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1.
Int J Nanomedicine ; 16: 2949-2963, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33907401

RESUMO

Purpose: Prostate cancer (PCa) is one of the most common malignancies in males. Despite the success of immunotherapy in many malignant cancers, strategies are still needed to improve therapeutic efficacy in PCa. This study aimed to investigate the effects of Akkermansia muciniphila-derived extracellular vesicles (Akk-EVs) on PCa and elucidate the underlying immune-related mechanism. Methods: Akk-EVs were isolated by ultracentrifugation and intravenously injected to treat syngeneic PCa-bearing immune-competent mice. Immunophenotypic changes in immune cells, such as cytotoxic T lymphocytes and macrophages, were measured via flow cytometry analysis. Histological examination was used to detect morphological changes in major organs after Akk-EVs treatments. In vitro, flow cytometry was performed to confirm the effects of Akk-EVs on the activation of CD8+ T cells. Quantitative PCR and immunofluorescence staining were carried out to test the impact of Akk-EVs on macrophage polarization. Cell counting kit-8 (CCK-8) analysis, colony formation assays, and scratch wound healing assays were conducted to assess the effects of Akk-EVs-treated macrophages on the proliferation and invasion of PCa cells. CCK-8 assays also confirmed the impact of Akk-EVs on the viability of normal cells. Results: Intravenous injection of Akk-EVs in immune-competent mice reduced the tumor burden of PCa without inducing obvious toxicity in normal tissues. This treatment elevated the proportion of granzyme B-positive (GZMB+) and interferon γ-positive (IFN-γ+) lymphocytes in CD8+ T cells and caused macrophage recruitment, with increased tumor-killing M1 macrophages and decreased immunosuppressive M2 macrophages. In vitro, Akk-EVs increased the number of GZMB+CD8+ and IFN-γ+CD8+ T cells and M1-like macrophages. In addition, conditioned medium from Akk-EVs-treated macrophages suppressed the proliferation and invasion of prostate cells. Furthermore, the effective dose of Akk-EVs was well-tolerated in normal cells. Conclusion: Our study revealed the promising prospects of Akk-EVs as an efficient and biocompatible immunotherapeutic agent for PCa treatment.

2.
Theranostics ; 11(5): 2395-2409, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500732

RESUMO

Alzheimer's disease (AD) is currently ranked as the third leading cause of death for eldly people, just behind heart disease and cancer. Autophagy is declined with aging. Our study determined the biphasic changes of miR-331-3p and miR-9-5p associated with AD progression in APPswe/PS1dE9 mouse model and demonstrated inhibiting miR-331-3p and miR-9-5p treatment prevented AD progression by promoting the autophagic clearance of amyloid beta (Aß). Methods: The biphasic changes of microRNAs were obtained from RNA-seq data and verified by qRT-PCR in early-stage (6 months) and late-stage (12 months) APPswe/PS1dE9 mice (hereinafter referred to as AD mice). The AD progression was determined by analyzing Aß levels, neuron numbers (MAP2+) and activated microglia (CD68+IBA1+) in brain tissues using immunohistological and immunofluorescent staining. MRNA and protein levels of autophagic-associated genes (Becn1, Sqstm1, LC3b) were tested to determine the autophagic activity. Morris water maze and object location test were employed to evaluate the memory and learning after antagomirs treatments in AD mice and the Aß in the brain tissues were determined. Results: MiR-331-3p and miR-9-5p are down-regulated in early-stage of AD mice, whereas up-regulated in late-stage of AD mice. We demonstrated that miR-331-3p and miR-9-5p target autophagy receptors Sequestosome 1 (Sqstm1) and Optineurin (Optn), respectively. Overexpression of miR-331-3p and miR-9-5p in SH-SY5Y cell line impaired autophagic activity and promoted amyloid plaques formation. Moreover, AD mice had enhanced Aß clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p antagomirs at late-stage. Conclusion: Our study suggests that using miR-331-3p and miR-9-5p, along with autophagic activity and amyloid plaques may distinguish early versus late stage of AD for more accurate and timely diagnosis. Additionally, we further provide a possible new therapeutic strategy for AD patients by inhibiting miR-331-3p and miR-9-5p and enhancing autophagy.

