs, particularly for milk-triggered EoE. Further studies are needed to better identify the broad TCR repertoire relevant to food triggers.


Assuntos
Esofagite Eosinofílica , Humanos , Criança , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/genética , Alimentos/efeitos adversos , Alérgenos , Receptores de Antígenos de Linfócitos T/genética
14.
BMC Psychiatry ; 23(1): 756, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37845676

RESUMO

BACKGROUND: Therapeutic efficacies of repetitive transcranial magnetic stimulation (rTMS) for improving cognitive functions in patients with deficit/hyperactivity disorder (ADHD) remained unclear. The aim of this meta-analysis was to investigate the therapeutic efficacy of rTMS focusing on different cognitive performances. METHODS: Major databases were searched electronically from inception to February 2023 by using keywords mainly "rTMS" and "ADHD" to identify randomized controlled trials (RCTs) that investigated the therapeutic efficacy of rTMS for improving cognitive functions assessed by standardized tasks in patients with ADHD. The overall effect size (ES) was calculated as standardized mean difference (SMD) based on a random effects model. RESULTS: Meta-analysis of five RCTs with 189 participants (mean age of 32.78 and 8.53 years in adult and child/adolescent populations, respectively) demonstrated that rTMS was more effective for improving sustained attention in patients with ADHD compared with the control groups (SMD = 0.54, p = 0.001).Our secondary analysis also showed that rTMS was more effective for improving processing speed than the control groups (SMD = 0.59, p = 0.002) but not for enhancing memory or executive function. CONCLUSIONS: Our results supported the therapeutic efficacy of rTMS for improving sustained attention and processing speed. However, the limitation of available data warrants further studies to verify these findings.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulação Magnética Transcraniana , Adulto , Adolescente , Criança , Humanos , Estimulação Magnética Transcraniana/métodos , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Cognição , Função Executiva , Velocidade de Processamento
15.
Phytother Res ; 37(5): 1839-1849, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36512326

RESUMO

Salidroside, a prominent active ingredient in traditional Chinese medicines, is garnering increased attention because of its unique pharmacological effects against ischemic heart disease via MAPK signaling, which plays a critical role in regulating the evolution of ventricular hypertrophy. However, the function of Salidroside on myocardial hypertrophy has not yet been elucidated. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with Salidroside (100 mg kg-1  day-1 ) by oral gavage for 3 weeks starting 1 week after surgery. Four weeks after TAC surgery, the mice were subjected to echocardiography and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes were used to validate the protective effects of Salidroside in response to Angiotensin II (Ang II, 1 µM) stimulation. Here, we proved that Salidroside dramatically inhibited hypertrophic reactions generated by pressure overload and isoproterenol (ISO) injection. Salidroside prevented the activation of the TAK1-JNK/p38 axis. Salidroside pretreatment of TAK1-inhibited cardiomyocytes shows no additional attenuation of Ang II-induced cardiomyocytes hypertrophy and signaling pathway activation. The overexpression of constitutively active TAK1 removed the protective effects of Salidroside on myocardial hypertrophy. TAC-induced increase of TLR4 protein expression was reduced considerably in the Salidroside treated mice. Transient transfection of small interfering RNA targeting TLR4 (siTLR4) in cardiomyocytes did not further decrease the activation of the TAK1/JNK-p38 axis. In conclusion, Salidroside functioned as a TLR4 inhibitor and displayed anti-hypertrophic action via the TAK1/JNK-p38 pathway.


