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1.
Langmuir ; 37(14): 4137-4146, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33813823

RESUMO

Hydroxyapatite (HA) is the main inorganic component of human bones and teeth. It has good biocompatibility and bioactivity, which promotes its good application prospects in the field of bone drug carriers. In this study, tetraethylenepentamine-graphene (rGO-TEPA)/CaCO3:HA composite microspheres were prepared via microwave hydrothermal synthesis using rGO-TEPA/CaCO3 solid microspheres as intermediates. Furthermore, the incompletely transformed CaCO3 was removed by soaking in a citric acid buffer to obtain rGO-TEPA/HA hollow composite microspheres. The two types of as-prepared composite microspheres exhibited sea urchin-like structures, large BET surface areas, and good dispersibility. Mouse preosteoblast cells (MC3T3-E1) were used for in vitro cytotoxicity experiments. The in vitro cell viability test showed that the two composite drug carriers exhibited noncytotoxicity. Moreover, the doxorubicin (DOX) loading and releasing investigations revealed that the two types of prepared carriers had mild storage-release behaviors and good pH responsiveness. Hence, these rGO-TEPA/HA hollow microspheres have promising applications as bone drug carriers.


Assuntos
Materiais Biomiméticos , Osso e Ossos/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Durapatita , Grafite , Microesferas , Ouriços-do-Mar , Animais , Osso e Ossos/citologia , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/farmacologia , Etilenodiaminas , Concentração de Íons de Hidrogênio , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos
2.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672735

RESUMO

Lipodystrophy is a common complication in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART). Previous studies demonstrated that endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) is involved in lipodystrophy; however, the detailed mechanism has not been fully described in human adipogenic cell lineage. We utilized adipose tissue-derived stem cells (ADSCs) obtained from human subcutaneous adipose tissue, and atazanavir (ATV), a protease inhibitor (PI), was administered to ADSCs and ADSCs undergoing adipogenic conversion. Marked repression of adipogenic differentiation was observed when ATV was administered during 10 days of ADSC culture in adipogenic differentiation medium. Although ATV had no effect on ADSCs, it significantly induced apoptosis in differentiating adipocytes. ATV treatment also caused the punctate appearance of CCAAT-enhancer-binding (C/EBP) protein homologous protein (CHOP), and altered expression of CHOP and GRP78/Bip, which are the representation of ER stress, only in differentiating adipocytes. Administration of UPR inhibitors restored adipogenic differentiation, indicating that ER stress-mediated UPR was induced in differentiating adipocytes in the presence of ATV. We also observed autophagy, which was potentiated in differentiating adipocytes by ATV treatment. Thus, adipogenic cell atrophy leads to ATV-induced lipodystrophy, which is mediated by ER stress-mediated UPR and accelerated autophagy, both of which would cause adipogenic apoptosis. As our study demonstrated for the first time that ADSCs are unsusceptible to ATV and its deleterious effects are limited to the differentiating adipocytes, responsible target(s) for ATV-induced lipodystrophy may be protease(s) processing adipogenesis-specific protein(s).


Assuntos
Adipócitos/patologia , Adipogenia , Antirretrovirais/efeitos adversos , Sulfato de Atazanavir/uso terapêutico , Diferenciação Celular , Estresse do Retículo Endoplasmático , Lipodistrofia/induzido quimicamente , Células-Tronco/patologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo/patologia , Terapia Antirretroviral de Alta Atividade , Apoptose/efeitos dos fármacos , Sulfato de Atazanavir/farmacologia , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Dano ao DNA , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Fator de Transcrição CHOP/metabolismo
3.
Life Sci ; 272: 119246, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33607156

RESUMO

AIMS: Memory impairment is determined to be the most well-known symptom of Alzheimer's disease (AD). Although cell therapy seems is an efficient therapeutic strategy to attenuate the AD-related memory impairment, transplanted cells have a short lifespan and do not survive long term in the recipient animals. Herein, we investigated whether the combination therapy of Selenium nanoparticles (SeNPs) and stem cells attenuates the neurotoxicity in an AD animal model. MATERIAL AND METHODS: The adipose-derived mesenchymal stem cells (AMSCs) were transplanted in the AD model. In addition to cell injections, the animals also received oral administration of SeNPs (0.4 mg/kg) for one month. Recognition memory, cell survival, and BDNF concentration were assessed using the novel object recognition task, immunofluorescence, and ELISA methods. KEY FINDINGS: Our results showed that the combined therapy was more effective in increasing the discrimination index than the administering SeNPs or AMSCs alone. Moreover, SeNPs and stem cells together had the greatest effects in reducing the deposition of Aß and increasing the concentration of BDNF. Ultimately, the survival and proliferation of transplanted cells were more in the group that received stem cells besides SeNPs. SIGNIFICANCE: Taken together, it seems that the transplantation of MSCs combined with SeNPs could achieve better results in the neuroprotection in the AD model than a conventional treatment of SeNPs or stem cells alone.


