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INTRODUCTION: This study aimed to explore the functional connectivity of the primary visual cortex (V1) in children with anisometropic amblyopia by using the resting-state functional connectivity analysis method and determine whether anisometropic amblyopia is associated with changes in brain function. METHODS: Functional magnetic resonance imaging (fMRI) data were obtained from 16 children with anisometropia amblyopia (CAA group) and 12 healthy children (HC group) during the resting state. The Brodmann area 17 (BA17) was used as the region of interest, and the functional connection (FC) of V1 was analyzed in both groups. A two-sample t test was used to analyze the FC value between the two groups. Pearson's correlation was used to analyze the correlation between the mean FC value in the brain function change area of the CAA group and the best corrected visual acuity (BCVA) of amblyopia. p < 0.05 was considered statistically significant. RESULTS: There were no significant differences in age and sex between the CAA and HC groups (p > 0.05). Compared to the HC group, the CAA group showed lower FC values in BA17 and the left medial frontal gyrus, as well as BA17 and the left triangle inferior frontal gyrus. Conversely, the CAA group showed higher FC values in BA17 and the left central posterior gyrus. Notably, BCVA in amblyopia did not correlate with the area of change in mean FC in the brain function of the CAA group. CONCLUSION: Resting-state fMRI-based functional connectivity analysis indicates a significant alteration in V1 of children with anisometropic amblyopia. These findings contribute additional insights into the neuropathological mechanisms underlying visual impairment in anisometropic amblyopia.
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Ambliopia , Imageamento por Ressonância Magnética , Córtex Visual Primário , Acuidade Visual , Humanos , Ambliopia/fisiopatologia , Feminino , Masculino , Criança , Acuidade Visual/fisiologia , Córtex Visual Primário/fisiopatologia , Anisometropia/fisiopatologia , Mapeamento Encefálico/métodos , Descanso/fisiologia , Córtex Visual/fisiopatologia , Córtex Visual/diagnóstico por imagemRESUMO
While previous studies have found that living arrangements and religiosity can influence the subjective well-being (SWB) of older adults, they have tended to investigate each of these aspects separately. Engaging with this gap, the current study examines the relationship between living arrangements, religious attendance, and the SWB of older adults, as well as the mediating effect of religious attendance on the relationship between the other two factors. A total of 875 older adults from 40 villages or communities in a Tibetan area in China (Gannan) were surveyed. An ordinary least square regression was used to evaluate the relationship between SWB and living arrangements and/or religious attendance. A structural equation model was then used to test the mediating role played by religious attendance in the association between living arrangements and SWB. The results showed that older adults in the selected study areas who were co-residing with their children and/or spouse had a higher level of SWB compared to those living alone. While religious attendance was positively associated with older adults' SWB, the findings showed that living with their spouse or children decreased their frequency of attendance at religious activities. In contrast, it was found that living alone directly decreased older adults' SWB, but increased the frequency of their participation in religious events, thus indirectly promoting their SWB. A key implication of this study is its confirmation that religious attendance plays an important mediating role in the relationship between living arrangements and SWB.
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População do Leste Asiático , Bem-Estar Psicológico , Religião , Idoso , Humanos , China , Características de ResidênciaRESUMO
Purpose: Anisometropic amblyopia usually occurs during early childhood and results in monocular visual deficit. Recent neuroimaging studies have demonstrated structural and functional alterations in pediatric anisometropic amblyopia (PAA) patients. However, the relationship between structural and functional alterations remains largely unknown. The aim of this study was to investigate the relationship between structural and functional alterations in PAA patients. Materials and Methods: Eighteen PAA patients and 14 healthy children underwent a multimodal MRI scanning including T1WI and functional MRI (fMRI). Voxel-based morphometry was used to assess structural alterations between PAA patients and healthy children. Regional homogeneity (ReHo) was used to investigate changes in local spontaneous brain activity in the enrolled subjects. Correlations between structural, functional alterations, and clinical information were analyzed in the PAA group. Results: Compared with healthy children, PAA patients exhibited significantly reduced ReHo of spontaneous brain activity in the right superior temporal gyrus (STG) and right middle frontal gyrus (MFG) and increased gray matter volume in the right lobules 4 and 5 of the cerebellum. The gray matter volume of the right lobules 4 and 5 of the cerebellum was negatively correlated with the ReHo values of the right MFG. Conclusions: Our findings may suggest that PAA patients experience structural and functional abnormalities in brain regions related to oculomotor and visual-spatial information. In addition, the increased gray matter volume may compensate the decreased brain activity in the oculomotor regions, which reflects compensatory or neural plasticity in PAA patients.