3.
Autophagy ; : 1-17, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33143524

RESUMO

Senile osteoporosis (OP) is often concomitant with decreased autophagic activity. OPTN (optineurin), a macroautophagy/autophagy (hereinafter referred to as autophagy) receptor, is found to play a pivotal role in selective autophagy, coupling autophagy with bone metabolism. However, its role in osteogenesis is still mysterious. Herein, we identified Optn as a critical molecule of cell fate decision for bone marrow mesenchymal stem cells (MSCs), whose expression decreased in aged mice. Aged mice revealed osteoporotic bone loss, elevated senescence of MSCs, decreased osteogenesis, and enhanced adipogenesis, as well as optn- / - mice. Importantly, restoring Optn by transplanting wild-type MSCs to optn- / - mice or infecting optn- / - mice with Optn-containing lentivirus rescued bone loss. The introduction of a loss-of-function mutant of OptnK193R failed to reestablish a bone-fat balance. We further identified FABP3 (fatty acid binding protein 3, muscle and heart) as a novel selective autophagy substrate of OPTN. FABP3 promoted adipogenesis and inhibited osteogenesis of MSCs. Knockdown of FABP3 alleviated bone loss in optn- / - mice and aged mice. Our study revealed that reduced OPTN expression during aging might lead to OP due to a lack of FABP3 degradation via selective autophagy. FABP3 accumulation impaired osteogenesis of MSCs, leading to the occurrence of OP. Thus, reactivating OPTN or inhibiting FABP3 would open a new avenue to treat senile OP. Abbreviations: ADIPOQ: adiponectin, C1Q and collagen domain containing; ALPL: alkaline phosphatase, liver/bone/kidney; BGLAP/OC/osteocalcin: bone gamma carboxyglutamate protein; BFR/BS: bone formation rate/bone surface; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A/p21: cyclin-dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CDKN2B/p15: cyclin dependent kinase inhibitor 2B; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; COL1A1: collagen, type I, alpha 1; Ct. BV/TV: cortical bone volume fraction; Ct. Th: cortical thickness; Es. Pm: endocortical perimeter; FABP4/Ap2: fatty acid binding protein 4, adipocyte; H2AX: H2A.X variant histone; HE: hematoxylin and eosin; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MAR: mineral apposition rate; MSCs: bone marrow mesenchymal stem cells; NBR1: NBR1, autophagy cargo receptor; OP: osteoporosis; OPTN: optineurin; PDB: Paget disease of bone; PPARG: peroxisome proliferator activated receptor gamma; Ps. Pm: periosteal perimeter; qRT-PCR: quantitative real-time PCR; γH2AX: Phosphorylation of the Serine residue of H2AX; ROS: reactive oxygen species; RUNX2: runt related transcription factor 2; SA-GLB1: senescence-associated (SA)-GLB1 (galactosidase, beta 1); SP7/Osx/Osterix: Sp7 transcription factor 7; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; Tb. BV/TV: trabecular bone volume fraction; Tb. N: trabecular number; Tb. Sp: trabecular separation; Tb. Th: trabecular thickness; µCT: micro computed tomography.

4.
Dis Model Mech ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033107

RESUMO

Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila (A. muc), a gut probiotic, ameliorates systemic inflammation by tightening intestinal barrier. In this study, fractured mice intragastrically administrated with A. muc were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muc at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis and can be stimulated by PDGF-BB. Moreover, A. muc treatment significantly reduced gut permeability and inflammation at early stage. Dextran Sulfate Sodium (DSS) was used to disrupt the gut barrier to determine the role of gut barrier in fracture healing and whether A. muc still can stimulate bone fracture healing. As expected, A. muc evidently improved gut barrier, reduced inflammation, and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muc reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB positive preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidences about the involvement of type H vessels in fracture healing and suggests the potential of A. muc as a promising strategy for bone healing.

