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1.
Theranostics ; 9(15): 4525-4541, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31285777

RESUMO

Evidence indicates that microRNAs (miRNAs) play vital roles in regulating osteogenic differentiation and bone formation. Methods: Here, we show that a polyethyleneimine (PEI)-functionalized graphene oxide (GO) complex efficiently loaded with the miR-214 inhibitor is assembled into silk fibroin/hydroxyapatite (SF/HAP) scaffolds that spatially control the release of the miR-214 inhibitor. Results: SF/HAP/GO scaffolds with nanosized GO show high mechanical strength, and their hierarchical microporous structures promote cell adhesion and growth. The SF/HAP/GO-PEI scaffolds loaded with mir-214 inhibitor (SF/HAP/GPM) were tested for their ability to enhance osteogenic differentiation by inhibiting the expression of miR-214 while inversely increasing the expression of activating transcription factor 4 (ATF4) and activating the Akt and ERK1/2 signaling pathways in mouse osteoblastic cells (MC3T3-E1) in vitro. Similarly, the scaffolds activated the osteoblastic activity of endogenous osteoblast cells to repair critical-sized bone defects in rats without the need for loading osteoblast cells. Conclusion: This technology is used to increase osteogenic differentiation and mineralized bone formation in bone defects, which helps to achieve cell-free scaffold-based miRNA-inhibitor therapy for bone tissue engineering.

2.
Int J Mol Med ; 44(2): 608-616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173188

RESUMO

Hypercholesterolemia is a key factor leading to ß­cell dysfunction, but its underlying mechanisms remain unclear. Secretagogin (Scgn), a Ca2+ sensor protein that is expressed at high levels in the islets, has been shown to play a key role in regulating insulin secretion through effects on the soluble N­ethylmaleimide­sensitive factor attachment receptor protein complexes. However, further studies are required to determine whether Scgn plays a role in hypercholesterolemia­associated ß­cell dysfunction. The present study investigated the involvement of a microRNA­24 (miR­24)­to­Scgn regulatory pathway in cholesterol­induced ß­cell dysfunction. In the present study, MIN6 cells were treated with increasing concentrations of cholesterol and then, the cellular functions and changes in the miR­24­to­Scgn signal pathway were observed. Excessive uptake of cholesterol in MIN6 cells increased the expression of miR­24, resulting in a reduction in Sp1 expression by directly targeting its 3' untranslated region. As a transcriptional activator of Scgn, downregulation of Sp1 decreased Scgn levels and subsequently decreased the phosphorylation of focal adhesion kinase and paxillin, which is regulated by Scgn. Therefore, the focal adhesions in insulin granules were impaired and insulin exocytosis was reduced. The present study concluded that a miR­24­to­Scgn pathway participates in the mechanism regulating cholesterol accumulation­induced ß­cell dysfunction.

3.
J Cell Biochem ; 120(9): 14791-14803, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31090954

RESUMO

Diabetes and periodontal diseases have a mutual promoting relationship that induces severe tissue damage and cell death. The potential roles of microRNAs (miRNAs) and the type of cell death involved in diabetes-associated periodontitis are obscure. The gingival tissues of patients were obtained and MC3T3-E1 cells were costimulated with high glucose and lipopolysaccharide (LPS). Osseous morphometric analysis was evaluated with micro-CT, and histological characteristics were measured by hematoxylin/eosin and immunohistochemical staining. Cytokine secretion was confirmed by enzyme-linked immunosorbent assay, and reactive oxygen species (ROS) was measured using a DCFH-DA probe kit. Gene expression was measured by real-time quantitative reverse transcription PCR (qRT-PCR), and protein expression was assessed by Western blot and immunofluorescence analysis. The miR-214 level, receptor-interacting serine-threonine protein (RIP) 1, RIP3, and phospho-mixed lineage kinase domain-like (p-MLKL) protein expression were elevated in the inflamed gingival tissues of diabetes-associated periodontitis patients, with activating transcription factor 4 (ATF4) expression showing the opposite effect. The high glucose (22 mM) could not induce significant increase of RIP1, RIP3, and p-MLKL; however, the high glucose and LPS (500-1000 ng/mL) cotreatment resulted in increase in the number of RIP1, RIP3, and p-MLKL in MC3T3-E1 cells. NAC (ROS inhibitor) inhibited RIP1, RIP3, and increased ATF4; however, necrostatin-1 (Nec-1) (RIP1 inhibitor) specifically inhibited the protein expression of RIP1 and RIP3 and had no influence on ATF4. The use of antagomir-214 suppressed the expression of miR-214, RIP1, RIP3, and p-MLKL, but increased ATF4 protein level in glucose and LPS-induced cells. ATF4 knockdown by ATF4 small interfering RNA offset the effect of antagomir-214. RIP1- and RIP3-dependent necroptosis was confirmed in the inflamed gingival tissues of diabetes-associated periodontitis patients and high glucose- and LPS- cotreated cells. It was suggested that miR-214-targeted ATF4 participated in the regulation of necroptosis in vivo and in vitro.

