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1.
Biochem Biophys Res Commun ; 624: 53-58, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35932580

RESUMO

KDM2A is a histone demethylase, which primarily catalyzes the demethylation of H3K36me2. Abnormal expression of KDM2A is observed in many types of cancers; however, the molecular events connected to KDM2A expression remain unclear. We report that KDM2A performs an oncogenic function in esophageal squamous cell carcinoma (ESCC) and is robustly expressed in ESCC cells. ShRNA-mediated knockdown of KDM2A resulted in a significant inhibition of the malignant phenotype of ESCC cell lines, whereas ectopic expression of KDM2A showed the opposite effect. We also analyzed the function of KDM2A using a CRISPR-CAS9 depletion system and subsequent rescue experiment, which also indicated a cancerous role of KDM2A. Interestingly, analysis of the gene expression network controlled by KDM2A using RNA-seq revealed an unexpected feature: KDM2A could induce expression of a set of well-documented oncogenic genes, including IL6 and LAT2, while simultaneously suppressing another set of oncogenes, including MAT2A and HMGCS1. Targeted inhibition of the upregulated oncogene in the KDM2A-depleted cells led to a synergistic suppressive effect on the malignant phenotype of ESCC cells. Our results revealed the dual role of KDM2A in ESCC cells, which may have therapeutic implications.

2.
Part Fibre Toxicol ; 19(1): 55, 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933442

RESUMO

As an emerging pollutant in the life cycle of plastic products, micro/nanoplastics (M/NPs) are increasingly being released into the natural environment. Substantial concerns have been raised regarding the environmental and health impacts of M/NPs. Although diverse M/NPs have been detected in natural environment, most of them display two similar features, i.e.,high surface area and strong binding affinity, which enable extensive interactions between M/NPs and surrounding substances. This results in the formation of coronas, including eco-coronas and bio-coronas, on the plastic surface in different media. In real exposure scenarios, corona formation on M/NPs is inevitable and often displays variable and complex structures. The surface coronas have been found to impact the transportation, uptake, distribution, biotransformation and toxicity of particulates. Different from conventional toxins, packages on M/NPs rather than bare particles are more dangerous. We, therefore, recommend seriously consideration of the role of surface coronas in safety assessments. This review summarizes recent progress on the eco-coronas and bio-coronas of M/NPs, and further discusses the analytical methods to interpret corona structures, highlights the impacts of the corona on toxicity and provides future perspectives.


Assuntos
Poluentes Ambientais , Nanopartículas , Microplásticos , Nanopartículas/toxicidade , Medição de Risco
3.
Front Med (Lausanne) ; 9: 907727, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911397

RESUMO

Background: We use longitudinal chest CT images to explore the effect of steroids therapy in COVID-19 pneumonia which caused pulmonary lesion progression. Materials and Methods: We retrospectively enrolled 78 patients with severe to critical COVID-19 pneumonia, among which 25 patients (32.1%) who received steroid therapy. Patients were further divided into two groups with severe and significant-severe illness based on clinical symptoms. Serial longitudinal chest CT scans were performed for each patient. Lung tissue was segmented into the five lung lobes and mapped into the five pulmonary tissue type categories based on Hounsfield unit value. The volume changes of normal tissue and pneumonia fibrotic tissue in the entire lung and each five lung lobes were the primary outcomes. In addition, this study calculated the changing percentage of tissue volume relative to baseline value to directly demonstrate the disease progress. Results: Steroid therapy was associated with the decrease of pneumonia fibrotic tissue (PFT) volume proportion. For example, after four CT cycles of treatment, the volume reduction percentage of PFT in the entire lung was -59.79[±12.4]% for the steroid-treated patients with severe illness, and its p-value was 0.000 compared to that (-27.54[±85.81]%) in non-steroid-treated ones. However, for the patient with a significant-severe illness, PFT reduction in steroid-treated patients was -41.92[±52.26]%, showing a 0.275 p-value compared to -37.18[±76.49]% in non-steroid-treated ones. The PFT evolution analysis in different lung lobes indicated consistent findings as well. Conclusion: Steroid therapy showed a positive effect on the COVID-19 recovery, and its effect was related to the disease severity.