Assuntos
Transtornos da Memória/terapia , Células-Tronco Mesenquimais/metabolismo , Selênio/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Modelos Animais de Doenças , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Nanopartículas Metálicas/uso terapêutico , Neuroproteção/efeitos dos fármacos , Ratos , Ratos Wistar , Células-Tronco/efeitos dos fármacos , Estreptozocina/farmacologia
4.
Toxicol Lett ; 342: 6-19, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33581290

RESUMO

2,2',4,4'-Tetrabromodiphenyl ether (BDE47), a flame retardant, is extensively distributed in the food chain. However, whether BDE47 affects Leydig cell development during prepuberty remains unclear. BDE47 was daily gavaged to 21-day-old Sprague-Dawley male rats with 0 (corn oil), 0.1, 0.2, and 0.4 mg/kg for 14 days. BDE47 did not affect the body weight or testis weight of rats. It significantly increased serum testosterone level at 0.4 mg/kg, but decreased luteinizing hormone (LH) level without affecting estradiol level. BDE47 induced Leydig cell hyperplasia (the number of CYP11A1-positive Leydig cells increased), and up-regulated the expression of Scarb1, Star, Hsd11b1, Pcna, and Ccnd1 in the testis. BDE47 significantly reduced p53 and p21 levels but increased CCND1 level. It also markedly increased the phosphorylation of AKT1, AKT2, ERK1/2, and CREB. BDE47 significantly up-regulated the expression of Scarb1, Star, and Hsd11b1 and stimulated androgen production by immature Leydig cells from rats under basal, LH, and 8Br-cAMP stimulated conditions at 100 nM in vitro. In conclusion, BDE47 increased Leydig cell number and up-regulated the expression of Scarb1 and Star, thereby leading to increased testosterone synthesis.


Assuntos
Éteres Difenil Halogenados/toxicidade , Células Intersticiais do Testículo/fisiologia , Maturidade Sexual/fisiologia , Células-Tronco/efeitos dos fármacos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Células Cultivadas , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Relação Dose-Resposta a Droga , Hormônio Foliculoestimulante , Regulação da Expressão Gênica/efeitos dos fármacos , Éteres Difenil Halogenados/administração & dosagem , Éteres Difenil Halogenados/química , Hormônio Luteinizante , Masculino , Estrutura Molecular , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo
5.
Int J Mol Med ; 47(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33537804

RESUMO

Quercetin (Quer) is a typical antioxidant flavonoid from plants that is involved in bone metabolism, as well as in the progression of inflammatory diseases. Elevated levels of tumor necrosis factor­α (TNF­α), a typical pro­inflammatory cytokine, can affect osteogenesis. In the present study, TNF­α was used to establish an in vitro model of periodontitis. The effects of Quer on, as well as its potential role in the osteogenic response of human periodontal ligament stem cells (hPDLSCs) under TNF­α­induced inflammatory conditions and the underlying mechanisms were then investigated. Within the appropriate concentration range, Quer did not exhibit any cytotoxicity. More importantly, Quer significantly attenuated the TNF­α induced the suppression of osteogenesis­related genes and proteins, alkaline phosphatase (ALP) activity and mineralized matrix in the hPDLSCs. These findings were associated with the fact that Quer inhibited the activation of the NF­κB signaling pathway, as well as the expression of NLRP3 inflammation­associated proteins in the inflammatory microenvironment. Moreover, the silencing of NLRP3 by small interfering RNA (siRNA) was found to protect the hPDLSCs against TNF­α­induced osteogenic damage, which was in accordance with the effects of Quer. On the whole, the present study demonstrates that Quer reduces the impaired osteogenesis of hPDLSCs under TNF­α­induced inflammatory conditions by inhibiting the NF­κB/NLRP3 inflammasome pathway. Thus, Quer may prove to be a potential remedy against periodontal bone defects.


