RESUMO
The progression of osteoarthritis (OA) includes the initial inflammation, subsequent degradation of the extracellular matrix (ECM), and chondrocyte apoptosis. Down syndrome candidate region 1 (DSCR1) is a stress-responsive gene and expresses in varied types of cells, including chondrocytes. Bioinformatics analysis of GSE103416 and GSE104739 datasets showed higher DSCR1 expression in the inflamed cartilage tissues and chondrocytes of OA. DSCR1 had two major isoforms, isoform 1 (DSCR1-1) and isoform 4 (DSCR1-4). We found that DSCR1-1 had a faster (in vitro) and higher expression (in vivo) response to OA compared to DSCR1-4. IL-1ß-induced apoptosis, inflammation, and ECM degradation in chondrocytes were attenuated by DSCR1-1 overexpression. DSCR1-1 triggered the phosphorylation of cAMP response element-binding 1 (CREB1) at 133 serine sites by decreasing calcineurin activity. Moreover, activated CREB1 moved into the cell nucleus and combined in the promoter regions of aldehyde dehydrogenase 2 (ALDH2), thus enhancing its gene transcription. ALDH2 could recover Wnt/ß-catenin signaling transduction by enhancing phosphorylation of ß-catenin at 33/37 serine sites and inhibiting the migration of ß-catenin protein from the cellular matrix to the nucleus. In vivo, adenoviruses (1 × 108 PFU) overexpressing DSCR1-1 were injected into the articular cavity of C57BL/6 mice with medial meniscus surgery-induced OA, and it showed that DSCR1-1 overexpression ameliorated cartilage injury. Collectively, our study demonstrates that DSCR1-1 may be a potential therapeutic target of OA.
Assuntos
Condrócitos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Osteoartrite , Via de Sinalização Wnt , Condrócitos/metabolismo , Animais , Osteoartrite/metabolismo , Osteoartrite/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Humanos , Camundongos , Aldeído-Desidrogenase Mitocondrial/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , beta Catenina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Apoptose/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genéticaRESUMO
Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell cell migration and invasion assay data in Fig. 3C and D, and the tumour images shown in Fig. 4A were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had already been published. In addition, certain of the data panels shown in Fig. 3C were overlapping, such that the data from the same original source had been selected to represent the results from allegedly differently performed experiments. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 15: 42174224, 2017; DOI: 10.3892/mmr.2017.6493].
RESUMO
A major challenge for magnetic skyrmions in atomically thin van der Waals (vdW) materials is reliable skyrmion detection. Here, based on rigorous first-principles calculations, we show that all-electrical skyrmion detection is feasible in two-dimensional vdW magnets via scanning tunneling microscopy (STM) and in planar tunnel junctions. We use the nonequilibrium Green's function method for quantum transport in planar junctions, including self-energy due to electrodes and working conditions, going beyond the standard Tersoff-Hamann approximation. We obtain a very large tunneling anisotropic magnetoresistance (TAMR) around the Fermi energy for a graphite/Fe3GeTe2/germanene/graphite vdW tunnel junction. For atomic-scale skyrmions, the noncollinear magnetoresistance (NCMR) reaches giant values. We trace the origin of the NCMR to spin mixing between spin-up and -down states of pz and dz2 character at the surface atoms. Both TAMR and NCMR are drastically enhanced in tunnel junctions with respect to STM geometry due to orbital symmetry matching at the interface.
RESUMO
This study aimed to explore the effects on resorption of cervical disc herniation (CDH) and clinical outcomes of surgery. Cervical microendoscopic laminoplasty (CMEL), which is commonly preferable to anterior corpectomy and fusion, was applied to patients with 1- to 3-level degenerative cervical myelopathy (DCM). DCM patients with 1-3 levels DCM underwent either conservation treatment or CMEL. In conservation-treated patients (53 cases), CDH volume remained unchanged with no improvement in JOA and VAS scores. Conversely, 63 patients with 1-3 levels DCM were prospectively enrolled and exhibited a profound decrease in CDH volume: 89.1% of CDHs (123/138) regressed over 10%, 64.5% of CDHs (89/138) regressed over 25%, while 27.5% and 6.5% of CDHs (38/138 and 9/138) largely regressed over 50% and 75%, respectively. Meanwhile, the JOA and VAS scores were improved in different ways. Intriguingly, CDH volume changes correlated significantly with elevations in JOA scores, indicating an association of clinical CDH resolution with neurological recovery. We showed that CMEL induced clinically related diminishment of CDH and alleviation of clinical symptoms in patients with 1- to 3-level myelopathy and that it could help avoid anterior dissection of the disc to some extent.