4.
Front Immunol ; 13: 884006, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911717

RESUMO

Background: Organ transplantation is currently an effective method for treating organ failure. Long-term use of immunosuppressive drugs has huge side effects, which severely restricts the long-term survival of patients. Schistosoma can affect the host's immune system by synthesizing, secreting, or excreting a variety of immunomodulatory molecules, but its role in transplantation was not well defined. In order to explore whether Schistosoma-related products can suppress rejection and induce long-term survival of the transplant, we used soluble egg antigen (SEA) of Schistosoma japonicum in mouse skin transplantation models. Materials and methods: Each mouse was intraperitoneally injected with 100 µg of SEA three times a week for four consecutive weeks before allogenic skin transplant. Skin transplants were performed on day 0 to observe graft survival. Pathological examination of skin grafts was conducted 7 days post transplantation. The skin grafts were subjected to mRNA sequencing. Bioinformatics analysis was conducted and the expression of hub genes was verified by qPCR. Flow cytometry analysis was performed to evaluate the immune status and validate the results from bioinformatic analysis. Results: The mean survival time (MST) of mouse skin grafts in the SEA-treated group was 11.67 ± 0.69 days, while that of the control group was 8.00 ± 0.36 days. Pathological analysis showed that Sj SEA treatment led to reduced inflammatory infiltration within skin grafts 7 days after allogenic skin transplantation. Bioinformatics analysis identified 86 DEGs between the Sj SEA treatment group and the control group, including 39 upregulated genes and 47 downregulated genes. Further analysis revealed that Sj SEA mediated regulation on cellular response to interferon-γ, activation of IL-17 signaling and chemokine signaling pathways, as well as cytokine-cytokine receptor interaction. Flow cytometry analysis showed that SEA treatment led to higher percentages of CD4+IL-4+ T cells and CD4+Foxp3+ T cells and decreased CD4+IFN-γ+ T cells in skin transplantation. Conclusion: Sj SEA treatment suppressed rejection and prolonged skin graft survival by regulating immune responses. Sj SEA treatment might be a potential new therapeutic strategy to facilitate anti-rejection therapy and even to induce tolerance.


Assuntos
Schistosoma japonicum , Animais , Antígenos de Helmintos , Terapia de Imunossupressão , Interferon gama , Camundongos , Transplante de Pele
5.
RSC Adv ; 12(33): 21056-21065, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35919838

RESUMO

A new strategy was established for the degradation of wastewater-based organic pollutants. Laser-induced plasma (LIP) was used as an alternative UV light source to realise rapid photodegradation of methylene blue (MB), an organic pollutant. A conventional 1064 nm Nd:YAG laser was used for plasma excitation to degrade MB solutions. The results show that the LIP effectively degraded the organic matter, and the degradation efficiency was related to the UV component with wavelength less than 400 nm. The compositions of the plasma excited by different dielectric substrates are different owing to various mechanisms involving moderate heat dissipation and sonoluminescence. However, metallic substrates, especially Fe, can enhance the proportion of UV light and accelerate the degradation efficiency. In the process of methylene blue degradation, solution parameters, such as initial dye concentration, pH, irradiation time and hydrogen peroxide concentration, will affect the degradation efficiency. The conditions of effective degradation of methylene blue (10 mg L-1 MB-1 concentration, 50 mL L-1 H2O2 concentration, pH = 3 and P = 60 mW) were obtained in this study, which can provide reference for practical application.

6.
Front Cardiovasc Med ; 9: 894888, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935625

RESUMO

Purpose: Dabigatran concentrations monitoring are gaining importance of special situations, but limited data are available for the expected peak and trough levels. The hemoclot thrombin inhibitor (HTI) is dabigatran-calibrated quantitative determination of dabigatran concentration. This study aims to validate HTI assay as the quantification choice of dabigatran, and providing the expected peak and trough levels. Materials and Methods: This is a multi-center methodology validate study, including seven hospitals from Beijing, Shanghai, Henan, Hunan, Chongqing, and Fujian. We retrospectively analyzed plasma samples taken from 118 healthy subjects and 183 patients receiving dabigatran. Dabigatran concentrations were measured with HTI assay and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Linear regression, Spearman correlation and Bland-Altman analysis were used in this study. Results: The mean concentration ratio of HPLC-MS/MS and HTI assays was 1.03 and 0.98 at 2 and 12 h, and the acceptance ranges for both the ratio limit as well as the limit of agreement were met, suggesting good agreement between the HTI-derived plasma concentrations and HPLC-MS/MS. The reference detection range of single dose dabigatran 150 mg in healthy subjects was 33-159 ng/ml. About 500 blood samples were taken from 183 patients suggested that the expected peak and trough levels range of dabigatran 110 mg was about 95-196 and 36-92 ng/ml. Conclusion: Hemoclot thrombin inhibitor assay can be a good quantitative detection method of dabigatran. Expected peak and trough levels provide a basis for the rational use of dabigatran, and provide important Asian population data for the update of the international clinical guidelines for hematological testing. Clinical Trial Registration: [https://clinicaltrials.gov], identifier [NCT03161496].