Assuntos
Inflamassomos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteogênese/efeitos dos fármacos , Ligamento Periodontal/patologia , Quercetina/farmacologia , Células-Tronco/patologia , Fator de Necrose Tumoral alfa/toxicidade , Adolescente , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Adulto Jovem
6.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445804

RESUMO

Neural progenitor cells (NPCs) are self-renewing and multipotent cells that persist in the postnatal and adult brain in the subventricular zone and the hippocampus. NPCs can be expanded in vitro to be used in cell therapy. However, expansion is limited, since the survival and proliferation of adult NPCs decrease with serial passages. Many signaling pathways control NPC survival and renewal. Among these, purinergic receptor activation exerts differential effects on the biology of adult NPCs depending on the cellular context. In this study, we sought to analyze the effect of a general blockade of purinergic receptors with suramin on the proliferation and survival of NPCs isolated from the subventricular zone of postnatal rats, which are cultured as neurospheres. Treatment of neurospheres with suramin induced a significant increase in neurosphere diameter and in NPC number attributed to a decrease in apoptosis. Proliferation and multipotency were not affected. Suramin also induced an increase in the gap junction protein connexin43 and in vascular endothelial growth factor, which might be involved in the anti-apoptotic effect. Our results offer a valuable tool for increasing NPC survival before implantation in the lesioned brain and open the possibility of using this drug as adjunctive therapy to NPC transplantation.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Antagonistas Purinérgicos/farmacologia , Receptores Purinérgicos/metabolismo , Células-Tronco/efeitos dos fármacos , Suramina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/metabolismo , Masculino , Células-Tronco Neurais/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Arch Oral Biol ; 123: 105034, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33472098

RESUMO

OBJECTIVE: This study aimed to investigate the effect of epigallocatechin gallate (EGCG) on the proliferation, mineralization, inflammation and hypoxia responses of human dental pulp stem cells (hDPSCs) in vitro and its effect on inflammatory pulp tissue in rats in vivo. DESIGN: The optimum concentration of EGCG was selected by creating a dose response curve. Expression of odontogenic/osteogenic-related genes and inflammatory cytokines after stimulation with Lipopolysaccharide (LPS) was detected by real-time PCR. Under hypoxic conditions, cell proliferation and expression of reactive oxygen species (ROS) and superoxide dismutase (SOD) were detected.In vivo, the maxillary first molars of SD rats were pulpotomized and stimulated with 5 mg/mL LPS for 30 min. Normal saline and EGCG were used to flush the pulp chamber. After 2 months, samples were removed for micro-CT scanning and HE staining. RESULTS: CCK-8 assay revealed that 10 µg/mL EGCG had no significant effect on the proliferation of hDPSCs. EGCG inhibited expression of IL-1ß, IL-6, and TNF-α. Furthermore, EGCG rescued cell proliferation ability, increased SOD activity and reduced ROS expression under hypoxia.In vivo, reduced inflammatory cell accumulation was observed in the coronal pulp in the EGCG group, while in the control group, diffuse inflammatory cells were observed in the radicular pulp. CONCLUSION: EGCG had no obvious effects on calcified nodule formation but significantly inhibited the inflammatory response of hDPSCs and inhibited apoptosis of hDPSCs caused by hypoxia injury. In vivo, EGCG exerts inhibitory effects on pulp tissue inflammation.


Assuntos
Catequina/análogos & derivados , Polpa Dentária/citologia , Células-Tronco/efeitos dos fármacos , Animais , Apoptose , Catequina/farmacologia , Hipóxia Celular , Células Cultivadas , Humanos , Inflamação , Ratos , Ratos Sprague-Dawley
8.
Science ; 371(6524): 52-57, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33384370

RESUMO

Neuroendocrine (NE) cells are epithelial cells that possess many of the characteristics of neurons, including the presence of secretory vesicles and the ability to sense environmental stimuli. The normal physiologic functions of solitary airway NE cells remain a mystery. We show that mouse and human airway basal stem cells sense hypoxia. Hypoxia triggers the direct differentiation of these stem cells into solitary NE cells. Ablation of these solitary NE cells during hypoxia results in increased epithelial injury, whereas the administration of the NE cell peptide CGRP rescues this excess damage. Thus, we identify stem cells that directly sense hypoxia and respond by differentiating into solitary NE cells that secrete a protective peptide that mitigates hypoxic injury.


