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1.
Bone ; 187: 117172, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38909879

RESUMEN

Gain-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) can cause high-bone-mass (HBM) phenotype, with 19 identified mutations so far. The A242T mutation in LRP5 has been found in 9 families, making it one of the most prevalent mutations. However, the correlation between the A242T mutation and HBM phenotype remains unverified in animal models. This study aimed to investigate the bone properties in a new transgenic mouse model carrying the LRP5 A241T missense mutation, equivalent to A242T in humans. Heterozygous Lrp5A241T mice were generated using CRISPR/Cas9 genome editing. Body weight increased with age from 4 to 16 weeks, higher in males than females, with no difference between Lrp5A241T mice and wild-type control. Micro-CT showed slightly longer femur and notably elevated trabecular bone mass of the femur and fifth lumbar spine with higher bone mineral density, bone volume fraction, and trabecular thickness in Lrp5A241T mice compared to wild-type mice. Additionally, increased cortical bone thickness and volume of the femur shaft and skull were observed in Lrp5A241T mice. Three-point bending tests of the tibia demonstrated enhanced bone strength properties in Lrp5A241T mice. Histomorphometry confirmed that the A241T mutation increased bone formation without affecting osteoblast number and reduced resorption activities in vivo. In vitro experiments indicated that the LRP5 A241T mutation enhanced osteogenic capacity of osteoblasts with upregulation of the Wnt signaling pathway, with no significant impact on the resorptive activity of osteoclasts. In summary, mice carrying the LRP5 A241T mutation displayed high bone mass and quality due to enhanced bone formation and reduced bone resorption in vivo, potentially mediated by the augmented osteogenic potential of osteoblasts. Continued investigation into the regulatory mechanisms of its bone metabolism and homeostasis may contribute to the advancement of novel therapeutic strategies for bone disorders.

2.
J Hepatol ; 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38759889

RESUMEN

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

3.
Sci Total Environ ; 924: 171508, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38460682

RESUMEN

Fast fashion is driving the continued growth of the fashion industry's carbon emissions. Understanding how fast fashion consumption exacerbates carbon emissions is critical to guide mitigation strategies for the fashion industry. Taking jeans, a typical fast fashion product as an example, this study developed an LCA model to assess the carbon footprint of fast fashion consumption at global and national levels, and mitigation potentials of product service systems-related scenarios were then explored. Results show that the carbon footprint of fast fashion consumption is 2.50 kgCO2e/one wear jeans, 11 times higher than that of traditional fashion consumption. Jeans production and cross-broad transportation contributed 91 % of the carbon footprint of fast fashion consumption. Developed countries have a 53 % higher per capita carbon footprint of fast fashion consumption than developing countries. The second-hand trading model has the highest mitigation potential, reducing carbon emissions by 90 %. This study proposed an analytical framework for the carbon footprint of fast fashion consumption, which provides the basis for the environmental footprints of fast fashion products. Our findings provide insights into the carbon footprints of traditional and fast fashion consumption and strategies for the transition to circular fashion.

4.
Cell Chem Biol ; 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38382532

RESUMEN

Stem cells remain quiescent in vivo and become activated in response to external stimuli. However, the mechanism regulating the quiescence-activation balance of bone-marrow-derived mesenchymal stem cells (BM-MSCs) is still unclear. Herein, we demonstrated that CYP7B1 was the common critical molecule that promoted activation and impeded quiescence of BM-MSCs under inflammatory stimulation. Mechanistically, CYP7B1 degrades 25-hydroxycholesterol (25-HC) into 7α,25-dihydroxycholesterol (7α,25-OHC), which alleviates the quiescence maintenance effect of 25-HC through Notch3 signaling pathway activation. CYP7B1 expression in BM-MSCs was regulated by NF-κB p65 under inflammatory conditions. BM-MSCs from CYP7B1 conditional knockout (CKO) mice had impaired activation abilities, relating to the delayed healing of bone defects. Intravenous infusion of BM-MSCs overexpressing CYP7B1 could improve the pathological scores of mice with collagen-induced arthritis. These results clarified the quiescence-activation regulatory mechanism of BM-MSCs through the NF-κB p65-CYP7B1-Notch3 axis and provided insight into enhancing BM-MSCs biological function as well as the subsequent therapeutic effect.