Assuntos
Estenose da Valva Aórtica , Cardiomegalia , Receptor 4 Toll-Like , Animais , Camundongos , Ratos , Estenose da Valva Aórtica/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Células Cultivadas , Modelos Animais de Doenças , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/farmacologia , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
16.
Pestic Biochem Physiol ; 194: 105480, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37532346

RESUMO

Natural products are one of the important sources for the creation of new pesticides. Drupacine ((1R,11S,12S,13R,15S)-13-methoxy-5,7,21-trioxa-19-azahexacyclo[11.7.1.02,10.04,8.011,15.015,19]henicosa-2,4(8),9-trien-12-ol), isolated from Cephalotaxus sinensis (Chinese plum-yew), is a potent herbicidal compound containing an oxo-bridged oxygen bond structure. However, its molecular target still remains unknown. In this study, the targets of drupacine in Amaranthus retroflexus were identified by combining drug affinity responsive target stability (DARTS), cellular thermal shift assay coupled with mass spectrometry (CETSA MS), RNA-seq transcriptomic, and TMT proteomic analyses. Fifty-one and sixty-eight main binding proteins were identified by DARTS and CETSA MS, respectively, including nine co-existing binding proteins. In drupacine-treated A. retroflexus seedlings we identified 1389 up-regulated genes and 442 down-regulated genes, 34 up-regulated proteins, and 194 down-regulated proteins, respectively. Combining the symptoms and the biochemical profiles, Profilin, Shikimate dehydrogenase (SkDH), and Zeta-carotene desaturase were predicted to be the drupacine potential target proteins. At the same time, drupacine was found to bind SkDH stronger by molecular docking, and its inhibition on ArSkDH increased with the treatment concentration increase. Our results suggest that the molecular target of drupacine is SkDH, a new herbicide target, which lay a foundation for the rational design of herbicides based on new targets from natural products and enrich the target resources for developing green herbicides.


Assuntos
Produtos Biológicos , Herbicidas , Herbicidas/farmacologia , Herbicidas/química , Simulação de Acoplamento Molecular , Proteômica , Oxirredutases , Proteínas
17.
Chem Biodivers ; 20(8): e202300769, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37349855

RESUMO

Direct modulation of the non-kinase functions of cyclin and CDK-cyclin complexes poses challenges. We utilize hydrophobic tag (HyT) based small-molecule degraders induced degradation of cyclin T1 and its corresponding kinase partner CDK9. LL-CDK9-12 demonstrated the most potent and selective degradation ability, with DC50 values of 0.362 µM against CDK9 and 0.680 µM against cyclin T1. In prostate cancer cells, LL-CDK9-12 showed enhanced anti-proliferative activity than its parental molecule SNS032 and LL-K9-3, the previous reported CDK9-cyclin T1 degrader. Moreover, LL-CDK9-12 suppressed the downstream signaling of CDK9 and AR efficiently. Altogether, LL-CDK9-12 was an effective dual degrader of CDK9-cyclin T1 and helped study the unknown function of CDK9-cyclin T1. These results suggest that HyT-based degraders could be used as a strategy to induce the degradation of protein complexes, providing insights for the design of protein complexes' degraders.


Assuntos
Núcleo Celular , Ciclinas , Humanos , Masculino , Pontos de Checagem do Ciclo Celular , Núcleo Celular/metabolismo , Ciclina T/metabolismo , Ciclinas/metabolismo , Ligação Proteica
18.
BMC Biol ; 20(1): 240, 2022 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-36280838

RESUMO

BACKGROUND: The centrosome is one of the most important non-membranous organelles regulating microtubule organization and progression of cell mitosis. The coiled-coil alpha-helical rod protein 1 (CCHCR1, also known as HCR) gene is considered to be a psoriasis susceptibility gene, and the protein is suggested to be localized to the P-bodies and centrosomes in mammalian cells. However, the exact cellular function of HCR and its potential regulatory role in the centrosomes remain unexplored. RESULTS: We found that HCR interacts directly with astrin, a key factor in centrosome maturation and mitosis. Immunoprecipitation assays showed that the coiled-coil region present in the C-terminus of HCR and astrin respectively mediated the interaction between them. Astrin not only recruits HCR to the centrosome, but also protects HCR from ubiquitin-proteasome-mediated degradation. In addition, depletion of either HCR or astrin significantly reduced centrosome localization of CEP72 and subsequent MCPH proteins, including CEP152, CDK5RAP2, and CEP63. The absence of HCR also caused centriole duplication defects and mitotic errors, resulting in multipolar spindle formation, genomic instability, and DNA damage. CONCLUSION: We conclude that HCR is localized and stabilized at the centrosome by directly binding to astrin. HCR are required for the centrosomal recruitment of MCPH proteins and centriolar duplication. Both HCR and astrin play key roles in keeping normal microtubule assembly and maintaining genomic stability.