7.
Nat Commun ; 13(1): 4495, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918337

RESUMO

While hypoxia promotes carcinogenesis, tumour aggressiveness, metastasis, and resistance to oncological treatments, the impacts of hyperoxia on tumours are rarely explored because providing a long-lasting oxygen supply in vivo is a major challenge. Herein, we construct micro oxygen factories, namely, photosynthesis microcapsules (PMCs), by encapsulation of acquired cyanobacteria and upconversion nanoparticles in alginate microcapsules. This system enables a long-lasting oxygen supply through the conversion of external radiation into red-wavelength emissions for photosynthesis in cyanobacteria. PMC treatment suppresses the NF-kB pathway, HIF-1α production and cancer cell proliferation. Hyperoxic microenvironment created by an in vivo PMC implant inhibits hepatocarcinoma growth and metastasis and has synergistic effects together with anti-PD-1 in breast cancer. The engineering oxygen factories offer potential for tumour biology studies in hyperoxic microenvironments and inspire the exploration of oncological treatments.


Assuntos
Neoplasias da Mama , Hiperóxia , Cápsulas , Hipóxia Celular , Progressão da Doença , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Oxigênio , Microambiente Tumoral
8.
Dis Markers ; 2022: 1417104, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35811661

RESUMO

Objective: To evaluate the application of endoscopic ultrasound (EUS) combined with multislice spiral CT (MSCT) in the diagnosis and treatment of patients with gastric eminence lesions. Methods: A total of 160 patients with gastric eminence lesions enrolled in our hospital from June 2018 to June 2021 were included and received EUS and MSCT. The results of the two examinations and the postoperative pathological results were compared. Results: The common pathological types of gastric eminence lesions include polyps and stromal tumors, with the most common sites of lesions in the gastric antrum, followed by the fundus of the stomach and the gastric body. Gastric eminence lesions mostly originate from the mucosal layer and muscularis mucosa, accounting for 83.13% of the total. With pathological results as the gold standard, the detection rate of MSCT was 90.63%, and that of EUS was 78.13%. With the joint diagnosis as a reference, the receiver operating curve (ROC) revealed a higher diagnostic efficiency of MSCT and EUS. Conclusion: The accuracy of MSCT in the diagnosis of gastric eminence lesions is significantly higher than that of EUS, both of which can offer useful guidance for the choice of endoscopic treatment methods. The combination of MSCT and EUS examination before endoscopic gastroscopy may provide a better treatment efficacy on gastric protruding lesions with high safety.


Assuntos
Neoplasias Gástricas , Endossonografia/métodos , Gastroscopia/métodos , Humanos , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Tomografia Computadorizada Espiral
9.
J Pharm Biomed Anal ; 219: 114944, 2022 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-35863169

RESUMO

One-carbon metabolism is an important metabolic pathway involved in many diseases, such as congenital malformations, tumours, cardiovascular diseases, anaemia, depression, cognitive diseases and liver disease. However, the current methods have specific defects in detecting and qualifying the related compounds of one-carbon metabolism. In this study, a validated method was established to simultaneously quantify 22 one-carbon metabolites & co-factors in human plasma and applied to the study of correlation between one-carbon metabolism and colorectal cancer in human plasma samples, which were from 44 healthy subjects and 55 colorectal cancer patients. The method used ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-MS/MS), and the analytes included betaine, L-carnitine, L-cystathionine, L-cysteine, dimethylglycine, DL-homocysteic acid, homocysteine, methionine, pyridoxal hydrochloride, pyridoxamine dihydrochloride, pyridoxine dihydrochloride, S-(5'-Adenosyl)-L-homocysteine, serine, choline chloride, folic acid, glycine, pyridoxal phosphate monohydrate, riboflavin, taurine, 5-methyltetrahydrofolate, S-(5'-adenosyl)-L-methionine disulfate salt, trimethylamine oxide. The developed method was successfully applied to the quantification of 22 one-carbon metabolites & co-factors in human plasma from colorectal cancer patients and healthy individuals. The plasma concentrations of dimethylglycine was significantly decreased in the patients compared with the healthy individuals, while L-cystathionine was increased.