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Ambliopia/patologia , Ambliopia/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Substância Cinzenta/patologia , Mapeamento Encefálico , Cerebelo/patologia , Cerebelo/fisiopatologia , Criança , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Lobo Temporal/patologia , Lobo Temporal/fisiopatologiaRESUMO
Forkhead box protein M1 (FoxM1) has been associated with cancer progression and metastasis. However, the function of FoxM1 in tongue squamous cell carcinoma (TSCC) remains largely unknown. The purpose of this study was to determine the role of FoxM1 in regulation of epithelial-mesenchymal transition (EMT) and migration of TSCC cells. We found that FoxM1 induced EMT and increased invasion/migration capacity in SCC9 and SCC25 cells. FoxM1 stimulation increased c-Met, pAKT, and vimentin levels but decreased E-cadherin level. Chromatin immunoprecipitation assay established that FoxM1 is bound to the promoter of c-Met to activate its transcription. In turn, c-Met promoted the expression of FoxM1 and pAKT. Blocking AKT signaling attenuated the invasion and migration of SCC9 and SCC25 cells stimulated by FoxM1 or c-Met. These results indicate that a positive feedback loop controls the EMT and migration of TSCC cells induced by FoxM1 and c-Met through AKT. Furthermore, the expression levels of FoxM1, pAKT, and c-Met were found to significantly increase in TSCC tissues compared with normal tissues, and these three biomarkers were concomitantly expressed in TSCC tissues. Clinical association analyses indicated that the expression of FoxM1, c-Met, and pAKT was associated with clinicopathological characteristics of patients with TSCC including tumor stage, tumor size, and lymph node metastasis. Taken together, our findings suggest that FoxM1 promotes the EMT, invasion and migration of TSCC cells, and cross-talks with c-Met/AKT signaling to form a positive feedback loop to promote TSCC development.
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Carcinoma de Células Escamosas/metabolismo , Movimento Celular/fisiologia , Proteína Forkhead Box M1/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Neoplasias da Língua/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Retroalimentação Fisiológica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-met/genética , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Neoplasias da Língua/genética , Neoplasias da Língua/patologiaRESUMO
OBJECTIVE: Osteogenesis is vitally important for bone defect repair, and Zuo Gui Wan (ZGW) is a classic prescription in traditional Chinese medicine (TCM) for strengthening bones. However, the specific mechanism by which ZGW regulates osteogenesis is still unclear. The current study is based on a network pharmacology analysis to explore the potential mechanism of ZGW in promoting osteogenesis. METHODS: A network pharmacology analysis followed by experimental validation was applied to explore the potential mechanisms of ZGW in promoting the osteogenesis of bone marrow mesenchymal stem cells (BMSCs). RESULTS: In total, 487 no-repeat targets corresponding to the bioactive components of ZGW were screened, and 175 target genes in the intersection of ZGW and osteogenesis were obtained. And 28 core target genes were then obtained from a PPI network analysis. A GO functional enrichment analysis showed that the relevant biological processes mainly involve the cellular response to chemical stress, metal ions, and lipopolysaccharide. Additionally, KEGG pathway enrichment analysis revealed that multiple signaling pathways, including the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway, were associated with ZGW-promoted osteogensis. Further experimental validation showed that ZGW could increase alkaline phosphatase (ALP) activity as well as the mRNA and protein levels of ALP, osteocalcin (OCN), and runt related transcription factor 2 (Runx 2). What's more, Western blot analysis results showed that ZGW significantly increased the protein levels of p-PI3K and p-AKT, and the increases of these protein levels significantly receded after the addition of the PI3K inhibitor LY294002. Finally, the upregulated osteogenic-related indicators were also suppressed by the addition of LY294002. CONCLUSION: ZGW promotes the osteogenesis of BMSCs via PI3K/AKT signaling pathway.