Assuntos
Diferenciação Celular , Hipóxia/patologia , Células Neuroendócrinas/fisiologia , Oxigênio/fisiologia , Células-Tronco/fisiologia , Traqueia/citologia , Anaerobiose , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Contagem de Células , Deleção de Genes , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Mutantes , Células Neuroendócrinas/citologia , Prolil Hidroxilases/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Transativadores/genética
9.
Nutrients ; 13(1)2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33477388

RESUMO

There is evidence demonstrating that heart failure (HF) occurs in 1-2% of the global population and is often accompanied by comorbidities which contribute to increasing the prevalence of the disease, the rate of hospitalization and the mortality. Although recent advances in both pharmacological and non-pharmacological approaches have led to a significant improvement in clinical outcomes in patients affected by HF, residual unmet needs remain, mostly related to the occurrence of poorly defined strategies in the early stages of myocardial dysfunction. Nutritional support in patients developing HF and nutraceutical supplementation have recently been shown to possibly contribute to protection of the failing myocardium, although their place in the treatment of HF requires further assessment, in order to find better therapeutic solutions. In this context, the Optimal Nutraceutical Supplementation in Heart Failure (ONUS-HF) working group aimed to assess the optimal nutraceutical approach to HF in the early phases of the disease, in order to counteract selected pathways that are imbalanced in the failing myocardium. In particular, we reviewed several of the most relevant pathophysiological and molecular changes occurring during the early stages of myocardial dysfunction. These include mitochondrial and sarcoplasmic reticulum stress, insufficient nitric oxide (NO) release, impaired cardiac stem cell mobilization and an imbalanced regulation of metalloproteinases. Moreover, we reviewed the potential of the nutraceutical supplementation of several natural products, such as coenzyme Q10 (CoQ10), a grape seed extract, Olea Europea L.-related antioxidants, a sodium-glucose cotransporter (SGLT2) inhibitor-rich apple extract and a bergamot polyphenolic fraction, in addition to their support in cardiomyocyte protection, in HF. Such an approach should contribute to optimising the use of nutraceuticals in HF, and the effect needs to be confirmed by means of more targeted clinical trials exploring the efficacy and safety of these compounds.


Assuntos
Suplementos Nutricionais , Insuficiência Cardíaca/terapia , Animais , Antioxidantes/administração & dosagem , Citrus/química , Suplementos Nutricionais/estatística & dados numéricos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Extrato de Sementes de Uva/administração & dosagem , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Malus/química , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/fisiologia , Miocárdio/citologia , Óxido Nítrico/metabolismo , Apoio Nutricional , Olea/química , Extratos Vegetais/administração & dosagem , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Ubiquinona/administração & dosagem , Ubiquinona/análogos & derivados
10.
Biochem Biophys Res Commun ; 537: 109-117, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33388413

RESUMO

Dissipating energy by activating thermogenic adipose to combating obesity attracts many interests. Ski-interacting protein (Skip) has been known to play an important role in cell proliferation and differentiation, but whether it participates in energy metabolism is not known. Our previous study revealed that BTM-0512 could induce beige adipose formation, accompanying with up-regulation of Skip, but the role of Skip in metabolism was unknown. In this study, we mainly investigated whether Skip was involved in beige remodeling of subcutaneous white preadipocytes as well as in lipid metabolism of differentiated beige adipocytes. The results showed that in high fat diet-induced obesity mice, the protein levels of Skip in subcutaneous and visceral white adipose as well as in brown adipose were all down-regulated, especially in subcutaneous white adipose. Then we cultured subcutaneous adipose derived-stem cells (ADSCs) and found knock-down of Skip (siSkip) inhibited the expressions of thermogenic adipose specific genes including PRDM16 and UCP1 in both undifferentiated ADSCs and differentiated beige adipocytes, which could abolish the effects of BTM-0512 on beige remodeling. We further observed that siSkip affected multiple rate-limiting enzymes in lipid metabolism. The expressions of ACC, GPAT-1, HSL and ATGL were down-regulated, while CPT1α expression was up-regulated by siSkip. The expression of AMPK was also decreased by siSkip. In conclusion, our study demonstrated that Skip might play an important role in the beige remodeling of white adipocytes as well as lipid metabolism of beige adipose.


Assuntos
Tecido Adiposo Bege/metabolismo , Metabolismo dos Lipídeos , Monoéster Fosfórico Hidrolases/metabolismo , Sirtuína 1/metabolismo , Estilbenos/farmacologia , Tecido Adiposo Bege/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Dieta , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Monoéster Fosfórico Hidrolases/genética , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Termogênese/efeitos dos fármacos , Termogênese/genética , Proteína Desacopladora 1/metabolismo
11.
J Steroid Biochem Mol Biol ; 208: 105805, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33486080

RESUMO

Periodontitis is a chronic periodontal disease that contributes to tooth loss. In recent years, many animal studies have reported that vitamin D (VitD) deficiency results in chronic periodontitis. However, no studies have reported cases of early-onset periodontitis with VitD deficiency. This study reports a 5-year-old male patient with early-onset periodontitis, VitD deficiency and VitD receptor (VDR) mutation. The patient was treated with VitD and calcium, and received systematic periodontal treatment. During the 12-year treatment, the periodontal conditions of this patient were stable. Our in vitro study found that VitD could promote the expression of alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), bone morphogenetic protein 2 (BMP2), bone gamma-carboxyglutamate protein (BGLAP), and VDR in the early osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Meanwhile, VitD could downregulate mRNA expression levels of Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-1ß (IL-1ß) and protein levels of IL-6 in the tumor necrosis factor-α (TNF-α) -induced inflammation of PDLSCs. Therefore, sufficient VitD supply can be a potential treatment for VitD deficiency induced early-onset periodontitis.