Assuntos
Doenças da Medula Óssea , Deslocamento do Disco Intervertebral , Laminoplastia , Doenças da Medula Espinal , Humanos , Deslocamento do Disco Intervertebral/cirurgia , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Resultado do Tratamento , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/cirurgia , Estudos RetrospectivosRESUMO
Orbital hybridization at the Co/C60 interface been has proved to strongly enhance the magnetic anisotropy of the cobalt layer, promoting such hybrid systems as appealing components for sensing and memory devices. Correspondingly, the same hybridization induces substantial variations in the ability of the Co/C60 interface to support spin-polarized currents and can bring out a spin-filtering effect. The knowledge of the effects at both sides allows for a better and more complete understanding of interfacial physics. In this paper we investigate the Co/C60 bilayer in the role of a spin-polarized electrode in the La0.7Sr0.3MnO3/SrTiO3/C60/Co configuration, thus substituting the bare Co electrode in the well-known La0.7Sr0.3MnO3/SrTiO3/Co magnetic tunnel junction. The study revealed that the spin polarization (SP) of the tunneling currents escaping from the Co/C60 electrode is generally negative: i.e., inverted with respect to the expected SP of the Co electrode. The observed sign of the spin polarization was confirmed via DFT calculations by considering the hybridization between cobalt and molecular orbitals.
RESUMO
Magnetic skyrmionsâlocalized chiral spin structuresâshow great promise for spintronic applications. The recent discovery of two-dimensional (2D) magnets opened new opportunities for topological spin structures in atomically thin van der Waals (vdW) materials. Despite recent progress in stabilizing metastable skyrmions in 2D magnets, their lifetime, essential for applications, has not been explored yet. Here, using first-principles calculations and atomistic spin simulations, we predict that compressive strain leads to stabilizing zero-field skyrmions with diameters close to 10 nm in a Fe3GeTe2/germanene vdW heterostructure. The origin of these unique skyrmions is attributed to the high tunability of Dzyaloshinskii-Moriya interaction and magnetocrystalline anisotropy energy by strain, which generally holds for Fe3GeTe2 heterostructures with buckled substrates. Furthermore, we calculate the energy barriers protecting skyrmions against annihilation and their lifetimes using transition-state theory. We show that nanoscale skyrmions in strained Fe3GeTe2/germanene can be stable for hours at temperatures up to 20 K.
RESUMO
We demonstrate, based on low-temperature scanning tunneling microscopy (STM) and spectroscopy, a pronounced negative differential resistance (NDR) in spin-crossover (SCO) molecular devices, where a FeII SCO molecule is deposited on surfaces. The STM measurements reveal that the NDR is robust with respect to substrate materials, temperature, and the number of SCO layers. This indicates that the NDR is intrinsically related to the electronic structure of the SCO molecule. Experimental results are supported by density functional theory (DFT) with nonequilibrium Green's function (NEGF) calculations and a generic theoretical model. While the DFT+NEGF calculations reproduce NDR for a special atomically sharp STM tip, the effect is attributed to the energy-dependent tip density of states rather than the molecule itself. We, therefore, propose a Coulomb blockade model involving three molecular orbitals with very different spatial localization as suggested by the molecular electronic structure.