6.
Ying Yong Sheng Tai Xue Bao ; 31(2): 554-562, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32476349

RESUMO

The key ecological function area plays an important role in providing ecosystem service. As the main players of economic activities in this area, the excessive dependence of local farmers on environmental resource will seriously influence ecological environment quality, and thus impair the ecosystem service. At present, it is urgent to explore the dependence of farmers' livelihoods on environmental resource and its influencing factors in key ecological function areas, which would provide reference for the formulation of environmental friendly regional development policies. We selected the Gannan Plateau as study area. Based on 581 survey data, we analyzed the dependence of farmers' livelihood on environmental resource, and used the ordinal multi-class Logistic regression model to identify its key impact factors. The results showed that local farmers were highly dependent on environmental resource in Gannan Plateau, which was mainly reflected in three aspects of food self-sufficiency, daily energy consumption and income source, with the dependence of 57.3%, 56.9% and 37.4%, respectively. There were significant differences in the dependence of different types of farmers' livelihoods on environmental resource, in that farmers with higher levels of education and higher non-agricultural levels had lower dependence and the farmers with high dependency ratio were more dependent on environmental resources. The factors including family dependency ratio, labor education level, proportion of migrant workers in labor force, family member leadership, ecological policy, and altitude had significant impact on farmers' environmental resource dependence. Among them, family dependency ratio and altitude had positive impact on it, while the proportion of migrant workers in labor force, labor education level, family member leadership, ecological policy had negative impact.


Assuntos
Ecossistema , Fazendeiros , Agricultura , China , Política Ambiental , Humanos
7.
Acta Biomater ; 111: 208-220, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32447063

RESUMO

Osteonecrosis of the femoral head (ONFH) frequently occurs after glucocorticoid (GC) treatment. Extracellular vesicles (EVs) are important nano-sized paracrine mediators of intercellular crosstalk. This study aimed to determine whether EVs from human urine-derived stem cells (USC-EVs) could protect against GC-induced ONFH and focused on the impacts of USC-EVs on angiogenesis and apoptosis to explore the mechanism by which USC-EVs attenuated GC-induced ONFH. The results in vivo showed that the intravenous administration of USC-EVs at the early stage of GC exposure could rescue angiogenesis impairment, reduce apoptosis of trabecular bone and marrow cells, prevent trabecular bone destruction and improve bone microarchitecture in the femoral heads of rats. In vitro, USC-EVs reversed the GC-induced suppression of endothelial angiogenesis and activation of apoptosis. Deleted in malignant brain tumors 1 (DMBT1) and tissue inhibitor of metalloproteinases 1 (TIMP1) proteins were enriched in USC-EVs and essential for the USC-EVs-induced pro-angiogenic and anti-apoptotic effects in GC-treated cells, respectively. Knockdown of TIMP1 attenuated the protective effects of USC-EVs against GC-induced ONFH. Our study suggests that USC-EVs are a promising nano-sized agent for the prevention of GC-induced ONFH by delivering pro-angiogenic DMBT1 and anti-apoptotic TIMP1. STATEMENT OF SIGNIFICANCE: This study demonstrates that the intravenous injection of extracellular vesicles from human urine-derived stem cells (USC-EVs) at the early stage of glucocorticoid (GC) exposure efficiently protects the rats from the GC-induced osteonecrosis of the femoral head (ONFH). Moreover, this study identifies that the promotion of angiogenesis and inhibition of apoptosis by transferring pro-angiogenic DMBT1 and anti-apoptotic TIMP1 proteins contribute importantly to the USC-EVs-induced protective effects against GC-induced ONFH. This study suggests the promising prospect of USC-EVs as a new nano-sized agent for protecting against GC-induced ONFH, and the potential of DMBT1 and TIMP1 as the molecular targets for further augmenting the protective function of USC-EVs.

8.
J Endocrinol ; 245(1): 93-100, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027602

RESUMO

Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.