Assuntos
Calcitriol/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Receptores de Calcitriol/genética , Deficiência de Vitamina D/tratamento farmacológico , Adolescente , Periodontite Agressiva/tratamento farmacológico , Periodontite Agressiva/genética , Periodontite Agressiva/patologia , Animais , Proteína Morfogenética Óssea 2/genética , Criança , Pré-Escolar , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Masculino , Osteocalcina/genética , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/crescimento & desenvolvimento , Células-Tronco/efeitos dos fármacos , Fator de Necrose Tumoral alfa , Vitamina D/metabolismo , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/patologia
12.
Cell Prolif ; 54(3): e12997, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33511708

RESUMO

OBJECTIVES: Stromal cell-derived factor-1 (SDF-1) actively directs endogenous cell homing. Exendin-4 (EX-4) promotes stem cell osteogenic differentiation. Studies revealed that EX-4 strengthened SDF-1-mediated stem cell migration. However, the effects of SDF-1 and EX-4 on periodontal ligament stem cells (PDLSCs) and bone regeneration have not been investigated. In this study, we aimed to evaluate the effects of SDF-1/EX-4 cotherapy on PDLSCs in vitro and periodontal bone regeneration in vivo. METHODS: Cell-counting kit-8 (CCK8), transwell assay, qRT-PCR and western blot were used to determine the effects and mechanism of SDF-1/EX-4 cotherapy on PDLSCs in vitro. A rat periodontal bone defect model was developed to evaluate the effects of topical application of SDF-1 and systemic injection of EX-4 on endogenous cell recruitment, osteoclastogenesis and bone regeneration in vivo. RESULTS: SDF-1/EX-4 cotherapy had additive effects on PDLSC proliferation, migration, alkaline phosphatase (ALP) activity, mineral deposition and osteogenesis-related gene expression compared to SDF-1 or EX-4 in vitro. Pretreatment with ERK inhibitor U0126 blocked SDF-1/EX-4 cotherapy induced ERK signal activation and PDLSC proliferation. SDF-1/EX-4 cotherapy significantly promoted new bone formation, recruited more CXCR4+ cells and CD90+ /CD34- stromal cells to the defects, enhanced early-stage osteoclastogenesis and osteogenesis-related markers expression in regenerated bone compared to control, SDF-1 or EX-4 in vivo. CONCLUSIONS: SDF-1/EX-4 cotherapy synergistically regulated PDLSC activities, promoted periodontal bone formation, thereby providing a new strategy for periodontal bone regeneration.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Exenatida/farmacologia , Ligamento Periodontal/citologia , Células Estromais/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Exenatida/metabolismo , Humanos , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células Estromais/metabolismo
13.
Life Sci ; 270: 119125, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513394

RESUMO

AIMS: Human periodontal ligament stem cells (hPDLSCs) tether the teeth to the surrounding bone and are considered as major functional stem cells responsible for regeneration of the alveolar bone and periodontal ligament tissue. However, the outcome of stem cell regenerative therapy is affected by the survival rate and their differentiation potential of transplanted cells. This is primarily because of local oxidative stress and chronic inflammation at the transplantation site. Therefore, our study aimed to explore whether a natural antioxidant, curcumin could increase the tissue regeneration ability of transplanted hPDLSCs. MAIN METHODS: A hydrogen peroxide environment and a rat cranial bone defect model were built to mimic the oxidative stress conditions in vitro and in vivo, respectively. We evaluated the effect of curcumin on oxidative status, apoptosis, mitochondrial function and osteogenic differentiation of H2O2-stimulated hPDLSCs in vitro. We also measured the effect of curcumin on cell viability and bone repair ability of transplanted hPDLSCs in vivo. KEY FINDINGS: Our data showed that curcumin enhanced cell proliferation, reduced the reactive oxygen species (ROS) levels and apoptosis, maintained the standard mitochondrial structure and function, and promoted osteogenic differentiation of H2O2-stimulated hPDLSCs. The extracellular regulated protein kinases 1/2 (Erk1/2) signaling pathway was determined to be involved in the osteogenic differentiation of the H2O2-stimulated hPDLSCs. Moreover, curcumin enhanced the viability and the bone repair ability of hPDLSCs in vivo. SIGNIFICANCE: Curcumin reduced apoptosis and promoted osteogenesis of the hPDLSCs under oxidative stress, and might therefore have a potential clinical use with respect to tissue regeneration.