10.
Sci Total Environ ; : 157560, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35901870

RESUMO

Biochar can mediate extracellular electron transfer (EET) of Shewanella oneidensis MR-1 and subsequently facilitate dissimilatory reduction of iron(III) minerals. Previous studies mainly focused on the interaction of biochar and membrane cytochrome complexes to reveal the mediating mechanisms between biochar and S. oneidensis MR-1. However, the influence of biochar on the production and activity of extracellular polymeric substances (EPS) has long been neglected, despite the fact that EPS are commonly exudated by S. oneidensis MR-1 and can participate in a variety of electron transfer processes due to their redox activity. Here, we performed a series of microbial ferrihydrite reduction experiments in combination with electrochemical voltametric and impedance analyses to investigate the role of biochar in the formation and transformation of cell EPS during EET. Results showed that the added biochar not only functioned as an electron shuttle facilitating electron transfer, but also induced the secretion of five times more EPS by S. oneidensis MR-1, leading to a 1.4-fold faster ferrihydrite reduction in comparison with biochar-free setups. We further extracted the secreted EPS and found that the proportion of redox-active exoproteins was significantly (p < 0.05) increased in the EPS and resulted in a higher electron exchange capacity in secreted EPS. Such increased exoprotein content also induced a higher ratio of exoprotein to exopolysaccharide, which largely dropped diffusion and electron transfer impedance of EPS to 1.1 and 18 Ω, respectively, and accelerated the EET and thus the ferrihydrite reduction. Overall, our findings revealed the interactions between biochar and EPS matrices, which could potentially play a critical role in EET processes in both environmental or biotechnological systems.

11.
Chem Commun (Camb) ; 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35903977

RESUMO

A ratiometric fluorescent and colorimetric dual-modal sensing strategy is reported to distinguish and detect D2O from H2O based on ground-state proton transfer for the first time. It enables synchronous dual-modal changes towards different fractions of D2O and facilitates naked-eye recognition. The probe can provide a more accurate monitoring protocol for D2O analysis.

12.
Acta Biochim Biophys Sin (Shanghai) ; 54(7): 1-13, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35880567

RESUMO

The incidence of endometrial cancer (EC) increases annually and tends to occur in younger women. A particularly important relationship exists between EC and metabolic disorders. As one of the most important components of lipid metabolism, phospholipids play an indispensable role in metabolic balance. LPCAT1 is a key enzyme regulating phospholipid metabolism. In this study, we perform further investigations to seek mechanistic insight of LPCAT1 in EC. Our results demonstrate that silencing of LPCAT1 inhibits the growth of endometrial cancer, while overexpression of LPCAT1 results in enhanced stemness and metastasis in endometrial cancer cell lines. Meanwhile, the contents of various phospholipids including phosphatidylethanolamine (PE), phosphatidylcholine (PC), and triglyceride (TG) change significantly after overexpression of LPCAT1. In addition, through RNA-sequencing and western blot analysis, we observe that the TGF-ß/Smad2/3 signaling pathway is of great importance in the tumor-promoting function of LPCAT1. LPCAT1 promotes the expressions of stem cell-related transcription factors and epithelial-mesenchymal transition (EMT) related proteins through the TGF-ß/Smad2/3 signaling pathway. Moreover, we find that TSI-01, which can inhibit the activity of LPCAT1, is able to restrain the proliferation of EC cell lines and promote cell apoptosis. Collectively, we demonstrate that LPCAT1 enhances the stemness and metastasis of EC by activating the TGF-ß/Smad2/3 signaling pathway and that TSI-01 may have potential use for the treatment of EC.


