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1.
EMBO J ; 42(9): e111762, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-36943004

RESUMO

Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis.


Assuntos
Células-Tronco Mesenquimais , Osteoporose , Humanos , Camundongos , Animais , Osteogênese/genética , Envelhecimento/metabolismo , Senescência Celular , Diferenciação Celular/genética , Osteoporose/metabolismo , Células da Medula Óssea , Proteína 1 de Ligação a Y-Box/metabolismo
2.
Cell Death Dis ; 13(10): 904, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36302749

RESUMO

Islet ß cell dysfunction and insulin resistance are the main pathogenesis of type 2 diabetes (T2D), but the mechanism remains unclear. Here we identify a rs3819316 C > T mutation in lncRNA Reg1cp mainly expressed in islets associated with an increased risk of T2D. Analyses in 16,113 Chinese adults reveal that Mut-Reg1cp individuals had higher incidence of T2D and presented impaired insulin secretion as well as increased insulin resistance. Mice with islet ß cell specific Mut-Reg1cp knock-in have more severe ß cell dysfunction and insulin resistance. Mass spectrometry assay of proteins after RNA pulldown demonstrate that Mut-Reg1cp directly binds to polypyrimidine tract binding protein 1 (PTBP1), further immunofluorescence staining, western blot analysis, qPCR analysis and glucose stimulated insulin secretion test reveal that Mut-Reg1cp disrupts the stabilization of insulin mRNA by inhibiting the phosphorylation of PTBP1 in ß cells. Furthermore, islet derived exosomes transfer Mut-Reg1cp into peripheral tissue, which then promote insulin resistance by inhibiting AdipoR1 translation and adiponectin signaling. Our findings identify a novel mutation in lncRNA involved in the pathogenesis of T2D, and reveal a new mechanism for the development of T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Células Secretoras de Insulina , Ilhotas Pancreáticas , RNA Longo não Codificante , Animais , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Resistência à Insulina/genética , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Humanos
3.
Nanoscale ; 12(38): 19992-20001, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-32996530

RESUMO

The design of Earth-abundant and cost-effective electrocatalysts for highly active and stable electrochemical water splitting in practical production is the primary demand. Herein, bimetallic oxides anchored to three-dimensional (3D) porous conductive nickel foam (NF) are constructed using a simple in situ hydrothermal method for efficient overall water splitting. The vertically aligned Mn3O4/Fe2O3 heterojunction nanosheets have synergy between hierarchical metal oxides and heterogeneous interface, and show excellent performance toward the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) in an alkaline environment. By adjusting the molar ratio of Fe : Mn, the morphology, composition and electronic structure of MnFeO-NF-x composites (x represents the ratio of Fe : Mn) can be adjusted to exhibit diverse catalytic activities. In particular, MnFeO-NF-0.4 (0.4 indicates the Fe : Mn ratio of 0.4 : 1) and MnFeO-NF-0.8 display outstanding performance with ultralow overpotentials of 157 mV for the OER and 64 mV for the HER to achieve a current density of 10 mA cm-2, respectively. Furthermore, MnFeO-NF-0.4 and MnFeO-NF-0.8 are assembled into a water splitting electrolyzer, which can reach a current density of 10 mA cm-2 with a low voltage of 1.59 V. Interestingly, Mn-M (M = Co, Ni, and Mo) products can be obtained easily by using different metal salts, indicating the universality of the current one-pot hydrothermal method.

4.
Sci Rep ; 8(1): 2175, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29391558

RESUMO

In a previous study, we reported ten new polyoxygenated cyathane diterpenoids, neocyathins A-J, and their anti-neuroinflammatory effects from the liquid culture of the medicinal Basidiomycete Cyathus africanus. In the present study, eight new highly polyoxygenated cyathane diterpenoids, named neocyathins K-R (1-8), were isolated from the solid culture of C. africanus cultivated on cooked rice, together with three known congeners (9-11). The structures and the absolute configurations of the new compounds were elucidated through comprehensive NMR and HRESIMS spectroscopic data, electronic circular dichroism (ECD) data, and chemical conversion. Compounds 1 and 2 represent the first reported naturally occurring compounds with 4,9-seco-cyathane carbon skeleton incorporating an unprecedented medium-sized 9/7 fused ring system, while the 3,4-seco-cyathane derivative (3) was isolated from Cyathus species for the first time. All compounds were evaluated for their neurotrophic and anti-neuroinflammatory activity. All the isolates at 1-25 µM displayed differential nerve growth factor (NGF)-induced neurite outgrowth-promoting activity in PC-12 cells, while one of the compounds, allocyathin B2 (11), inhibited NO production in lipopolysaccharide (LPS)-stimulated microglia BV-2 cells. In addition, molecular docking studies showed that compound 11 generated interactions with the inducible nitric oxide synthase (iNOS) protein.


Assuntos
Agaricales/química , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Macrófagos/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Oxigênio/química , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Diterpenos/química , Macrófagos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fatores de Crescimento Neural/metabolismo , Óxido Nítrico/metabolismo , Células PC12 , Ratos
5.
Sci Rep ; 7(1): 8883, 2017 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-28827545

RESUMO

Ten new polyoxygenated cyathane diterpenoids, named neocyathins A-J (1-10), together with four known diterpenes (11-14), were isolated from the liquid culture of the medicinal basidiomycete fungus Cyathus africanus. The structures and configurations of these new compounds were elucidated through comprehensive spectroscopic analyses including 1D NMR, 2D NMR (HSQC, HMBC, NOESY) and HRESIMS, and electronic circular dichroism (ECD) data. Neuroinflammation is implicated in the pathogenesis of various neurodegenerative diseases, such as Alzheimers' disease (AD). All isolated compounds were evaluated for the potential anti-neuroinflammatory activities in BV2 microglia cells. Several compounds showed differential effects on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated and Aß1-42-treated mouse microglia cell line BV-2. Molecular docking revealed that bioactive compounds (e.g., 11) could interact with iNOS protein other than COX-2 protein. Collectively, our results suggested that this class of cyathane diterpenoids might serve as important lead compounds for drug discovery against neuroinflammation in AD.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Cyathus/química , Diterpenos/química , Diterpenos/farmacologia , Animais , Linhagem Celular , Dicroísmo Circular , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Espectroscopia de Ressonância Magnética , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Modelos Moleculares , Conformação Molecular , Estrutura Molecular
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