Assuntos
Curcumina/farmacologia , Ligamento Periodontal/metabolismo , Transplante de Células-Tronco/métodos , Animais , Apoptose/efeitos dos fármacos , Osso e Ossos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Curcumina/metabolismo , Feminino , Humanos , Ligamentos/metabolismo , Masculino , Dente Molar/metabolismo , Osteogênese/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Adulto Jovem
14.
Int J Nanomedicine ; 16: 61-73, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33442250

RESUMO

Objective: Cell sheet technology (CST) is advantageous for repairing alveolar bone defects in clinical situations, and osteogenic induction before implantation may result in enhanced bone regeneration. Herein, we observed the effect of gold nanoparticles (AuNPs) on osteogenic differentiation of periodontal ligament stem cell (PDLSC) sheets and explored their potential mechanism of action. Methods: PDLSCs were cultured in cell sheet induction medium to obtain cell sheets. PDLSC sheets were treated with or without AuNPs. Alkaline phosphatase, alizarin red S, von Kossa, and immunofluorescence staining were used to observe the effects of AuNPs on the osteogenic differentiation of PDLSC sheets. Western blotting was performed to evaluate the osteogenic effects and autophagy activity. The cell sheets were transplanted into the dorsa of nude mice, and bone regeneration was analyzed by micro-CT and histological staining. Results: AuNPs could promote the osteogenic differentiation of PDLSC sheets by upregulating bone-related protein expression and mineralization. The 45-nm AuNPs were more effective than 13-nm AuNPs. Additional analysis demonstrated that their ability to promote differentiation could depend on activation of the autophagy pathway through upregulation of microtubule-associated protein light chain 3 and downregulation of sequestosome 1/p62. Furthermore, AuNPs significantly promoted the bone regeneration of PDLSC sheets in ectopic models. Conclusion: AuNPs enhance the osteogenesis of PDLSC sheets by activating autophagy, and 45-nm AuNPs were more effective than 13-nm AuNPs. This study may provide an AuNP-based pretreatment strategy for improving the application of CST in bone repair and regeneration.


Assuntos
Autofagia/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Ouro/farmacologia , Nanopartículas Metálicas/química , Ligamento Periodontal/fisiologia , Células-Tronco/citologia , Fosfatase Alcalina/metabolismo , Animais , Fosfatos de Cálcio/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Nanopartículas Metálicas/ultraestrutura , Camundongos Nus , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Osteopontina/metabolismo , Osteoprotegerina/metabolismo , Ligamento Periodontal/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Microtomografia por Raio-X
15.
Ecotoxicol Environ Saf ; 210: 111892, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33429317

RESUMO

Human activities have generated air pollution, with extremely small particles (PM 2.5, particulate matter less than 2.5 µm in diameter) and liquid droplets, which become a menace to human health. Among the pollutants, polycyclic aromatic hydrocarbons (PAHs), which enhance the risks of pulmonary dysfunction and cancer development, have been extensively studied. Numerous studies have addressed the effects of PAHs on the respiratory system, whereas the effects on lung stem/progenitor cells remain unknown. Here, we provide evidence that benzo[a]pyrene (BaP), a major toxic PAH, induces fibrotic changes with a loss of α-1,6-fucosylation in CD54+CD157+CD45- cells (lung stem cells). In studies with aryl hydrocarbon receptor (AHR) antagonist, we found that these effects by BaP are independent of the canonical AHR pathway. In addition, these BaP-induced fibrotic changes are reduced by TGF-ß antagonist, suggesting an alternative pathway of BaP toxicity is different from other PAH/AHR signaling pathways. Finally, it was observed that BaP impairs the spheroid formation and the podoplanin expression of CD54+CD157+CD45- cells, indicating that BaP suppresses the differentiation of lung stem cells. Taken together, our findings reveal specific BaP-induced injuries in CD54+CD157+CD45- cells.