Assuntos
Neoplasias do Endométrio , Transdução de Sinais , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Neoplasias do Endométrio/metabolismo , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Fosfolipídeos , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo
13.
Nanoscale ; 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35899773

RESUMO

Although there is growing interest in enhancement of single-photon emission (SPE) in two-dimensional transition metal dichalcogenides, particularly when introducing strain by the generation of wrinkles in monolayer WSe2, understanding the effects of the wrinkle type on the response has been lacking. In this work, by investigating the electronic and optical properties of monolayer WSe2 with wrinkles by first principles calculations, we gain insight into the tunability of the response, where the band gap is found to be modulated by the wrinkle type. Our detailed analyses of the local electronic structures show that the strain distribution from regions with different local strain magnitudes and types affect the band alignments. We demonstrate that introducing a wrinkle in the monolayer results in a red-shift, including the bright A exciton and the lowest energy dark exciton, and the dependence on strain is consistent with available measurements. The energy difference between the A exciton and the lowest mid-gap energy for a single Se vacancy in the wrinkled WSe2 monolayer as a function of strain is consistent with a suggestion on the origin of SPE in monolayer WSe2. Our results will encourage engineering of wrinkle types for enhanced SPE at specific wavelengths, which could potentially originate from hybridization of the localized strained dark exciton and a mid-gap point-defect exciton.

14.
Artigo em Inglês | MEDLINE | ID: mdl-35886459

RESUMO

The hazards of antibiotics as emerging contaminants to aquatic ecosystems and human health have received global attention. This study investigates the presence, concentration levels, spatial and temporal distribution patterns, and their potential risks to aquatic organisms and human health of sulfonamides (SAs) in the Shaanxi section of the Weihe River. The SA pollution in the Weihe River was relatively less than that in other rivers in China and abroad. The spatial and temporal distribution showed that the total concentrations of SAs in the Weihe River were highest in the main stream (ND-35.296 ng/L), followed by the south tributary (3.718-34.354 ng/L) and north tributary (5.476-9.302 ng/L) during the wet water period. Similarly, the order of concentration from highest to lowest during the flat water period was main stream (ND-3 ng/L), north tributary (ND-2.095 ng/L), and south tributary (ND-1.3 ng/L). In addition, the ecological risk assessment showed that the SAs other than sulfadiazine (SDZ) and sulfamethoxazole (SMZ) posed no significant risk (RQS < 0.01) to the corresponding sensitive species during both periods, with no significant risk to human health for different age groups, as suggested by the health risk assessment. The risk of the six SAs to both aquatic organisms and human health decreased significantly from 2016 to 2021.


Assuntos
Rios , Poluentes Químicos da Água , Antibacterianos/análise , Organismos Aquáticos , China , Ecossistema , Monitoramento Ambiental , Humanos , Medição de Risco , Sulfonamidas/toxicidade , Água , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
15.
Nature ; 607(7919): 480-485, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35859196

RESUMO

Pyroelectricity describes the generation of electricity by temporal temperature change in polar materials1-3. When free-standing pyroelectric materials approach the 2D crystalline limit, how pyroelectricity behaves remained largely unknown. Here, using three model pyroelectric materials whose bonding characters along the out-of-plane direction vary from van der Waals (In2Se3), quasi-van der Waals (CsBiNb2O7) to ionic/covalent (ZnO), we experimentally show the dimensionality effect on pyroelectricity and the relation between lattice dynamics and pyroelectricity. We find that, for all three materials, when the thickness of free-standing sheets becomes small, their pyroelectric coefficients increase rapidly. We show that the material with chemical bonds along the out-of-plane direction exhibits the greatest dimensionality effect. Experimental observations evidence the possible influence of changed phonon dynamics in crystals with reduced thickness on their pyroelectricity. Our findings should stimulate fundamental study on pyroelectricity in ultra-thin materials and inspire technological development for potential pyroelectric applications in thermal imaging and energy harvesting.