Assuntos
Adipócitos Bege/metabolismo , Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/metabolismo , Proteínas Semelhantes a Angiopoietina/metabolismo , Mitocôndrias/metabolismo , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Bege/citologia , Adipócitos Brancos/citologia , Tecido Adiposo Branco/citologia , Adiposidade/genética , Proteínas Semelhantes a Angiopoietina/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Ácidos Graxos não Esterificados/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Interferência de RNA , Transdução de Sinais , Triglicerídeos/sangue
9.
Bone Res ; 7: 18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263627

RESUMO

Osteoporosis is a debilitating bone disease affecting millions of people. Here, we used human urine-derived stem cells (USCs), which were noninvasively harvested from unlimited and easily available urine, as a "factory" to obtain extracellular vesicles (USC-EVs) and demonstrated that the systemic injection of USC-EVs effectively alleviates bone loss and maintains bone strength in osteoporotic mice by enhancing osteoblastic bone formation and suppressing osteoclastic bone resorption. More importantly, the anti-osteoporotic properties of USC-EVs are not notably disrupted by the age, gender, or health condition (with or without osteoporosis) of the USC donor. Mechanistic studies determined that collagen triple-helix repeat containing 1 (CTHRC1) and osteoprotegerin (OPG) proteins are enriched in USC-EVs and required for USC-EV-induced pro-osteogenic and anti-osteoclastic effects. Our results suggest that autologous USC-EVs represent a promising novel therapeutic agent for osteoporosis by promoting osteogenesis and inhibiting osteoclastogenesis by transferring CTHRC1 and OPG.

10.
Angew Chem Int Ed Engl ; 58(31): 10553-10557, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31165539

RESUMO

Tunable protein assemblies not only hold a dominant position in vital biological events but are also a significant theme in supramolecular chemistry. Herein, we demonstrated that the intertubular aggregation of microtubules (MTs) could be efficiently regulated by a synergistic polypeptide-tubulin interaction and host-guest complexation. The benzylimidazolium-modified antimitotic peptide (BP) could recognize the MTs and concurrently form stable inclusion complexes with avirulent cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) in different binding stoichiometries. The self-assembling morphology of MTs was converted from fibrous to nanoparticulate aggregates via extensive BP⊂CB[8] cross-linkage, leading to significant cell apoptosis and tumor ablation in vivo. The targeted (BP⊂CB[8])@MT ternary assembly provides a facile supramolecular method to enhance the protein-protein interactions, which may be developed as a therapy for degenerative diseases, such as cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Imidazóis/farmacologia , Microtúbulos/efeitos dos fármacos , Peptídeos/química , Tubulina (Proteína)/metabolismo , Células A549 , Animais , Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/química , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Agregados Proteicos/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Tubulina (Proteína)/química
11.
Theranostics ; 9(9): 2678-2693, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31131061

RESUMO

Poor wound healing affects millions of people worldwide each year and needs better therapeutic strategies. Synechococcus elongatus PCC 7942 is a naturally occurring photoautotrophic cyanobacterium that can be easily obtained and large-scale expanded. Here, we investigated the therapeutic efficacy of this cyanobacterium in a mouse model of acute burn injury and whether the secretion of extracellular vesicles (EVs), important mediators of cell paracrine activity, is a key mechanism of the cyanobacterium-induced regulation of wound healing. Methods: The effects of Synechococcus elongatus PCC 7942 on burn wound healing in mice under light or dark conditions were evaluated by measuring wound closure rates, histological and immunofluorescence analyses. A series of assays in vivo and in vitro were conducted to assess the impact of the cyanobacterium on angiogenesis. GW4869 was used to interfere with the secretion of EVs by the cyanobacterium and the abilities of the GW4869-pretreated and untreated Synechococcus elongatus PCC 7942 to regulate endothelial angiogenesis were compared. The direct effects of the cyanobacterium-derived EVs (S. elongatus-EVs) on angiogenesis, wound healing and expressions of a class of pro-inflammatory factors that have regulatory roles in wound healing were also examined. Results: Synechococcus elongatus PCC 7942 treatment under light and dark conditions both significantly promoted angiogenesis and burn wound repair in mice. In vitro, the cyanobacterium enhanced angiogenic activities of endothelial cells, but the effects were markedly blocked by GW4869 pretreatment. S. elongatus-EVs were capable of augmenting endothelial angiogenesis in vitro, and stimulating new blood vessel formation and burn wound healing in mice. The expression of interleukin 6 (IL-6), which has an essential role in angiogenesis during skin wound repair, was induced in wound tissues and wound healing-related cells by S. elongatus-EVs and Synechococcus elongatus PCC 7942. Conclusion: Synechococcus elongatus PCC 7942 has the potential as a promising strategy for therapeutic angiogenesis and wound healing primarily by the delivery of functional EVs, not by its photosynthetic activity. The promotion of IL-6 expression may be a mechanism of the cyanobacterium and its EVs-induced pro-angiogenic and -wound healing effects.