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Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Osteogênese , Farmacologia em Rede , Diferenciação Celular , Transdução de SinaisRESUMO
OBJECTIVES: In this study, a new type of dental implant by covering the surface of the titanium (Ti) implant with zinc-magnesium (Zn-Mg) alloy was designed, to study the antibacterial and antioxidant effects of Mg alloy on titanium (Ti) implants in oral implant restoration. METHODS: Human gingival fibroblasts (HGFs), S. sanguinis, and F. nucleatum bacteria were used to detect the bioactivity and antibacterial properties of Mg alloy-coated Ti implants. In addition, B6/J mice implanted with different materials were used to further detect their antibacterial and antioxidant properties. RESULTS: The results showed that Mg alloy could better promote the adhesion and proliferation and improve the alkaline phosphatase (ALP) activity of HGFs, which contributed to better improved stability of implant osseointegration. In addition, Mg alloy could better inhibit the proliferation of S. sanguinis, while no significant difference was found in the proliferation of F. nucleatum between the two implants. In the mouse model, the peripheral inflammatory reaction and oxidative stress of the Mg alloy implant were significantly lower than those of the Ti alloy implant. CONCLUSIONS: Zn-Mg alloy-coated Ti implants could better inhibit the growth of Gram-positive bacteria in the oral cavity, inhibit oxidative stress, and facilitate the proliferation activity of HGFs and the potential of osteoblast differentiation, thus, better increasing the stability of implant osseointegration.
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Antibacterianos/farmacologia , Antioxidantes/farmacologia , Implantes Dentários , Magnésio/farmacologia , Titânio , Ligas/química , Ligas/farmacologia , Animais , Antibacterianos/química , Antioxidantes/química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Biologia Computacional , Implantes Dentários/efeitos adversos , Implantes Dentários/microbiologia , Planejamento de Prótese Dentária , Gengiva/citologia , Gengiva/efeitos dos fármacos , Gengiva/metabolismo , Humanos , Magnésio/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osseointegração/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Propriedades de Superfície , Titânio/química , Zinco/farmacologiaRESUMO
Salivary adenoid cystic carcinoma (SACC), one of the most common malignant tumors in the head and neck region, is characterized by high postoperative recurrence rate and poor prognosis. Microwave (MW) ablation possesses advantages in preserving SACC patients' facial aesthetics and oral function, but unfortunately, it suffers from low therapeutic efficacy due to the limited MW-thermal efficiency. Moreover, the insufficient thermal ablation may aggravate hypoxic state in tumors, which is deleterious to the treatment of residual tumors and aggressive tumors. Hence, MW ablation has been rarely applied in treating head and neck tumors in recent years. To minimize the unfavorable outcomes and maximize the therapeutic effects of MW ablation, a MW sensitizer coupled with a self-sufficient oxygen nanoagent was employed for the first time in MW ablation to treat head and neck tumors. We prepared a graphene-containing metal-organic framework (ZIF67@Gr-PEG), which exhibited excellent MW thermal conversion ability endowed by the incorporated Gr and showed in situ oxygen generation capacity derived from the ZIF67 matrix. In an animal experiment, ZIF67@Gr-PEG-based MW ablation with a temperature up to 66.1 °C exhibited a high tumor ablation rate. More importantly, insufficient MW ablation-induced high expressions of HIF-1α and VEGF were observed in our experiment, whereas the levels of tumor hypoxia and angiogenesis were efficiently decreased in MW ablation with the assistance of ZIF67@Gr-PEG nanocomposites (NCs). Notably, our strategy for MW ablation not only evidences the great potential of ZIF67@Gr-PEG but also promotes the translation of thermotherapeutic graphene from basic research to clinical practice.