5.
Adv Sci (Weinh) ; 11(10): e2303388, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38145956

RESUMEN

Regular quiescence and activation are important for the function of bone marrow mesenchymal stem cells (BMMSC), multipotent stem cells that are widely used in the clinic due to their capabilities in tissue repair and inflammatory disease treatment. TNF-α is previously reported to regulate BMMSC functions, including multilineage differentiation and immunoregulation. The present study demonstrates that TNF-α impedes quiescence and promotes the activation of BMMSC in vitro and in vivo. Mechanistically, the TNF-α-induced expression of KAT2A promotes the succinylation of VCP at K658, which inhibits the interaction between VCP and MFN1 and thus inhibits mitophagy. Furthermore, activated BMMSC exhibits stronger fracture repair and immunoregulation functions in vivo. This study contributes to a better understanding of the mechanisms of BMMSC quiescence and activation and to improving the effectiveness of BMMSC in clinical applications.


Asunto(s)
Células Madre Mesenquimatosas , Factor de Necrosis Tumoral alfa , Factor de Necrosis Tumoral alfa/metabolismo , Mitofagia , Células Madre Mesenquimatosas/metabolismo , Diferenciación Celular
6.
Psychol Med ; 53(15): 7375-7384, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38078747

RESUMEN

BACKGROUND: Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis. METHODS: Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0-11 years), and late (12-17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use. RESULTS: The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord. CONCLUSIONS: Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.


Asunto(s)
Experiencias Adversas de la Infancia , Cannabis , Trastornos Psicóticos , Esquizofrenia , Humanos , Niño , Cannabis/efectos adversos , Estudios de Casos y Controles , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/etiología , Trastornos Psicóticos/psicología , Esquizofrenia/epidemiología , Esquizofrenia/complicaciones
7.
Nat Commun ; 14(1): 8154, 2023 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-38071226

RESUMEN

Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Linfocitos T CD8-positivos/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/genética , Receptor de Muerte Celular Programada 1/metabolismo , Agotamiento de Células T , Succinatos/farmacología , Succinatos/metabolismo , Epigénesis Genética
8.
Sensors (Basel) ; 23(21)2023 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-37960363

RESUMEN

The field of view and single-star measurement accuracy are crucial metrics for assessing the performance of a star sensor. The field of view determines the spatial range of stars that can be captured by the sensor, while the single-star measurement accuracy determines the precision of attitude determination and control for the star sensor. The optical system of conventional star sensors is constrained by imaging relationships. Once the detector is determined, improving either the field of view or the single-star measurement accuracy will result in the degradation of the other. To address this issue, we propose an optical system for star sensors with accuracy performance varying with the field of view. By controlling the relationship between the field focal length of the optical system and the field of view, it is possible to simultaneously enhance both the field of view and the single-star measurement accuracy. We have designed corresponding optical systems to address the requirements for improving the single-star measurement accuracy and field of view. The design results confirm the feasibility of this star sensor. The star sensors are capable of simultaneously meeting the requirements for star pattern recognition and attitude determination, presenting broad application prospects in fields such as space navigation.

9.
BMC Plant Biol ; 23(1): 501, 2023 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-37848871

RESUMEN

BACKGROUND: The cotton industry suffers significant yield losses annually due to Verticillium wilt, which is considered the most destructive disease affecting the crop. However, the precise mechanisms behind this disease in cotton remain largely unexplored. METHODS: Our approach involved utilizing transcriptome data from G. australe which was exposed to Verticillium dahliae infection. From this data, we identified ethylene-responsive factors and further investigated their potential role in resistance through functional validations via Virus-induced gene silencing (VIGS) in cotton and overexpression in Arabidopsis. RESULTS: A total of 23 ethylene response factors (ERFs) were identified and their expression was analyzed at different time intervals (24 h, 48 h, and 72 h post-inoculation). Among them, GauERF105 was selected based on qRT-PCR expression analysis for further investigation. To demonstrate the significance of GauERF105, VIGS was utilized, revealing that suppressing GauERF105 leads to more severe infections in cotton plants compared to the wild-type. Additionally, the silenced plants exhibited reduced lignin deposition in the stems compared to the WT plants, indicating that the silencing of GauERF105 also impacts lignin content. The overexpression of GauERF105 in Arabidopsis confirmed its pivotal role in conferring resistance against Verticillium dahliae infection. Our results suggest that WT possesses higher levels of the oxidative stress markers MDA and H2O2 as compared to the overexpressed lines. In contrast, the activities of the antioxidant enzymes SOD and POD were higher in the overexpressed lines compared to the WT. Furthermore, DAB and trypan staining of the overexpressed lines suggested a greater impact of the disease in the wild-type compared to the transgenic lines. CONCLUSIONS: Our findings provide confirmation that GauERF105 is a crucial candidate in the defense mechanism of cotton against Verticillium dahliae invasion, and plays a pivotal role in this process. These results have the potential to facilitate the development of germplasm resistance in cotton.