Assuntos
Proteínas de Ciclo Celular , Centríolos , Animais , Centríolos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Centrossomo/metabolismo , Mitose , Ubiquitinas/genética , Fuso Acromático/metabolismo , Mamíferos
19.
Int J Mol Sci ; 24(4)2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36835473

RESUMO

Rice (Oryza sativa) is one of the most important crops grown worldwide, and saline-alkali stress seriously affects the yield and quality of rice. It is imperative to elucidate the molecular mechanisms underlying rice response to saline-alkali stress. In this study, we conducted an integrated analysis of the transcriptome and metabolome to elucidate the effects of long-term saline-alkali stress on rice. High saline-alkali stress (pH > 9.5) induced significant changes in gene expression and metabolites, including 9347 differentially expressed genes (DEGs) and 693 differentially accumulated metabolites (DAMs). Among the DAMs, lipids and amino acids accumulation were greatly enhanced. The pathways of the ABC transporter, amino acid biosynthesis and metabolism, glyoxylate and dicarboxylate metabolism, glutathione metabolism, TCA cycle, and linoleic acid metabolism, etc., were significantly enriched with DEGs and DAMs. These results suggest that the metabolites and pathways play important roles in rice's response to high saline-alkali stress. Our study deepens the understanding of mechanisms response to saline-alkali stress and provides references for molecular design breeding of saline-alkali resistant rice.


Assuntos
Oryza , Transcriptoma , Oryza/genética , Álcalis/farmacologia , Metaboloma/genética , Ciclo do Ácido Cítrico , Regulação da Expressão Gênica de Plantas , Perfilação da Expressão Gênica
20.
Int J Mol Sci ; 24(11)2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-37298082

RESUMO

Soil saline-alkalization inhibits plant growth and development and seriously affects crop yields. Over their long-term evolution, plants have formed complex stress response systems to maintain species continuity. R2R3-MYB transcription factors are one of the largest transcription factor families in plants, widely involved in plant growth and development, metabolism, and stress response. Quinoa (Chenopodium quinoa Willd.), as a crop with high nutritional value, is tolerant to various biotic and abiotic stress. In this study, we identified 65 R2R3-MYB genes in quinoa, which are divided into 26 subfamilies. In addition, we analyzed the evolutionary relationships, protein physicochemical properties, conserved domains and motifs, gene structure, and cis-regulatory elements of CqR2R3-MYB family members. To investigate the roles of CqR2R3-MYB transcription factors in abiotic stress response, we performed transcriptome analysis to figure out the expression file of CqR2R3-MYB genes under saline-alkali stress. The results indicate that the expression of the six CqMYB2R genes was altered significantly in quinoa leaves that had undergone saline-alkali stress. Subcellular localization and transcriptional activation activity analysis revealed that CqMYB2R09, CqMYB2R16, CqMYB2R25, and CqMYB2R62, whose Arabidopsis homologues are involved in salt stress response, are localized in the nucleus and exhibit transcriptional activation activity. Our study provides basic information and effective clues for further functional investigation of CqR2R3-MYB transcription factors in quinoa.


Assuntos
Arabidopsis , Chenopodium quinoa , Chenopodium quinoa/genética , Chenopodium quinoa/metabolismo , Sequência de Aminoácidos , Proteínas de Plantas/metabolismo , Genes myb , Arabidopsis/genética , Fatores de Transcrição/metabolismo , Filogenia , Regulação da Expressão Gênica de Plantas
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