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Oral mucositis (OM) is a common complication during chemotherapy characterized by ulceration, mucosa atrophy, and necrosis, which seriously interferes with nutritional intake and oncotherapy procedures among patients. However, the efficacy of current treatments for OM remains limited. Cannabidiol (CBD) is a natural cannabinoid with multiple biological activities, including antioxidant and anti-inflammatory potential. In this study, we aimed to investigate the chemopreventive effects and mechanisms of CBD in protecting C57BL/6N mice and human oral keratinocytes (HOK) from 5-fluorouracil- (5-FU-) induced OM. Here, we found that CBD alleviated the severity of 5-FU-induced OM in mice, including improved survival, decreased body weight loss, reduced ulcer sizes, and improved clinical scores. Histologically, CBD restored epithelial thickness and normal structure in tongue tissues. Meanwhile, CBD attenuated reactive oxygen species (ROS) overproduction and improved the antioxidant response, suppressed the inflammatory response, promoted the proliferation of epithelial cells, and inhibited 5-FU-induced apoptosis. In vitro, consistent outcomes showed that CBD suppressed cellular ROS levels, enhanced antioxidant ability, reduced inflammatory response, promoted proliferation, and inhibited apoptosis in 5-FU-treated HOK cells. In particular, CBD upregulated the expression levels of antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase 1 (NQO1), by increasing the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreasing Kelch-like ECH-associated protein 1 (Keap1). Notably, the Nrf2 inhibitor ML385 reversed the protective effect of CBD. Nrf2-siRNA transfection also significantly blunted the antioxidant effect of CBD in in vitro OM model. Collectively, our findings suggested that CBD protected against 5-FU-induced OM injury at least partially via the Nrf2/Keap1/ARE signaling pathways, highlighting the therapeutic prospects of CBD as a novel strategy for chemotherapy-induced OM.
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Antineoplásicos , Canabidiol , Estomatite , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Fluoruracila/farmacologia , Heme Oxigenase-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Estomatite/induzido quimicamente , Estomatite/tratamento farmacológicoRESUMO
Background and Objectives: Chronic inflammation of bone tissue often results in bone defects and hazards to tissue repair and regeneration. Cannabidiol (CBD) is a natural cannabinoid with multiple biological activities, including anti-inflammatory and osteogenic potential. This study aimed to investigate the efficacy and mechanisms of CBD in the promotion of bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation in the inflammatory microenvironment. Methods and Results: BMSCs isolated from C57BL/6 mice, expressed stem cell characteristic surface markers and presented multidirectional differentiation potential. The CCK-8 assay was applied to evaluate the effects of CBD on BMSCs' vitality, and demonstrating the safety of CBD on BMSCs. Then, BMSCs were stimulated with lipopolysaccharide (LPS) to induce inflammatory microenvironment. We found that CBD intervention down-regulated mRNA expression levels of inflammatory cytokines and promoted cells proliferation in LPS-treated BMSCs, also reversed the protein and mRNA levels downregulation of osteogenic markers caused by LPS treatment. Moreover, CBD intervention activated the cannabinoid receptor 2 (CB2) and the p38 mitogen-activated protein kinase (MAPK) signaling pathway. While AM630, a selective CB2 inhibitor, reduced phosphorylated (p)-p38 levels. In addition, AM630 and SB530689, a selective p38 MAPK inhibitor, attenuated the enhancement of osteogenic markers expression levels by CBD in inflammatory microenvironment, respectively. Conclusions: CBD promoted osteogenic differentiation of BMSCs via the CB2/p38 MAPK signaling pathway in the inflammatory microenvironment.
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The sustainable development of pension systems has been investigated from a financial perspective worldwide. However, the pension adequacy and its effect on the sustainability of a national pension system are still understudied. Using actual replacement rate and modified living standards replacement rate, this study empirically evaluates whether China's New Rural Pension Scheme (NRPS) grants enough livelihood protection for the rural residents in the Northwestern China. The results show that the NRPS fails to meet the basic needs of the elderly people (i.e., age of sixty years or older) or the middle-aged people (forty-five to fifty-nine years old), while it only provides limited protection for the young people (sixteen to forty-four years old). These findings suggest that the current NRPS benefits are very low in the Northwestern China and policy reforms should be further implemented to improve the sustainable development of the New Rural Pension Scheme.