Asunto(s)
Arabidopsis , Ascomicetos , Verticillium , Gossypium/genética , Gossypium/metabolismo , Arabidopsis/genética , Lignina/metabolismo , Peróxido de Hidrógeno/metabolismo , Verticillium/fisiología , Ascomicetos/metabolismo , Etilenos , Resistencia a la Enfermedad/genética , Enfermedades de las Plantas/genética , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/metabolismo
10.
iScience ; 26(10): 107852, 2023 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-37766971

RESUMEN

Polymer-ceramic composites are commonly used as flexoelectric films. In existing studies, the flexoelectric effect of composites are generally improved by adjusting the material structures or adding ferroelectric materials. Further improvement of flexoelectric response has encountered a bottleneck. Considering from a new perspective, this study innovatively proposes to prepare the uniformly dispersed BT-PVDF composite films with giant flexoelectric response by surfactant SDS-assisted treatment. According to the engineering applications, tilt sensors have been fabricated with the SDS/BT-PVDF composite films. The prepared tilt sensors can accurately sense the tilt change in a small-angle range (0-10°) between the coaxial connecting parts, the response signal changes significantly (49.25-72.35 mV/°), and the response speed can reach 0.166 s. The research provides a new idea for improving the flexoelectric response and also paves a way for developing tilt sensors through a low-cost, facile, and reliable method, showing potential applications including bending sensing and structural health monitoring.

11.
Bone Res ; 11(1): 30, 2023 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-37280207

RESUMEN

As the major cell precursors in osteogenesis, mesenchymal stem cells (MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversial. Composed of multiple constituent enhancers, super enhancers (SEs) are powerful cis-regulatory elements that identify genes that ensure sequential differentiation. The present study demonstrated that SEs were indispensable for MSC osteogenesis and involved in osteoporosis development. Through integrated analysis, we identified the most common SE-targeted and osteoporosis-related osteogenic gene, ZBTB16. ZBTB16, positively regulated by SEs, promoted MSC osteogenesis but was expressed at lower levels in osteoporosis. Mechanistically, SEs recruited bromodomain containing 4 (BRD4) at the site of ZBTB16, which then bound to RNA polymerase II-associated protein 2 (RPAP2) that transported RNA polymerase II (POL II) into the nucleus. The subsequent synergistic regulation of POL II carboxyterminal domain (CTD) phosphorylation by BRD4 and RPAP2 initiated ZBTB16 transcriptional elongation, which facilitated MSC osteogenesis via the key osteogenic transcription factor SP7. Bone-targeting ZBTB16 overexpression had a therapeutic effect on the decreased bone density and remodeling capacity of Brd4fl/fl Prx1-cre mice and osteoporosis (OP) models. Therefore, our study shows that SEs orchestrate the osteogenesis of MSCs by targeting ZBTB16 expression, which provides an attractive focus and therapeutic target for osteoporosis. Without SEs located on osteogenic genes, BRD4 is not able to bind to osteogenic identity genes due to its closed structure before osteogenesis. During osteogenesis, histones on osteogenic identity genes are acetylated, and OB-gain SEs appear, enabling the binding of BRD4 to the osteogenic identity gene ZBTB16. RPAP2 transports RNA Pol II from the cytoplasm to the nucleus and guides Pol II to target ZBTB16 via recognition of the navigator BRD4 on SEs. After the binding of the RPAP2-Pol II complex to BRD4 on SEs, RPAP2 dephosphorylates Ser5 at the Pol II CTD to terminate the transcriptional pause, and BRD4 phosphorylates Ser2 at the Pol II CTD to initiate transcriptional elongation, which synergistically drives efficient transcription of ZBTB16, ensuring proper osteogenesis. Dysregulation of SE-mediated ZBTB16 expression leads to osteoporosis, and bone-targeting ZBTB16 overexpression is efficient in accelerating bone repair and treating osteoporosis.