RESUMO
Inflammation and fibrosis are the important pathophysiologic processes in diabetic kidney disease (DKD), which is induced by epigenetics, especially histone posttranslational modification (HPTMs). Recent reports highlighted that butyrate, one of the short-chain fatty acids (SCFAs) primarily originated from the fermentation of dietary fiber in the gut, attenuates inflammation and fibrosis in the prevention and treatment of DKD; however, the molecular mechanisms are still unclear. Histone lysine butyrylation (Kbu), a novel histone modification marker induced by butyrate, has been found to be involved in the regulation of pathophysiological processes. To reveal the mechanisms of butyrate-induced histone (Kbu), in the prevention and treatment of DKD, both DKD models in vivo and in vitro were treated with sodium butyrate (NaB). Our results confirmed that exogenous NaB improved the disorder of glucose and lipid metabolism, prevented proteinuria and renal failure, and inhibited renal inflammation and fibrosis. Meanwhile, NaB also induced histone Kbu and H3K9 butyrylation (H3K9bu) in vivo and in vitro; however, inhibition of histone Kbu with the histone modification enzyme p300 inhibitor A485 reversed the anti-inflammatory and anti-fibrosis effects of NaB. In conclusion, our data reveal that NaB antagonizes renal inflammatory and fibrosis injury and attenuates DKD possibly via histone Kbu, suggesting that butyrate-induced histone Kbu or H3K9bu may be an important molecular mechanism in the pathogenesis and treatment of DKD.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Ácido Butírico/farmacologia , Ácido Butírico/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Histonas/metabolismo , Humanos , Inflamação/tratamento farmacológico , Processamento de Proteína Pós-TraducionalRESUMO
All-electrical writing and reading of spin states attract considerable attention for their promising applications in energy-efficient spintronics devices. Here we show, based on rigorous first-principles calculations, that the spin properties can be manipulated and detected in molecular spinterfaces, where an iron tetraphenyl porphyrin (FeTPP) molecule is deposited on boron-substituted graphene (BG). Notably, a reversible spin switching between the S=1 and S=3/2 states is achieved by a gate electrode. We can trace the origin to a strong hybridization between the Fe-d_{z^{2}} and B-p_{z} orbitals. Combining density functional theory with nonequilibrium Green's function formalism, we propose an experimentally feasible three-terminal setup to probe the spin state. Furthermore, we show how the in-plane quantum transport for the BG, which is non-spin polarized, can be modified by FeTPP, yielding a significant transport spin polarization near the Fermi energy (>10% for typical coverage). Our work paves the way to realize all-electrical spintronics devices using molecular spinterfaces.
RESUMO
STUDY DESIGN: An algorithm was developed with MATLAB platform to automatically quantify the volume of cervical disc herniation (CDH) based on the sagittal magnetic resonance images. This automated program was used for CDH data set, and then compared with manual measurement results confirming its reliability. OBJECTIVE: The aim was to develop a new software for automated CDH volume measurement. SUMMARY OF BACKGROUND DATA: CDH compresses the spinal cord, regarding as the leading cause of cervical myelopathy. However, the CDH volume, of great value to clinical symptoms, can be only manually measured with no-excellent but acceptable interobserver reliability. This was due to the manual error of outlining CDH area and inclusion of structure posterior vertebra. No studies has proposed such an automated algorithm of CDH volume quantification which is standardised to quantify the accurate volume of CDH thus helping doctors easily evaluate CDH progressing. METHODS: The algorithm of CDH volume measurement was proposed. This program was then tested for 490 CDHs data set, from 185 patients with two repeated magnetic resonance imaging detections. Three individual observers manually measured the volumes of these CDHs, to justify the accuracy of this software. CDH volume was either in the classic way or the revised way excluding the influence of structure posterior vertebra. RESULTS: The automated software was successfully developed on MATLAB platform, with no difference found with manual measurements (average level) in CDH volume measurement. The change ratios in CDH volumes were profoundly consistent with manual observation, showing the error of 5.8% in median. The revised method elevated the absolute value of ratio by amplifying the percentage change. CONCLUSION: Our developed automated volumetry system was an standardized and accurate way, with selective removal module of structure posterior vertebra, replaceable for manual volume measurement of CDH, which was useful for spinal surgeons diagnosing and treating CDH disease.
Assuntos
Deslocamento do Disco Intervertebral , Algoritmos , Inteligência Artificial , Humanos , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Reprodutibilidade dos TestesRESUMO
Exosomes derived from mesenchymal stem cells (MSCs) have been considered as an alternative for cell therapy of acute spinal cord injury (ASCI). However, the underlying mechanism remains unclear. Here, ASCI mouse model and hypoxic cell model were established to evaluate the effects of MSCs and MSCs-derived exosomes (MSCs-exo). The results showed that both MSCs and MSCs-exo inhibited the production of ROS and ferrous iron, upregulated the expression of ferroptosis suppressor FSP1, and enhanced repair of neurological function in the ASCI mice. Besides, MSCs and MSCs-exo attenuated hypoxia-induced neuronal cell ferroptosis and increased cell proliferation. Further study demonstrated that lncGm36569 was enriched in the MSCs-exo. Through bioinformatics analysis and luciferase assay, we confirmed that lncGm36569 acted as a competitive RNA of miR-5627-5p to induce FSP1 upregulation. Furthermore, overexpression of miR-5627-5p reversed the therapeutic effects of lncGm36569 on neuronal cell ferroptosis. In conclusion, MSCs-exosomes lncGm36569 inhibited neuronal cell ferroptosis through miR-5627-5p/FSP1 axis, thereby attenuating neuronal dysfunction.