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Financiamento Governamental/estatística & dados numéricos , Pensões/estatística & dados numéricos , Desenvolvimento Sustentável/economia , China , Financiamento Governamental/métodos , Financiamento Governamental/tendências , Programas Governamentais/métodos , Humanos , Estudos Longitudinais , Qualidade de Vida/legislação & jurisprudência , Aposentadoria , População Rural , Fatores Socioeconômicos , Desenvolvimento Sustentável/legislação & jurisprudência , Desenvolvimento Sustentável/tendênciasRESUMO
The microwave dynamic therapy (MDT) mediated by cytotoxic reactive oxygen species (ROS) is a promising anticancer therapeutic method. However, the therapeutic efficiency of MDT is restricted by several limitations including insufficient ROS generation, strong proangiogenic response, and low tumor-targeting efficiency. Herein, we find that Cu-based nanoparticles can produce oxygen under microwave (MW) irradiation to raise the generation of ROS, such as â¢O2, â¢OH and 1O2, especially â¢O2. On this basis, a nanoengineered biomimetic strategy is designed to improve the efficiency of MDT. After intravenous administration, the nanoparticles accumulate to the tumor site through targeting effect mediated by biomimetic modification, and it can continuously produce oxygen to raise the levels of ROS in tumor microenvironment under MW irradiation for MDT. Additionally, Apatinib is incorporated as antiangiogenic drug to downregulate the expression of vascular endothelial growth factor (VEGF), which can effectively inhibit the tumor angiogenesis after MDT. Hence, the tumor inhibition rate is as high as 96.79%. This study provides emerging strategies to develop multifunctional nanosystems for efficient tumor therapy by MDT.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Biomimética , Linhagem Celular Tumoral , Humanos , Neoplasias/tratamento farmacológico , Espécies Reativas de Oxigênio , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/uso terapêuticoRESUMO
The treatment of bone defects has plagued clinicians. Exosomes, the naturally secreted nanovesicles by cells, exhibit great potential in bone defect regeneration to realize cell-free therapy. In this work, we successfully revealed that human umbilical cord mesenchymal stem cells-derived exosomes could effectively promote the proliferation, migration, and osteogenic differentiation of a murine calvariae preosteoblast cell line in vitro. Considering the long period of bone regeneration, to effectively exert the reparative effect of exosomes, we synthesized an injectable hydroxyapatite (HAP)-embedded in situ cross-linked hyaluronic acid-alginate (HA-ALG) hydrogel system to durably retain exosomes at the defect sites. Then, we combined the exosomes with the HAP-embedded in situ cross-linked HA-ALG hydrogel system to repair bone defects in rats in vivo. The results showed that the combination of exosomes and composite hydrogel could significantly enhance bone regeneration. Our experiment provides a new strategy for exosome-based therapy, which shows great potential in future tissue and organ repair.
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Exossomos , Células-Tronco Mesenquimais , Alginatos , Animais , Regeneração Óssea , Durapatita , Humanos , Ácido Hialurônico , Hidrogéis , Camundongos , Osteogênese , Ratos , Cordão UmbilicalRESUMO
Neuregulin 4 (Nrg4) is a brown fat-enriched endocrine factor that exerts beneficial metabolic effects on insulin resistance and hepatic steatosis. Autophagy is a mechanism that is essential for preventing hepatic steatosis. The aim of this study was to explore whether Nrg4 ameliorates hepatic steatosis by inducing autophagy. Aged C57BL/6 mice were maintained on a high fat diet with or without Nrg4 intervention for 3 months. Lipid accumulation in the liver was investigated. Autophagy related protein levels along with related signaling pathways that regulate autophagy were evaluated. In addition, the effects of Nrg4 on autophagy were also determined in cultured L-02 cells. Nrg4 decreased high-fat induced intrahepatic lipid content both in vivo and in vitro. Autophagy level in the liver also decreased in obese mice and Nrg4 intervention reactivated autophagy. Further, Nrg4 intervention was found to have activated autophagy via the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway. Moreover, when the AMPK/mTOR pathway was suppressed or autophagy was inhibited, the beneficial effects of Nrg4 intervention on hepatic steatosis were diminished. These results indicated that Nrg4 intervention attenuated hepatic steatosis by promoting autophagy in the liver of aged obese mice. Additionally, Nrg4 induced autophagy via the AMPK/mTOR signaling pathway.