14.
Cell Prolif ; 56(5): e13471, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37199039

RESUMEN

Robust allogeneic immune reactions after transplantation impede the translational pace of human embryonic stem cells (hESCs)-based therapies. Selective genetic editing of human leucocyte antigen (HLA) molecules has been proposed to generate hESCs with immunocompatibility, which, however, has not been specifically designed for the Chinese population yet. Herein, we explored the possibility of customizing immunocompatible hESCs based on Chinese HLA typing characteristics. We generated an immunocompatible hESC line by disrupting HLA-B, HLA-C, and CIITA genes while retaining HLA-A*11:01 (HLA-A*11:01-retained, HLA-A11R ), which covers ~21% of the Chinese population. The immunocompatibility of HLA-A11R hESCs was verified by in vitro co-culture and confirmed in humanized mice with established human immunity. Moreover, we precisely knocked an inducible caspase-9 suicide cassette into HLA-A11R hESCs (iC9-HLA-A11R ) to promote safety. Compared with wide-type hESCs, HLA-A11R hESC-derived endothelial cells elicited much weaker immune responses to human HLA-A11+ T cells, while maintaining HLA-I molecule-mediated inhibitory signals to natural killer (NK) cells. Additionally, iC9-HLA-A11R hESCs could be induced to undergo apoptosis efficiently by AP1903. Both cell lines displayed genomic integrity and low risks of off-target effects. In conclusion, we customized a pilot immunocompatible hESC cell line based on Chinese HLA typing characteristics with safety insurance. This approach provides a basis for establishment of a universal HLA-AR bank of hESCs covering broad populations worldwide and may speed up the clinical application of hESC-based therapies.


Asunto(s)
Células Madre Embrionarias Humanas , Humanos , Animales , Ratones , Células Madre Embrionarias , Alelos , Antígeno HLA-A11/genética , Antígeno HLA-A11/metabolismo , Pueblos del Este de Asia , Células Endoteliales , Edición Génica , Antígenos HLA/genética , Histocompatibilidad , Diferenciación Celular
15.
Psychol Med ; 53(15): 7418-7427, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37129249

RESUMEN

BACKGROUND: While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis. METHODS: We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status. RESULTS: Controls (86.1%) and FEPp (75.63%) were most likely to report 'because of friends' as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: 'to feel better' as their RFUC (χ2 = 50.97; p < 0.001). RFUC 'to feel better' was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC 'with friends' was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC 'to feel better' with heavy cannabis use and with FEPp-control status. CONCLUSIONS: Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use 'to feel better'. People who reported their reason for first using cannabis to 'feel better' were more likely to progress to heavy use and develop a psychotic disorder than those reporting 'because of friends'.


Asunto(s)
Cannabis , Fumar Marihuana , Trastornos Psicóticos , Humanos , Cannabis/efectos adversos , Estudios de Casos y Controles , Fumar Marihuana/efectos adversos , Trastornos Psicóticos/epidemiología , Factores de Riesgo
16.
Food Res Int ; 164: 112443, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36738008

RESUMEN

Starch-stabilized Pickering emulsions were employed as a novel particulate filler in myofibrillar protein (MP)-based gels for improving the gelling characteristics. The role of emulsions prepared by native starches (NS) with distinctive crystalline types (i.e., A-type waxy corn starch, B-type potato starch, and C-type pea starch) and their OSA-modified counterparts (A-OS, B-OS, C-OS) in the gelling performance was evaluated and compared with MP-stabilized-emulsion. Compared with MP-emulsion, starch-emulsion caused substantial increases in the gelling properties, notably for OSA-starch emulsions. Herein, A-OS exhibited up to 1.26-, 5.3-, and 2.9-fold increments in storage modulus, gel strength, and water holding capacity relative to pure MP gel, respectively, higher than B-OS and C-OS. Moreover, light microscopy evinced a more compact gel network filled with smaller and uniform oil droplets when A-OS emulsions were incorporated into the gels. The addition of OSA-starch emulsions, especially A-OS emulsion, facilitated the protein conformational conversion from α-helix to ß-sheet and caused a marked reduction of free sulfhydryls in the gels; yet, the chemical forces that stabilized the gels altered, where remarkable reinforcements in hydrogen bond and hydrophobic interaction were detected, in support of the construction of splendid MP gels. Hence, OSA-starch emulsions show promise as functional components in meat products.