Assuntos
Queimaduras/terapia , Células Endoteliais/efeitos dos fármacos , Vesículas Extracelulares/fisiologia , Pele/efeitos dos fármacos , Synechococcus/fisiologia , Cicatrização/efeitos dos fármacos , Compostos de Anilina/farmacologia , Animais , Compostos de Benzilideno/farmacologia , Queimaduras/genética , Queimaduras/metabolismo , Queimaduras/patologia , Linhagem Celular , Linhagem Celular Transformada , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais/efeitos da radiação , Vesículas Extracelulares/química , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Luz , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/efeitos da radiação , Pele/irrigação sanguínea , Pele/lesões , Pele/efeitos da radiação , Synechococcus/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Cicatrização/fisiologia , Cicatrização/efeitos da radiação
12.
J Breast Cancer ; 22(1): 15-28, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30941230

RESUMO

Purpose: Pokemon, also known as ZBTB7A, belongs to the POZ and Krüppel (POK) family of transcription repressors and is implicated in tumor progression as a key proto-oncogene. This present study aimed at determining the mechanism by which Pokemon inhibits transforming growth factor ß (TGFß)-Smad4 pathway-dependent proliferation arrest of breast cancer cells via specificity protein 1 (SP1). Methods: Over-expressing plasmid or small interfering RNA (siRNA) transfection was used to regulate Pokemon levels. The EdU incorporation assay, MTS assay, and clone formation were used to identify the inhibitory effect of Pokemon siRNA on cell proliferation. Quantitative real-time polymerase chain reaction assay confirmed that Pokemon deletion inhibited the expression of proliferation-associated genes. The dual-luciferase reporter assay, electrophoretic mobility shift assay, and co-immunoprecipitation assay were used to analyze binding between Pokemon, Smad4, and SP1. Results: Pokemon deletion induced proliferation arrest of breast cancer cells and inhibited the expression of proliferation-associated genes, especially Smad4. Pokemon bound with SP1 to interdict Smad4 promoter activity. Information on clinical samples was obtained from The Cancer Genome Atlas data, in which the Pokemon mRNA levels showed a negative correlation with Smad4 levels in different subtypes of breast cancer in two independent datasets. Conclusion: We demonstrated that Pokemon binds to SP1 to down-regulate Smad4 expression, thereby promoting proliferation of breast cancer cells. This suggests that Pokemon is a potential TGFß-signaling participant in breast cancer progression.