Assuntos
Exossomos , Ferroptose , Células-Tronco Mesenquimais , MicroRNAs , Traumatismos da Medula Espinal , Animais , Exossomos/metabolismo , Ferroptose/genética , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/terapiaRESUMO
The complex behavior of the simplest atomic-scale conductors indicates that the electrode structure itself is significant in the design of future nanoscale devices. In this study, the structural asymmetry of metallic atomic contacts formed between two macroscopic Au electrodes at room temperature was investigated. Characteristic signatures of the structural asymmetries were detected by fast current-voltage (I-V) measurements with a time resolution of approximately 100 µs. Statistical analysis of more than 300,000 I-V curves obtained from more than 1000 contact-stretching processes demonstrates that the current rectification properties are correlated with the conductance of the nanocontacts. A substantial suppression of the variation in current rectification was observed for the atomic contacts with integer multiples of the conductance quantum. Statistical analysis of the time-resolved I-V curves revealed that the current rectification variations increased significantly from 500 µs onward before the breakage of the atomic contacts. Ab initio atomistic simulations of the stretching processes and corresponding I-V characteristics confirmed the magnitude of the rectification and related it to the structural asymmetries in the breakdown process of the junctions. Overall, we provide a better understanding of the interplay between geometric and electronic structures at atomically defined metal-metal interfaces by probing charge transport properties in extremely sensitive nanocontacts.
RESUMO
STUDY DESIGN: Retrospective study on 185 patients with 490 cervical disc herniation (CDH). OBJECTIVE: The aim of this study was to compare the changes in volumes of CDH in patients with degenerative cervical myelopathy (DCM) surgically treated by expansive open-door laminoplasty (EOLP) or cervical microendoscopic laminoplasty (CMEL). SUMMARY OF BACKGROUND DATA: Spontaneous resorption of CDH was shown in patients with DCM after conservation treatment, but very few in surgically treated patients. Our previous study identified the clinical efficiency of CMEL to treat DCM but how CDH sized postoperatively, as well as comparing to EOLP, was unknown. METHODS: Consecutive patients with DCM from December 2015 to December 2019, who underwent MRI evaluation, receiving CMEL or EOLP, and repeat MRI in follow-up were included. The volume of CDH were monitored using the picture archiving and communication system, further calculating the incidence of CDH with volume regression and the percentage changes of CDH volume. The correlations of possible determines with CDH volume changes were analyzed by Spearman rank correlation coefficient. RESULTS: A total of 89 patients (215 CDHs, EOLP-group) and 96 patients (275 CDHs, CMEL-group) was surveyed, respectively. Resultantly, volume of CDH was decreased postoperatively in both EOLP and CMEL cases. But this CDH volume regression was more profound in CMEL groups (incidence of 81.2% from 223/275, median volume change ratio of -26.7%, occurring from 1 month after CMEL), statistically different from EOLP group (50.2% from 108/215, median volume change ratio of -5.4%, none-appearance within 1 month). Patients information as sex, age, and follow-up time, not CDH significant, was significantly correlated with CDH volume changes. CONCLUSION: Patients who underwent CMEL developed a postoperative reduction of CDH volume, with more popularity, greater degree and earlier-staged than EOLP-patients. Young females with longer follow-up time were more likely occur.Level of Evidence: 4.
Assuntos
Deslocamento do Disco Intervertebral , Laminoplastia , Espondilose , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Feminino , Humanos , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Deslocamento do Disco Intervertebral/cirurgia , Estudos Retrospectivos , Espondilose/cirurgia , Resultado do TratamentoRESUMO
The discovery of two-dimensional (2D) magnetic materials provides an ideal testbed for manipulating the magnetic properties at the atomically thin and 2D limit. This review gives recent progress in the emergent 2D magnets and heterostructures, focusing on the theory side. We summarize different theoretical models, ranging from the atomic to micrometer-scale, used to describe magnetic orders. Then, the current strategies for tuning magnetism in 2D materials are further discussed, such as electric field, magnetic field, strain, optics, chemical functionalization, and spin-orbit engineering. Finally, we conclude with the future challenges and opportunities for 2D magnetism.