Asunto(s)
Almidón , Amilopectina , Emulsiones/química , Excipientes , Geles/química , Almidón/química
17.
JCI Insight ; 8(6)2023 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-36795489

RESUMEN

Mesenchymal stem cells (MSCs) possess strong immunoregulatory functions, one aspect of which is recruiting monocytes from peripheral vessels to local tissue by secreting monocyte chemoattractant protein 1 (MCP1). However, the regulatory mechanisms of MCP1 secretion in MSCs are still unclear. Recently, the N6-methyladenosine (m6A) modification was reported to be involved in the functional regulation of MSCs. In this study, we demonstrated that methyltransferase-like 16 (METTL16) negatively regulated MCP1 expression in MSCs through the m6A modification. Specifically, the expression of METTL16 in MSCs decreased gradually and was negatively correlated with the expression of MCP1 after coculture with monocytes. Knocking down METTL16 markedly enhanced MCP1 expression and the ability to recruit monocytes. Mechanistically, knocking down METTL16 decreased MCP1 mRNA degradation, which was mediated by the m6A reader YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2). We further revealed that YTHDF2 specifically recognized m6A sites on MCP1 mRNA in the CDS region and thus negatively regulated MCP1 expression. Moreover, an in vivo assay showed that MSCs transfected with METTL16 siRNA showed greater ability to recruit monocytes. These findings reveal a potential mechanism by which the m6A methylase METTL16 regulates MCP1 expression through YTHDF2-mediated mRNA degradation and suggest a potential strategy to manipulate MCP1 expression in MSCs.


Asunto(s)
Células Madre Mesenquimatosas , Monocitos , Monocitos/metabolismo , Quimiocina CCL2/genética , Adenosina/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Células Madre Mesenquimatosas/metabolismo
18.
Open Med (Wars) ; 18(1): 20230636, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36760721

RESUMEN

The object was to enhance the bioactivity of pure polyether-ether-ketone (PEEK) by incorporating nano-TiO2 (n-TiO2) and investigate its potential mechanism. PEEK/n-TiO2 composite was manufactured using a 3D PEEK printer and characterized by scanning electron microscopy (SEM), 3D profiler, energy-dispersive spectroscopy, and Fourier-transform infrared (FT-IR) analyses. Cytocompatibility was tested using SEM, fluorescence, and cell counting kit-8 assays. Osteogenic differentiation was evaluated by osteogenic gene and mineralized nodule levels. The expression of the candidate miRNAs were detected in composite group, and its role in osteogenic differentiation was studied. As a results the 3D-printed PEEK/n-TiO2 composite (Φ = 25 mm, H = 2 mm) was successfully fabricated, and the TiO2 nanoparticles were well distributed and retained the nanoscale size of the powder. The Ra value of the composite surface was 2.69 ± 0.29, and Ti accounted for 22.29 ± 12.09% (in weight), and FT-IR analysis confirmed the characteristic peaks of TiO2. The cells in the composite group possessed better proliferation and osteogenic differentiation abilities than those in the PEEK group. miR-154-5p expression was decreased in the composite group, and the inhibition of miR-154-5p significantly enhanced the proliferation and osteogenic differentiation abilities. In conclusion, 3D-printed PEEK/n-TiO2 composite enhanced cytocompatibility and osteogenic induction ability by downregulating miR-154-5p, which provides a promising solution for improving the osteointegration of PEEK.

19.
Int J Biol Macromol ; 230: 123183, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36634797

RESUMEN

Effects of octenylsuccinic anhydride (OSA) esterification on the morphology, crystalline structure, and emulsifying properties of three representative starches with different crystalline types, namely waxy corn starch (A-type), potato starch (B-type), and pea starch (C-type) were investigated. XRD patterns testified OSA substitution occurred principally in the amorphous region without affecting the crystalline patterns, whereas SEM verified esterification was mainly a surface phenomenon. However, OSA esterification caused a decrease in the peak intensity and area of small-angle X-ray scattering profiles, indicating the semi-crystalline lamellae ordering was impeded to a certain extent. Compared with A- and C-type starches, B-type starch had a stronger affinity for OSA, as manifested by its higher degree of substitution (DS), graver surface detriment, and depressed order of semi-crystalline lamellae. The emulsifying properties of all starches were pronouncedly improved by OSA modification, especially for A-type starch even with comparatively lower DS. Pickering emulsion stabilized by OSA-modified A-type starch (A-OSAS) with smaller droplet size and more uniform droplet size distribution exhibited more splendiferous stability relative to the other two modified starches. Moreover, rheological tests revealed A-OSAS possessed the highest apparent viscosity and storage modulus (G'), insinuating strong intermolecular interactions between starch granules at the interface and/or in the continuous phase.


Asunto(s)
Almidón , Amilopectina , Emulsiones/química , Tamaño de la Partícula , Almidón/química , Viscosidad
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