4.
J Biomed Nanotechnol ; 15(4): 728-741, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30841966

RESUMO

ZrO2-NPs are widely applied in industry, biomedicine and dentistry, e.g., foundry sands, refractories, ceramics dental prostheses, dental implant coatings and bone defect restorative materials. To date, little information is available on the potential adverse effects and toxic mechanism in human organs associated with exposure to ZrO2-NPs. The biodistribution of ZrO2-NPs and the consequent oxidative stress in the spleen, kidney, heart, brain, and lung at six time points after a single injection of ZrO2-NPs were examined. Histopathological and immunohistochemical changes were also examined. RNA-Seq analysis was conducted in organs with high ZrO2-NPs accumulations or obvious histopathological changes (brain and spleen). Exposure to the ZrO2-NPs led to persistent oxidative stress and cell proliferation promotion/inhibition in various organs. RNA-Seq results of the spleen and brain point to significant gene expression changes. Metabolism was identified as leading pathways in the spleen. This study proves ZrO2-NPs likely have negative impacts on various organs, and exhibit potential disease risks.


Assuntos
Nanopartículas , Administração Intravenosa , Animais , Humanos , Óxidos , Ratos , Distribuição Tecidual , Zircônio
5.
J Cardiovasc Pharmacol Ther ; 23(2): 162-173, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28954528

RESUMO

Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid accumulation and endothelial dysfunction. Cytoglobin has been shown to exert protective effects under oxidative stress conditions. The aim of this study was to determine whether recombinant human cytoglobin (rhCYGB) has protective effects against atherosclerosis. We intraperitoneally injected rhCYGB (0, 4, or 7 mg/kg BW) into the atherosclerotic rats daily for 60 days. The rhCYGB injections reduced low-density lipoprotein cholesterol (LDL-C) levels and increased high-density lipoprotein cholesterol levels in a dose-dependent manner, rhCYGB (7 mg/kg) significantly attenuated atherosclerosis. Blood proteins were separated by 2-dimensional electrophoresis and analyzed by mass spectrometry, and the majority of the proteins in question were participated in oxidative stress pathways and cardiovascular diseases. Human hepatocellular liver carcinoma cell line (HepG2) cells were treated with oleic acid (0.3 mmol/L), and Human acute monocytic leukemia cell line (THP-1) cells were incubated with oxidized LDL (ox-LDL; 50 µg/mL) to induce foam cell (FC) formation in vitro. Treatment with different concentrations of rhCYGB (0, 5, 10, and 15 µg/mL) significantly decreased the lipid droplet levels in HepG2 cells and cholesterol ester levels in FCs. Moreover, rhCYGB significantly increased superoxide dismutase and glutathione peroxidase activity and decreased malondialdehyde and nicotinamide adenine dinucleotide phosphate oxidase activity in cells. In addition, rhCYGB decreased NO and Reactive oxygen species (ROS) levels in FCs by functioning as an NO dioxygenase enzyme and ROS scavenger. Taken together, our findings indicate that rhCYGB prevented atherosclerosis by regulating lipid metabolism and oxidative stress. Our study provides insights into the possible usefulness of rhCYGB as an antiatherosclerosis agent.