RESUMO
The spin transport across a zero-dimensional (0D) single-molecule sandwiched by two-dimensional (2D) van der Waals (vdW) ferromagnetic electrodes may open vast opportunities to create novel mixed-dimensional spintronics devices. However, this remains unexplored yet. Inspired by the recent discovery of 2D intrinsic ferromagnets Fe3GeTe2, using first-principles spin transport calculations, we show that single-molecule junctions based on Fe3GeTe2 can yield perfect spin filtering and a significant magnetoresistance (MR) of up to â¼6075%. This remarkable MR is more than 2 orders of magnitude higher than the MR obtained for the corresponding junctions with conventional ferromagnetic metals (e.g., Ni, Fe, and Co). We demonstrate the results of two representative examples that are feasible in the experiments: (i) A benzene or (ii) bezenedithiol (BDT) connected either through a scanning tunneling microscope or break-junction setups. We find that the conductance of BDT junctions is more than 10 times larger than that of the benzene junction due to a much stronger hybridization effect at the molecule-metal interfaces. The key mechanism of the perfect spin filtering and large MR in single-molecule junctions is mainly determined by the intrinsic properties of Fe3GeTe2 electrodes, while the actual conductance is determined by the hybridization strength of the majority spin channel at the molecule-metal interfaces. It is also predicted that the perfect spin filtering and the remarkably huge MR are highly insensitive to structural variations, interface defects, and stacking orders of the electrodes. Our results provide important insights for expanding molecular spintronics platforms from conventional ferromagnetic metals to new 2D vdw magnets.
RESUMO
BACKGROUND: Punicalagin (PUN) is a common anti-inflammatory polyphenol. However, the function and mechanism of PUN in osteoarthritis remains unknown. METHODS: Chondrocytes were isolated from rats, and confirmed by toluidine blue staining and immunofluorescence. Chondrocytes were challenged by lipopolysaccharide (LPS), and rat osteoarthritis model was established by Hulth method. The secretion of inflammatory factors, cell viability and apoptosis were tested via enzyme linked immunosorbent assay (ELISA), MTT and flow cytometry. The levels of forkhead box O1 (Foxo1), proteoglycan 4 (Prg4), hypoxia-inducible factor-3α (HIF3α), autophagy-related genes or extracellular matrix (ECM)-related proteins were examined via quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot or immunohistochemistry. The cartilage tissue damage was assessed via hematoxylin-eosin (HE) staining, toluidine blue staining and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL) staining. RESULTS: LPS triggered inflammatory injury in chondrocytes. PUN promoted autophagy to mitigate LPS-induced inflammatory injury. Foxo1 silence attenuated the effect of PUN on LPS-mediated autophagy inhibition and inflammatory injury. Promotion of Prg4/HIF3α axis abolished the influence of Foxo1 knockdown on LPS-mediated chondrocytes injury. PUN mitigated the inflammatory injury in rat osteoarthritis model by promoting autophagy and inhibiting inflammation and ECM degradation via Foxo1/Prg4/HIF3α axis. CONCLUSION: PUN attenuates LPS-induced chondrocyte injury and osteoarthritis progression by regulating Foxo1/Prg4/HIF3α axis.
Assuntos
Taninos Hidrolisáveis/farmacologia , Osteoartrite , Animais , Apoptose , Autofagia , Condrócitos , Taninos Hidrolisáveis/uso terapêutico , Proteínas do Tecido Nervoso , Osteoartrite/tratamento farmacológico , Proteoglicanas , Ratos , Fatores de TranscriçãoRESUMO
BACKGROUND: The main pathological feature of acute spinal cord injury (ASCI) is neuronal apoptosis and Long non-coding RNA (lncRNA) myocardial infarction-related transcript (MIAT) is involved in the regulation of neuronal apoptosis. This study aimed to investigate the role and potential mechanism of LncRNA MIAT in neuronal apoptosis induced by ASCI. METHODS: After Lenti-MIAT lentivirus was microinjected into ASCI rats, Basso, Beattie and Bresnahan Score, Hematoxylin-eosin staining, TUNEL staining, immunohistochemical, immunofluorescence, quantitative real-time PCR and Western blot were used to observe the effect of LncRNA MIAT on the nerve function of ASCI rats. MTT and flow cytometry assays were used to identify the in vitro function of LncRNA MIAT. RNA immunoprecipitation, RNA pull-down, Cycloheximide chase and Chromatin immunoprecipitation combined with qPCR experiments were used to study the mechanism. RESULTS: The overexpression of LncRNA MIAT was conducive to the recovery of motor function in ASCI rats and repressed neuronal cell apoptosis and increased neuronal cell viability. Furthermore, the overexpression of LncRNA MIAT in PC12 cells upregulated RAD21 expression by repressing RAD21 protein degradation and further promoted VEGFA transcription to inhibit neuronal cell apoptosis, ultimately improved ASCI. CONCLUSION: Our data indicated that the overexpression of LncRNA MIAT activated VEGFA through RAD21 to inhibit neuronal cell apoptosis in ASCI.