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Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Fígado/efeitos dos fármacos , Neurregulinas/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Serina-Treonina Quinases TOR/metabolismo , Fatores Etários , Animais , Linhagem Celular , Dieta Hiperlipídica , Modelos Animais de Doenças , Ativação Enzimática , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de SinaisRESUMO
BACKGROUND: The authors of this meta-analysis evaluated whether there is a difference in the levels of serum and gingival crevicular fluid (GCF) matrix metalloproteinase (MMP)-9 between patients with periodontitis and periodontally healthy control participants. TYPES OF STUDIES REVIEWED: The authors searched PubMed, Embase, the Cochrane Library, and the China Biology Medicine disk databases for eligible studies in which the investigators reported the relationships between MMP-9 levels in serum and GCF and periodontitis. The authors pooled the standardized mean differences (SMDs) and 95% confidence intervals (CIs) from each study to evaluate the difference in the serum and GCF MMP-9 levels between patients with periodontitis and periodontally healthy control participants. RESULTS: Results of a meta-analysis of 6 case-control studies including a total of 923 healthy control participants and 557 patients with periodontitis indicated that serum MMP-9 levels were significantly higher in patients with periodontitis than in periodontally healthy control participants (SMD, 1.60; 95% CI, 0.17 to 3.03; P < .05). Results of a separate meta-analysis of 6 case-control studies including a total of 153 healthy control participants and 189 patients with periodontitis indicated that GCF MMP-9 levels were significantly higher in patients with periodontitis than in periodontally healthy control participants (SMD, 1.96; 95% CI, 0.76 to 3.16; P < .01). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The results of the meta-analysis revealed statistically significant differences in the MMP-9 levels in serum and GCF between patients with periodontitis and periodontally healthy control participants. These results cannot be used to confirm causality because the included studies were all case-control studies in which the investigators reported associations. Moreover, readers should view the results with caution because of the considerable heterogeneity among the studies included in the meta-analysis.
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Líquido do Sulco Gengival , Periodontite , Estudos de Casos e Controles , Humanos , Metaloproteinase 9 da MatrizRESUMO
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies, with high rates of mortality and morbidity worldwide. Owing to the special anatomical location of this tumor, an effective, minimally invasive treatment with low systemic toxicity is highly desirable. Hydrogels have shown great potential for tumor-targeting therapy, with excellent performance. However, there have been few reports on co-loading photosensitizers and chemotherapeutic drugs into hydrogels. In this study, we synthesized a nano doxorubicin-indocyanine green matrix metalloproteinase (MMP)-responsive hydrogel (denoted as NDIMH), combining chemotherapy and phototherapy, to achieve superior antitumor efficacy. METHODS: First, NDIMH was synthesized and characterized by scanning electron microscopy and drug-release assays. Second, the photosensitivity properties and antitumor efficiency of this drug delivery system were studied in vivo and in vitro. Last, the imaging and biodistribution of NDIMH were monitored using the Maestro EX in vivo imaging system. RESULTS: The nanodrugs loaded into the smart hydrogel exhibited uniform size distribution, excellent size stability, and a sustained release in the presence of MMP-2. NDIMH showed ideal photosensitivity characteristics under light. NDIMH with 808 nm near-infrared (NIR) irradiation effectively inhibited the viability, invasion, and metastasis of SCC-15 in vitro. After intratumoral injection of NDIMH with 808 nm NIR illumination, the hydrogels exhibited favorable synergistic antitumor efficacy and acceptable biosafety. Additionally, fluorescence imaging showed that NDIMH could significantly improve the retention of nanodrugs at the tumor site. CONCLUSION: The intratumoral injection of NDIMH with 808 nm NIR irradiation could be a promising chemophototherapy alternative for HNSCC.