6.
Int J Nanomedicine ; 12: 6633-6646, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28924347

RESUMO

Graphene-based materials (GBMs) are widely used in many fields, including biomedicine. To date, much attention had been paid to the potential unexpected toxic effects of GBMs. Here, we review the recent literature regarding the impact of GBMs on programmed cell death (PCD). Apoptosis, autophagy, and programmed necrosis are three major PCDs. Mechanistic studies demonstrated that the mitochondrial pathways and MAPKs (JNK, ERK, and p38)- and TGF-ß-related signaling pathways are implicated in GBMs-induced apoptosis. Autophagy, unlike apoptosis and necroptosis which are already clear cell death types, plays a vital pro-survival role in cell homeostasis, so its role in cell death should be carefully considered. However, GBMs always induce unrestrained autophagy accelerating cell death. GBMs trigger autophagy through inducing autophagosome accumulation and lysosome impairment. Mitochondrial dysfunction, ER stress, TLRs signaling pathways, and p38 MAPK and NF-κB pathways participate in GBMs-induced autophagy. Programmed necrosis can be activated by RIP kinases, PARP, and TLR-4 signaling in macrophages after GBMs exposure. Though apoptosis, autophagy, and necroptosis are distinguished by some characteristics, their numerous signaling pathways comprise an interconnected network and correlate with each other, such as the TLRs, p53 signaling pathways, and the Beclin-1 and Bcl-2 interaction. A better understanding of the mechanisms of PCD induced by GBMs may allow for a thorough study of the toxicology of GBMs and a more precise determination of the consequences of human exposure to GBMs. These determinations will also benefit safety assessments of the biomedical and therapeutic applications of GBMs.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Grafite/farmacologia , Animais , Humanos , Macrófagos/metabolismo , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Necrose/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia
7.
J Biomed Nanotechnol ; 13(12): 1682-1693, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29490756

RESUMO

A graded glass/graded zirconia (G/Z) system was previously synthesized via the infiltration of a low modulus nanosized glass into a zirconia surface. The bond strength of G/Z to veneering porcelains was demonstrated to be 3-fold higher than in zirconia-based systems. Nevertheless, biocompatibility testing prior to the possible clinical application of G/Z systems is essential. Herein, such biocompatibility testing was performed with L-929 fibroblasts seeded onto G/Z and yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) for 2-72 h. Assessments included an oral mucous membrane irritation test in conjunction with analyses of cell viability, cell morphology, cell cycle, cell apoptosis, oxidative stress responses, inflammatory cytokine expression, and cellular toxicity. Cell viability tests showed no significant decrease in G/Z- and Y-TZP-treated cells over 72 h. Fluorescence and SEM images demonstrated that cell spreading on Y-TZP and G/Z was similar; cells were flattened and well-spread. Oxidative stress data for G/Z- and Y-TZP-treated cells showed no significant difference in ROS production. Cellular toxicity results for G/Z did not elicit significant differences in LDH release compared with Y-TZP over 72 h. G/Z and Y-TZP had no significant differences in IL-1α, IL-8, PGE2, and TNF-α expression and elicited significantly increased IL-8 expression compared with that of the untreated control group. Cells that were cultured with G/Z showed no significant changes in cell cycle distribution compared with Y-TZP or the untreated control group. Cells that were cultured with Y-TZP and G/Z showed no apoptosis compared to untreated controls at 24 and 48 h. According to the oral mucous membrane irritation test, scores for the macroscopic and microscopic observations for both G/Z and Y-TZP sides were 0, demonstrating no consequent irritation. Therefore, the excellent biocompatibility of G/Z indicates that it has potential for future clinical applications.