Assuntos
Proteínas de Ligação a DNA/metabolismo , RNA Longo não Codificante/genética , Traumatismos da Medula Espinal/terapia , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica , Vetores Genéticos/administração & dosagem , Humanos , Células PC12 , Ratos , Recuperação de Função Fisiológica , Transdução de Sinais , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologiaRESUMO
Bone tissue engineering-based therapy for bone lesions requires the expansion of seeding cells, such as autologous mesenchymal stem cells (MSCs). A major obstacle to this process is the loss of the phenotype and differentiation capacity of MSCs subjected to passage. Recent studies have suggested that primary cilia, primordial organelles that transduce multiple signals, particularly hedgehog signals, play a role in senescence. Therefore, we explored the relationships among senescence, primary cilia, and hedgehog signaling in MSCs. Ageing of MSCs by expansion in vitro was accompanied by increased cell doubling time. The osteogenic capacity of aged MSCs at passage 4 was compromised compared to that of primary cells. P4 MSCs exhibited reductions in the frequency and length of primary cilia associated with decreased intensity of Arl13b staining on cilia. Senescence also resulted in downregulation of the expression of hedgehog components and CDKN2A. Suppression of ciliogenesis reduced the gene expression of both Gli1, a key molecule in the hedgehog signaling pathway and ALP, a marker of osteoblastic differentiation. This study demonstrated that the senescence of MSCs induced the loss of osteoblastic differentiation potency and inactivated hedgehog signaling associated with attenuated ciliogenesis, indicating that primary cilia play a mediating role in and are biomarkers of MSC senescence; thus, future antisenescence strategies involving manipulation of primary cilia could be developed.
RESUMO
Osteoporosis is a common debilitating bone disease characterized by loss of bone mass and degradation of the bone architecture, which is primarily driven by dysregulated differentiation of mesenchymal stem cells into bone-producing osteoblasts. Osteoblasts contribute to bone formation by secreting various proteins that guide the deposition of bone extracellular matrix, such as alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). The Wnt/ß-catenin pathway is widely recognized as a regulator of bone mass and is required to maintain bone homeostasis. Hormones have long been recognized as playing a key role in bone metabolism, and in recent years, growing evidence has shown that diabetes is a risk factor for osteoporosis. In the present study, we investigated the effects of the antidiabetic drug anagliptin on the differentiation and mineralization of osteoblasts induced by osteogenic medium. Anagliptin promotes insulin production via inhibition of dipeptidyl peptidase IV (DPP-4), an enzyme that targets the incretin hormone glucagon-like peptide 1 (GLP-1) for degradation. Our findings show that anagliptin significantly increases the differentiation of MSCs into osteoblasts via activation of RUNX2. Anagliptin significantly increased matrix deposition and mineralization by osteoblasts, as evidenced by elevated levels of ALP, OCN, OPN, and BMP-2. We further demonstrate that anagliptin activates the canonical and noncannonical Wnt signaling pathways and that silencing of Wnt/ß-catenin signaling completely abolished the effects of anagliptin. Thus, anagliptin might be a safe, effective therapy for type II diabetes that might show promise as a therapy against osteoporosis.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Pirimidinas/farmacologia , Células 3T3 , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Regulação da Expressão Gênica , Camundongos , Osteoblastos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Via de Sinalização WntRESUMO
The electric field is an important parameter to vary in a single-molecule experiment, because it can directly affect the charge distribution around the molecule. Yet, performing such an experiment with a well-defined electric field for a model chemical reaction at an interface has proven to be extremely difficult. Here, by combining a graphene field-effect transistor and a gate-tunable scanning tunneling microscope (STM), we reveal how this strategy enables the intramolecular H atom transfer of a metal-free macrocycle to be controlled with an external field. Experiments and theory both elucidate how the energetic barrier to tautomerization decreases with increasing electric field. The consistency between the two results demonstrates the potential in using electric fields to engineer molecular switching mechanisms that are ubiquitous in nanoscale electronic devices.