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Doxorrubicina/uso terapêutico , Hidrogéis/síntese química , Verde de Indocianina/uso terapêutico , Metaloproteinases da Matriz/metabolismo , Nanopartículas/química , Fotoquimioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Fluorescência , Humanos , Hidrogéis/química , Verde de Indocianina/farmacologia , Luz , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Invasividade Neoplásica , Metástase Neoplásica , Ratos , Distribuição TecidualRESUMO
Periodontal ligament stem cells (PDLSCs) have mesenchymal-stem-cells-like qualities, and are considered as one of the candidates of future clinical application in periodontal regeneration therapy. Enamel matrix derivative (EMD) is widely used in promoting periodontal regeneration. However, the effects of EMD on the proliferation and osteogenic differentiation of human PDLSCs grown on the Ti implant surface are still no clear. Therefore, this study examined the effects of EMD on human PDLSCs in vitro. Human PDLSCs were isolated from healthy participants, and seeded on the surface of Ti implant disks and stimulated with various concentrations of EMD. Cell proliferation was determined with Cell Counting Kit-8 (CCK-8). The osteogenic differentiation of PDLSCs was evaluated by the measurement of alkaline phosphatase (ALP) activity, Alizarin red staining, and real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. The results indicated that EMD at concentrations (5-60 µg/ml) increased the viability and proliferation of PDLSCs. The treatment with 30 and 60 µg/ml of EMD significantly elevated ALP activity, augmented mineralized nodule formation and calcium deposition, and upregulated the mRNA and protein levels of Runx-2 and osteocalcin (OCN) in the PDLSCs grown on the Ti surface. Further investigation found that EMD treatment did not change the protein levels of phosphatidylinositol-3-kinase (PI3K), p-PI3K, Akt and mTOR, but significantly upregulated the phosphorylated levels of Akt and mTOR. Collectively, these results suggest that EMD stimulation can promote the proliferation and osteogenic differentiation of PDLSCs grown on Ti surface, which is possibly associated with the activation of Akt/mTOR signaling pathway.
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Diferenciação Celular/efeitos dos fármacos , Proteínas do Esmalte Dentário/farmacologia , Osteogênese/efeitos dos fármacos , Ligamento Periodontal/citologia , Próteses e Implantes , Células-Tronco/citologia , Titânio/farmacologia , Fosfatase Alcalina/metabolismo , Proliferação de Células/efeitos dos fármacos , Separação Celular , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Humanos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/enzimologiaRESUMO
Periodontitis is a common chronic inflammatory disease. Recent studies have shown that chronic stress (CS) might modulate periodontal disease, but there are few models of CS-induced periodontitis, and the underlying mechanisms are unclear. The present study established a rat model of periodontitis associated with CS induced by nylon thread ligatures. The severity of periodontitis was evaluated in this model by radiographic and pathological examination. The inflammatory reaction indicated by the elevated serum levels of interleukin (IL)-1ß, IL-6 and IL-8 was assessed by enzyme-linked immunosorbent assay. Toll-like receptor-4 (TLR4) and glucocorticoid receptor-α (GR-α) expressions were detected by reverse transcriptase-PCR and western blotting. Open-field tests and serum corticosterone were used to evaluate CS. The results showed that CS induced behavioral changes and increased corticosterone levels of the animals with periodontitis. CS stimulation markedly increased alveolar bone loss, periodontal pocket depth and the number of plaques. It also enhanced the inflammatory reaction. These results suggest that CS accelerated the ligature-induced pathological changes associated with periodontitis. Further analysis of the mechanisms involved showed that GR-α expression was significantly downregulated in periodontal tissues of the animals undergoing CS. Blocking GR-α signaling in lipopolysaccharide and corticosteroid-treated human periodontal ligament fibroblast cells in vitro significantly upregulated the expression of p-Akt (protein kinase B) and TLR4, promoted nuclear factor-κB activity and increased levels of IL-1ß, IL-6 and IL-8. This research suggests that CS might accelerate the pathological progression of periodontitis by a GR-α signaling-mediated inflammatory response and that this may be a potential therapeutic target for the treatment of periodontal disease, particularly in patients with CS.