Assuntos
Colagem Dentária , Porcelana Dentária , Zircônio , Vidro , Teste de Materiais , Microscopia Eletrônica de Varredura , Propriedades de Superfície , Ítrio
8.
Cell Physiol Biochem ; 40(6): 1487-1505, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27997890

RESUMO

Inorganic nanomaterials have been widely applied in biomedicine. However, several studies have noted that inorganic nanoparticles can enter the brain and induce cytoskeletal remodeling, as well as electrophysiological alterations, which are related to neurodevelopmental disorders and neurodegenerative diseases. The toxic effects of inorganic nanomaterials on the cytoskeleton and electrophysiology are summarized in this review. The relationships between inorganic NPs-induced cytoskeletal and electrophysiological alterations in the central nervous system remain obscure. We propose several potential relationships, including those involving N-methyl-D-aspartate receptor function, ion channels, transient receptor potential channels, and the Rho pathway.


Assuntos
Sistema Nervoso Central/fisiopatologia , Citoesqueleto/metabolismo , Fenômenos Eletrofisiológicos , Compostos Inorgânicos/toxicidade , Nanopartículas/toxicidade , Animais , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Neurotransmissores/metabolismo
9.
Part Fibre Toxicol ; 13(1): 57, 2016 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-27799056

RESUMO

Due to their unique physicochemical properties, graphene-family nanomaterials (GFNs) are widely used in many fields, especially in biomedical applications. Currently, many studies have investigated the biocompatibility and toxicity of GFNs in vivo and in intro. Generally, GFNs may exert different degrees of toxicity in animals or cell models by following with different administration routes and penetrating through physiological barriers, subsequently being distributed in tissues or located in cells, eventually being excreted out of the bodies. This review collects studies on the toxic effects of GFNs in several organs and cell models. We also point out that various factors determine the toxicity of GFNs including the lateral size, surface structure, functionalization, charge, impurities, aggregations, and corona effect ect. In addition, several typical mechanisms underlying GFN toxicity have been revealed, for instance, physical destruction, oxidative stress, DNA damage, inflammatory response, apoptosis, autophagy, and necrosis. In these mechanisms, (toll-like receptors-) TLR-, transforming growth factor ß- (TGF-ß-) and tumor necrosis factor-alpha (TNF-α) dependent-pathways are involved in the signalling pathway network, and oxidative stress plays a crucial role in these pathways. In this review, we summarize the available information on regulating factors and the mechanisms of GFNs toxicity, and propose some challenges and suggestions for further investigations of GFNs, with the aim of completing the toxicology mechanisms, and providing suggestions to improve the biological safety of GFNs and facilitate their wide application.


Assuntos
Grafite/toxicidade , Nanopartículas/toxicidade , Animais , Vias de Administração de Medicamentos , Distribuição Tecidual
10.
J Invest Dermatol ; 135(5): 1425-1434, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25581502

RESUMO

Pressure ulcers (PUs) are serious skin injuries whereby the wound healing process is frequently stalled in the inflammatory phase. Myeloid-derived suppressor cells (MDSCs) accumulate as a result of inflammation and promote cutaneous wound healing by mechanisms that are not fully understood. Recently, MDSCs have been shown to differentiate into fibrocytes, which serve as emerging effector cells that enhance cell proliferation in wound healing. We postulate that in wound healing MDSCs not only execute their immunosuppressive function to regulate inflammation but also stimulate cell proliferation once they differentiate into fibrocytes. In the current study, by using full-thickness and PU mouse models, we found that Kruppel-like factor 4 (KLF4) deficiency resulted in decreased accumulation of MDSCs and fibrocytes, and wound healing was significantly delayed. Conversely, KLF4 activation by the plant-derived product Mexicanin I increased the number of MDSCs and fibrocytes and accelerated the wound healing. Collectively, our study revealed a previously unreported function of MDSCs in cutaneous wound healing and identified Mexicanin I as a potential agent to accelerate PU wound healing.


Assuntos
Proliferação de Células/fisiologia , Fibroblastos/patologia , Fatores de Transcrição Kruppel-Like/fisiologia , Células Mieloides/patologia , Lesão por Pressão/fisiopatologia , Pele/fisiopatologia , Cicatrização/fisiologia , Animais , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Lactonas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Receptores CCR2/metabolismo , Proteína A4 de Ligação a Cálcio da Família S100 , Proteínas S100/metabolismo , Sesquiterpenos/farmacologia
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