Assuntos
Poluentes Atmosféricos/toxicidade , Benzo(a)pireno/toxicidade , Pulmão/citologia , Células-Tronco/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Fibrose , Camundongos , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Células-Tronco/patologia , Fator de Crescimento Transformador beta/antagonistas & inibidores
16.
J Steroid Biochem Mol Biol ; 205: 105772, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33091596

RESUMO

Porcine pancreatic stem cells (pPSCs) can be induced to differentiate into insulin-producing cells in vitro and thus serve as a major cells source for ß-cell regeneration. However, this application is limited by the weak cell proliferation ability and low insulin induction efficiency. In this study, we explored the role of folic acid in the proliferation of pPSCs and the formation of insulin-secreting cells. We found that FA-treated pPSCs cells had a high EDU positive rate, and the proliferation marker molecules PCNA, CyclinD1 and c-Myc were up-regulated, while the expression of folate receptor α (FOLRα) was up-regulated. In further research, interference FOLRα or adding canonical Wnt signaling pathway or ERK signaling pathway inhibitors could significantly inhibit the effect of FA on pPSCs proliferation. Meanwhile, during the differentiation of pPSCs into insulin-secreting cells, we found that the maturation marker genes Insulin, NKX6.1, MafA, and NeuroD1 was upregulated in insulin-secreting cell masses differentiationed from pPSCs after FA treatment, and the functional molecules Insulin and C-peptide were increased, the ability to secrete insulin in response to high glucose was also increased. With the addition of Wnt and ERK signaling pathway inhibitors, the pro-differentiation effect of FA was weakened. In conclusion, FA promotes the proliferation of pPSCs by binding to folate receptor α (FOLRα) and increase the efficiency of directed differentiation of pPSCs into insulin-producing cells by regulating canonical Wnt and ERK signaling pathway. This study lays theoretical foundation for solving the bottleneck in the treatment of diabetes with stem cell transplantation in future.


Assuntos
Receptor 1 de Folato/genética , Ácido Fólico/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácido Fólico/química , Humanos , Células Secretoras de Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Suínos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
17.
Carbohydr Polym ; 251: 117079, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33142622

RESUMO

In this study, a surface modification strategy using natural biopolymers on titanium is proposed to improve bone healing and promote rapid and successful osseointegration of orthopedic implants. Titania nanotubes were fabricated via an anodization process and the surfaces were further modified with polyelectrolyte multilayers (PEMs) based on Tanfloc (a cationic tannin derivative) and glycosaminoglycans (heparin and hyaluronic acid). Scanning electron microscopy (SEM), water contact angle measurements, and X-ray photoelectron spectroscopy were used to characterize the surfaces. Adipose-derived stem cells (ADSCs) were seeded on the surfaces, and the cell viability, adhesion, and proliferation were investigated. Osteogenesis was induced and osteogenic differentiation of human ADSCs on the surfaces was evaluated via mineralization and protein expression assays, immunofluorescent staining, and SEM. The Tanfloc/heparin PEMs on titania nanotubes improved the rate of osteogenic differentiation of ADSCs as well as the bone mineral deposition, and is therefore a promising approach for use in orthopedic implants.


Assuntos
Tecido Adiposo/citologia , Heparina/química , Nanotubos/química , Polieletrólitos/química , Células-Tronco/citologia , Taninos/química , Titânio/química , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Anticoagulantes/química , Anticoagulantes/farmacologia , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Heparina/farmacologia , Humanos , Ácido Hialurônico/química , Osteogênese , Polieletrólitos/farmacologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Propriedades de Superfície , Taninos/farmacologia
18.
J Pharmacol Exp Ther ; 376(2): 281-293, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33318078

RESUMO

G protein-coupled estrogen receptor (GPER) might be involved in ulcerative colitis (UC), but the direct effect of GPER on UC is still unclear. We used male C57BL/6 mice to establish the acute colitis model with administration of dextran sulfate sodium and explored the effect of GPER on acute colitis and its possible mechanism. The selective GPER agonist G-1 inhibited weight loss and colon shortening and decreased the disease activity index for colitis and histologic damage in mice with colitis. All of these effects were prevented by a selective GPER blocker. G-1 administration prevented the dysfunction of tight junction protein expression and goblet cells in colitis model and thus inhibited the increase of mucosal permeability in colitis-suffering mice significantly. GPER activation reduced expression of glucose-regulating peptide-78 and anti-CCAAT/enhancer-binding protein homologous protein and attenuated the three arms of the unfolded protein response in colitis. G-1 therapy inhibited the increase of cleavage caspase-3- and TUNEL-positive cells in colonic crypts in the colitis model, increased the number of Ki67- and bromodeoxyuridine-positive cells in crypts, and reversed the decrease of cyclin D1 and cyclin B1 expression in colitis, indicating its protective effect on crypt cells. In cultured CCD841 cells, G-1 treatment fought against cell injury induced by endoplasmic reticulum stress. These findings demonstrate that GPER activation prevents colitis by protecting the colonic crypt cells, which are associated with inhibition of endoplasmic reticulum stress. SIGNIFICANCE STATEMENT: We demonstrate that G protein-coupled estrogen receptor (GPER) activation prevents dextran sulfate sodium-induced acute colitis by protecting the crypt cells, showing that it inhibited the crypt cell apoptosis and protected proliferation of crypt cells, which resulted in protection of the intestinal mucosal barrier. This protective effect was achieved (at least in part) by inhibiting endoplasmic reticulum stress. Mucosal healing is regarded as a key therapeutic target for colitis, and GPER is expected to become a new therapeutic target for colitis.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/metabolismo , Enterócitos/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Células-Tronco/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Apoptose , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Células Cultivadas , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/prevenção & controle , Estresse do Retículo Endoplasmático , Células Caliciformes/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Células-Tronco/metabolismo , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo , Resposta a Proteínas não Dobradas
19.
Artigo em Inglês | MEDLINE | ID: mdl-33035680