16.
Food Funct ; 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35861176

RESUMO

Protein-energy wasting (PEW) is prevalent in maintenance hemodialysis (MHD) patients, and is one of the major risk factors for poor outcomes and death. This study aimed to investigate the effects of non-protein calorie supplements on the nutritional status of MHD patients with PEW. MHD patients with PEW were enrolled in this multi-center, open-label, randomized controlled trial. Then, they were randomly assigned to the intervention group to receive the non-protein calorie supplements containing 280 kcal of energy every day for 6 months or the control group to complete all aspects of the study without receiving supplements. Patients in both groups received dietary counselling from dietitians. Data on nutritional assessments, anthropometric measurements, blood analysis and dietary recall were collected at the baseline and at six months from both groups. Statistical analyses were performed using analysis of covariance (ANCOVA) adjusted for sex and baseline values. Ninety-two MHD patients completed the study. A significant increase in the subjective global assessment (SGA) score was found in the intervention group compared with the control group (4.88 ± 1.41 vs. 4.40 ± 1.16, p = 0.044). The ratio of PEW patients (diagnosed with SGA ≤5) in the intervention group (61.2%) was also significantly lower than that in the control group (83.7%) (p < 0.001). Moreover, significant improvements in body mass index (20.81 ± 2.46 kg m-2vs. 19.51 ± 2.60 kg m-2, p < 0.001), nutrition risk screening 2002 (2.45 ± 1.40 vs. 3.12 ± 1.37, p = 0.038), mid-upper arm circumference (23.30 ± 2.78 cm vs. 21.75 ± 2.87 cm, p = 0.001), and mid-arm muscle circumference (20.51 ± 2.32 cm vs. 19.06 ± 2.92 cm, p = 0.005) were observed in the intervention group compared with the control group. Patients in the intervention group took in more dietary energy than the control group (26.96 ± 4.75 kcal per kg body weight per day vs. 24.33 ± 2.68 kcal per kg body weight per day, p < 0.001). In conclusion, non-protein calorie supplements may improve the nutritional status of MHD patients with PEW.

17.
Oxid Med Cell Longev ; 2022: 8956636, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35832491

RESUMO

Mutations of filamin B (FLNB) gene can lead to a spectrum of autosomal skeletal malformations including spondylocarpotarsal syndrome (SCT), Larsen syndrome (LRS), type I atelosteogenesis (AO1), type III atelosteogenesis (AO3), and boomerang dysplasia (BD). Among them, LRS is milder while BD causes a more severe phenotype. However, the molecular mechanism underlying the differences in clinical phenotypes of different FLNB variants has not been fully determined. Here, we presented two patients suffering from autosomal dominant LRS and autosomal recessive vitamin D-dependent rickets type IA (VDDR-IA). Whole-exome sequencing revealed two novel missense variants in FLNB, c.4846A>G (p.T1616A) and c.7022T>G (p.I2341R), which are located in repeat 15 and 22 of filamin B, respectively. The expression of FLNBI2341R in the muscle tissue from our LRS patient was remarkably increased. And in vitro studies showed that both variants led to a lack of filopodia and accumulation of the mutants in the perinuclear region in HEK293 cells. We also found that c.4846A>G (p.T1616A) and c.7022T>G (p.I2341R) regulated endochondral osteogenesis in different ways. c.4846A>G (p.T1616A) activated AKT pathways through inhibiting SHIP2, suppressed the Smad3 pathway, and impaired the expression of Runx2 in both Saos-2 and ATDC5 cells. c.7022T>G (p.I2341R) activated both AKT and Smad3 pathways and increased the expression of Runx2 in Saos-2 cells, while in ATDC5 cells it activated AKT pathways through inhibiting SHIP2, suppressed the Smad3 pathway, and reduced the expression of Runx2. Our study demonstrated the pathogenic mechanisms of two novel FLNB variants in two different clinical settings and proved that FLNB variants could not only directly cause skeletal malformations but also worsen skeletal symptoms in the setting of other skeletal diseases. Besides, FLNB variants differentially affect skeletal development which contributes to clinical heterogeneity of FLNB-related disorders.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core , Filaminas , Osteocondrodisplasias , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Nanismo/metabolismo , Facies , Filaminas/genética , Filaminas/metabolismo , Células HEK293 , Humanos , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
18.
Genome ; 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35849843