Assuntos
Periodontite/etiologia , Periodontite/metabolismo , Receptores de Glucocorticoides/metabolismo , Estresse Fisiológico , Estresse Psicológico , Animais , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Lipopolissacarídeos/imunologia , Masculino , NF-kappa B/metabolismo , Periodontite/patologia , Ratos , Receptores de Glucocorticoides/genéticaRESUMO
Cancer cells exhibit the reprogrammed metabolism mainly via aerobic glycolysis, a phenomenon known historically as the Warburg effect; however, the underlying mechanisms remain largely unknown. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in aerobic glycolysis of human epithelial ovarian cancer (EOC) and its molecular mechanisms. Our data showed that aberrant expression of FOXM1 significantly contributed to the reprogramming of glucose metabolism in EOC cells. Aerobic glycolysis and cell proliferation were down-regulated in EOC cells when FOXM1 gene expression was suppressed by RNA interference. Moreover, knockdown of FOXM1 in EOC cells significantly reduced glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) expression. FOXM1 bound directly to the GLUT1 and HK2 promoter regions and regulated the promoter activities and the expression of the genes at the transcriptional level. This reveals a novel mechanism by which glucose metabolism is regulated by FOXM1. Importantly, we further demonstrated that the expression levels of FOXM1, GLUT1 and HK2 were significantly increased in human EOC tissues relative to normal ovarian tissues, and that FOXM1 expression was positively correlated with GLUT1 and HK2 expression. Taken together, our results show that FOXM1 promotes reprogramming of glucose metabolism in EOC cells via activation of GLUT1 and HK2 transcription, suggesting that FOXM1 may be an important target in aerobic glycolysis pathway for developing novel anticancer agents.
Assuntos
Proteína Forkhead Box M1/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Hexoquinase/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Animais , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Reprogramação Celular/fisiologia , Feminino , Proteína Forkhead Box M1/biossíntese , Proteína Forkhead Box M1/genética , Transportador de Glucose Tipo 1/biossíntese , Transportador de Glucose Tipo 1/genética , Xenoenxertos , Hexoquinase/biossíntese , Hexoquinase/genética , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Regiões Promotoras Genéticas , Transcrição Gênica , TransfecçãoRESUMO
Gefitinib resistance remains a major problem in the treatment of lung adenocarcinoma. However, the molecular mechanisms of gefitinib resistance are not fully understood. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in gefitinib resistance of lung adenocarcinoma cells. In vitro drug sensitivity assays demonstrated that FOXM1 inhibition sensitized PC9/GR and HCC827/GR cells to gefitinib, whereas FOXM1 overexpression enhanced PC9 and HCC827 cell resistance to gefitinib. Increased FOXM1 resulted in the upregulation of hepatocyte growth factor receptor (MET), which led to activation of the protein kinase B (AKT) pathway, whereas knockdown of FOXM1 did the opposite. FOXM1 bound directly to the MET promoter regions and regulated the promoter activities and the expression of MET at the transcriptional level. Moreover, MET/AKT pathway upregulated the expression of FOXM1 in lung adenocarcinoma cells. Inhibition of pAKT by LY294002 or inhibition of pMET by PHA-665752 significantly inhibited the expression of FOXM1 in lung adenocarcinoma cells. Importantly, we further demonstrated that the expression levels of FOXM1, pAKT and MET were significantly increased in lung adenocarcinoma tissues relative to normal lung tissues, and these three biomarkers were concomitantly overexpressed in lung adenocarcinoma tissues. Taken together, our results indicate that FOXM1 promotes acquired resistance to gefitinib of lung adenocarcinoma cells, and FOXM1 crosstalks with MET/AKT signaling to form a positive feedback loop to promote lung adenocarcinoma development.