RESUMO

Hematopoiesis, the complex developmental process that forms blood components and replenishes the blood system, involves multiple intracellular and extracellular mechanisms. We previously demonstrated that lysophosphatidic acid (LPA), a lipid growth factor, has opposing regulatory effects on erythrocyte differentiation through activation of LPA receptors 2 and 3; yet the mechanisms underlying this process remain unclear. In this study, LPA2 is observed that highly expressed in common myeloid progenitors (CMP) in murine myeloid cells, whereas the expression of LPA3 displaces in megakaryocyte-erythroid progenitors (MEP) of later stage of myeloid differentiation. Therefore, we hypothesized that the switching expression of LPA2 and LPA3 determine the hematic homeostasis of mammalian megakaryocytic-erythroid lineage. In vitro colony-forming unit assays of murine progenitors reveal that LPA2 agonist GRI reduces the erythroblast differentiation potential of CMP. In contrast, LPA3 agonist OMPT increases the production of erythrocytes from megakaryocyte-erythrocyte progenitor cells (MEP). In addition, treatment with GRI reduces the erythroid, CMP, and MEP populations in mice, indicating that LPA2 predominantly inhibits myeloid differentiation at an early stage. In contrast, activation of LPA3 increases the production of terminally differentiated erythroid cells through activation of erythropoietic transcriptional factor. We also demonstrate that the LPA3 signaling is essential for restoration of phenylhydrazine (PHZ)-induced acute hemolytic anemia in mice and correlates to erythropoiesis impairment of Hutchinson-Gilford progeria Symptom (HGPS) premature aging expressed K562 model. Our results reveal the distinct roles of LPA2 and LPA3 at different stages of hematopoiesis in vivo, providing potentiated therapeutic strategies of anemia treatment.


Assuntos
Anemia Hemolítica/genética , Células Eritroides/metabolismo , Eritropoese/genética , Células Mieloides/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Células-Tronco/metabolismo , Anemia Hemolítica/induzido quimicamente , Anemia Hemolítica/tratamento farmacológico , Anemia Hemolítica/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/genética , Modelos Animais de Doenças , Células Eritroides/citologia , Células Eritroides/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Isoquinolinas/farmacologia , Células K562 , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Organotiofosfatos/farmacologia , Fenil-Hidrazinas/administração & dosagem , Ácidos Fosfatídicos/farmacologia , Receptores de Ácidos Lisofosfatídicos/agonistas , Receptores de Ácidos Lisofosfatídicos/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos
20.
Methods Mol Biol ; 2180: 555-567, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32797434

RESUMO

Adipose-derived stem cells (ASCs) reside in the stromal compartment of adipose tissue and can be easily harvested in large quantities through a clinically safe liposuction procedure. ASCs do not induce immunogenic reactions and rather exert immunosuppressive effects. Therefore, they can be used for both autologous and allogeneic transplantations. They hold great promise for cell-based therapies and tissue engineering. A prerequisite to the realization of this promise is the development of successful cryopreservation methods for ASCs. In this chapter, we describe a xeno-free- and chemically defined cryopreservation protocol, which can be used for various clinical applications of ASCs.


Assuntos
Adipócitos/citologia , Técnicas de Cultura de Células/métodos , Diferenciação Celular , Criopreservação/métodos , Crioprotetores/farmacologia , Células-Tronco/citologia , Engenharia Tecidual/métodos , Adipócitos/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Humanos , Células-Tronco/efeitos dos fármacos
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