RESUMO

Aquilaria sinensis is an important non-timber tree species for producing high-value agarwood, which is widely used as a traditional medicine and incense. Agarwood is the product of Aquilaria trees in response to injury and fungal infection. AP2/ERF transcription factors play important roles in plant stress responses and metabolite biosynthesis. In this study, 119 AsAP2/ERF genes were identified from the A. sinensis genome and divided into ERF, AP2, RAV and Soloist subfamilies. Their conserved motif, gene structure, chromosomal localization, and subcellular localization were characterized. A stress/defense-related ERF-associated amphiphilic repression (EAR) motif and an EDLL motif were identified. Moreover, 11 genes that were highly expressed in the agarwood layer in response to whole-tree agarwood induction technique (Agar-Wit) treatment were chosen, and their expression levels in response to MeJA, SA or salt treatment were further analyzed using qRT-PCR. Among the 11 genes, eight belonged to subgroup B-3. All 11 genes were significantly upregulated under salt treatment, while eight genes were significantly induced by both MeJA and SA. In addition, the gene clusters containing these upregulated genes on chromosomes were observed. The results obtained from this research not only provide useful information for understanding the functions of AP2/ERF genes in A. sinensis but also identify candidate genes and gene clusters to dissect their regulatory roles in agarwood formation for future research.

19.
Hepatology ; 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35849032

RESUMO

BACKGROUND AND AIMS: Liver fibrosis is a chronic disease characterized by different etiological agents; dysregulated interactions between hepatocytes and HSCs contribute to this disease. ß-arrestin 1 (ARRB1) plays an important role in liver fibrosis; however, the effect of ARRB1 on the crosstalk between hepatocytes and HSCs in liver fibrosis is unknown. The aim of this study is to investigate how ARRB1 modulates hepatocyte and HSC activation during liver fibrosis. APPROACH AND RESULTS: Normal and fibrotic human liver and serum samples were obtained. CCl4 -induced liver fibrosis and methionine-choline deficiency-induced NASH models were constructed. Primary hepatocytes and HSCs were isolated, and human hepatic LO2 and stellate LX2 cells were used. Small extracellular vesicles (EVs) were purified, and key proteins were identified. ARRB1 was up-regulated in hepatocytes and associated with autophagic blockage in liver fibrosis. ARRB1 increased the release of hepatocyte-derived small EVs by inhibiting multivesicular body lysosomal degradation and activating Rab27A, thereby activating HSCs. Proteomic analyses showed that mannan-binding lectin serine protease 1 (MASP1) was enriched in hepatocyte-derived small EVs and activated HSCs via p38 mitogen-activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling. ARRB1 up-regulated MASP1 expression in hepatocytes. MASP1 promoted liver fibrosis in mice. Clinically, MASP1 expression was increased in the serum and liver tissue of patients with liver fibrosis. CONCLUSIONS: ARRB1 up-regulates the release of hepatocyte-derived MASP1-enriched small EVs by regulating the autophagic-lysosomal/multivesicular body pathway and Rab27A. Hepatocyte-derived MASP1 activates HSCs to promote liver fibrogenesis through p38 MAPK/ATF2 signaling. Thus, MASP1 is a pivotal therapeutic target in liver fibrosis.

20.
J Phys Condens Matter ; 34(41)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35901791

RESUMO

In this paper, a phase-field model of Si-doped hafnium oxide-based ferroelectric thin films is established. And then, the synergistic effect of Si concentration and distribution on ferroelectric properties optimization of Si:HfO2ferroelectric thin films is studied with the proposed model. It is found that no matter how Si dopant is distributed in the film, the volume fraction of the ferroelectric phase in the film increases first and then decreases with the increase of Si concentration. However, compared with the uniform distribution, the layered distribution is more likely to great improve ferrelectric properties. When Si dopant is uniformly distributed in the film, the highest remanent polarization value that the film can obtain via Si concentration modulation is 38.7µC cm-2, and the corresponding Si concentration is 3.8 cat%, which is consistent with the experimental results. When Si dopant is layered in the film, and the concentration difference between the Si-rich and Si-poor layers is 7.6%, in the Si concentration range of 3.6 cat%-3.8 cat%, the residual polarization of the film reaches 46.4-46.8µC cm-2, which is 20% higher than that when Si dopant are evenly distributed in the film. The above results show that selecting the Si layered distribution mode and controlling the concentration difference between Si-rich and Si-poor layers in an appropriate range can greatly improve the films' ferroelectric properties and broaden the Si concentration optimization range of the ferroelectric properties of the films. The result provides further theoretical guidance on using Si doping to adjust the ferroelectric properties of hafnium oxide-based films.

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