13.
Clin Chim Acta ; 494: 52-57, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30876855

RESUMO

BACKGROUD: CCN3 is a novel adipokine and has emerged as a potential metabolic regulator. However, information regarding the role of CCN3 in type 2 diabetes mellitus (T2DM) remains unclear. This study measured for the first time serum CCN3 levels in T2DM and explored the correlations between its serum levels and various metabolic parameters in humans. METHODS: A total of 219 newly diagnosed T2DM (nT2DM) patients and 205 healthy control subjects, matched for age and sex ratio, were enrolled. Circulating CCN3 and TNF-α, IL-6 and MCP-1 were measured by ELISA. The anthropometric assessment and biochemical evaluation were done in all subjects. OGTT were performed in 34 healthy individuals to investigate the association of CCN3 with glucose. RESULTS: Serum CCN3 levels were significantly higher in nT2DM patients compared to those of the healthy controls (6.71[4.88, 8.56] vs. 4.51[3.55, 5.99] ng/ml, P < 0.01). Serum CCN3 positively correlated with BMI, WC, FAT%, TG, FPG, 2 h-PG, HbA1c, FIns, HOMA-IR, hs-CRP and TNF-α, IL-6 and MCP-1, but negatively with HOMA-ß in all individuals (P < 0.05). Multiple linear regression analysis indicated that BMI, HOMA-IR, TNF-α and MCP-1 were independently associated with CCN3. Multivariate logistic regression analysis demonstrated that CCN3 was correlated with nT2DM. Finally, area under ROC curve of CCN3 (gender and age adjusted) for predicting the presence of nT2DM was 0.725(95% CI: 0.676-0.773). After an oral glucose challenge, there was no obvious change in the circulating levels of CCN3 as compared to 0 min (P > 0.05). CONCLUSIONS: Elevation of CCN3 in nT2DM supports the hypothesis that CCN3 may serve as a risk factor associated with the pathogenesis of T2DM.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Inflamação/sangue , Resistência à Insulina , Proteína Sobre-Expressa em Nefroblastoma/sangue , Obesidade/sangue , Adulto , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Inflamação/complicações , Inflamação/metabolismo , Masculino , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , Obesidade/complicações , Obesidade/metabolismo
14.
BMC Endocr Disord ; 19(1): 12, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670019

RESUMO

BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a recently novel lipolytic adipokine implicated in regulation of glucose and lipid metabolism in many metabolic disorders. In vitro and animal studies suggest that thyroid hormones (TH) up-regulates ZAG production in hepatocytes. However, there is no data evaluating the possible relationship between ZAG and TH in a human model of hyperthyroidism. The objective of the present study is to assess the association of serum ZAG levels with TH and lipid profile in patients with hyperthyroidism before and after methimazole treatment. METHODS: A total of 120 newly diagnosed overt hyperthyroidism and 122 healthy control subjects were recruited. Of them, 39 hyperthyroidism patients were assigned to receive methimazole treatment as follow-up study for 2 months. RESULTS: The clinical consequence showed that serum ZAG levels were elevated in patients with hyperthyroidism (P < 0.01). Adjust for age, gender and BMI, serum ZAG levels were positively related with serum free T3 (FT3), free T4 (FT4) levels and negatively correlated with serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC) levels in hyperthyroidism subjects (all P < 0.01). After methimazole treatment, serum ZAG levels were decreased and the decline was associated with decreased FT3, FT4 and increased TC levels (all P < 0.001). CONCLUSION: We conclude that ZAG may be involved in the pathogenesis of lipid metabolism disorder in patients with hyperthyroidism. TRIAL REGISTRATION: ChiCTR-ROC-17012943 . Registered 11 October 2017, retrospectively registered.


Assuntos
Biomarcadores/sangue , Hipertireoidismo/sangue , Metimazol/uso terapêutico , Proteínas de Plasma Seminal/sangue , Hormônios Tireóideos/sangue , Adulto , Antitireóideos/uso terapêutico , Feminino , Seguimentos , Humanos , Hipertireoidismo/diagnóstico , Hipertireoidismo/tratamento farmacológico , Masculino , Prognóstico , Estudos Prospectivos
15.
Int J Obes (Lond) ; 42(8): 1418-1430, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30006580

RESUMO

BACKGROUND/AIM: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. Our previous studies indicated that zinc alpha2 glycoprotein (ZAG) alleviates palmitate (PA)-induced intracellular lipid accumulation in hepatocytes. This study is to further characterize the roles of ZAG on the development of hepatic steatosis, insulin resistance (IR), and inflammation. METHODS: ZAG protein levels in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in PA-treated hepatocytes were determined by western blotting. C57BL/6J mice injected with an adenovirus expressing ZAG were fed HFD for indicated time to induce hepatic steatosis, IR, and inflammation, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms underlying ZAG-regulated hepatic steatosis were further explored and verified in mice and hepatocytes. RESULTS: ZAG expression was decreased in NAFLD patient liver biopsy samples, obese mice livers, and PA-treated hepatocytes. Simultaneously, ZAG overexpression alleviated intracellular lipid accumulation via upregulating adiponectin and lipolytic genes (FXR, PPARα, etc.) while downregulating lipogenic genes (SREBP-1c, LXR, etc.) in obese mice as well as in cultured hepatocytes. ZAG improved insulin sensitivity and glucose tolerance via activation of IRS/AKT signaling. Moreover, ZAG significantly inhibited NF-ĸB/JNK signaling and thus resulting in suppression of obesity-associated inflammatory response in hepatocytes. CONCLUSIONS: Our results revealed that ZAG could protect against NAFLD by ameliorating hepatic steatosis, IR, and inflammation.


Assuntos
Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Proteínas de Plasma Seminal/metabolismo , Animais , Humanos , Fígado/química , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteínas de Plasma Seminal/análise , Proteínas de Plasma Seminal/genética , Transdução de Sinais/genética , Regulação para Cima/genética
16.
Bone Res ; 6: 9, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29619269

RESUMO

Osteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone formation. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about the role of omentin-1 in inflammatory osteoporosis. Here we generated global omentin-1 knockout (omentin-1-/-) mice and demonstrated that depletion of omentin-1 induces inflammatory bone loss-like phenotypes in mice, as defined by abnormally elevated pro-inflammatory cytokines, increased osteoclast formation and bone tissue destruction, as well as impaired osteogenic activities. Using an inflammatory cell model induced by tumor necrosis factor-α (TNF-α), we determined that recombinant omentin-1 reduces the production of pro-inflammatory factors in the TNF-α-activated macrophages, and suppresses their anti-osteoblastic and pro-osteoclastic abilities. In the magnesium silicate-induced inflammatory osteoporosis mouse model, the systemic administration of adenoviral-delivered omentin-1 significantly protects from osteoporotic bone loss and inflammation. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of inflammatory bone diseases by downregulating the pro-inflammatory cytokines.

17.
Biochem Biophys Res Commun ; 496(2): 287-293, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29317208

RESUMO

Recent studies have highlighted recruiting and activating brite adipocytes in WAT (so-called "browning") would be an attractive anti-obesity strategy. Zinc alpha2 glycoprotein (ZAG) as an important adipokine, is reported to ameliorate glycolipid metabolism and lose body weight in obese mice. However whether the body reducing effect mediated by browning programme remains unclear. Here, we show that overexpression of ZAG in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α, NRF-1/2 and mtTFA) and the key lipid metabolism lipases (ATGL, HSL, CPT1-A and p-acyl-CoA carboxylase). Additionally, those effects were dramaticlly abolished by H89/SB203580, revealing ZAG-induced browning depend on PKA and p38 MAPK signaling. Overall, our findings suggest that ZAG is a candidate therapeutic agent against obesity via induction of brown fat-like phenotype in white adipocytes.


Assuntos
Adipócitos Marrons/metabolismo , Proteínas de Transporte/genética , Regulação da Expressão Gênica , Glicoproteínas/genética , Metabolismo dos Lipídeos/genética , Células 3T3-L1 , Adipócitos Marrons/citologia , Adipócitos Marrons/efeitos dos fármacos , Adipocinas , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Carbono-Carbono Ligases/genética , Carbono-Carbono Ligases/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Proteínas de Transporte/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Imidazóis/farmacologia , Isoquinolinas/farmacologia , Lipase/genética , Lipase/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 1 Nuclear Respiratório/genética , Fator 1 Nuclear Respiratório/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Piridinas/farmacologia , Transdução de Sinais , Sulfonamidas/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
18.
Onco Targets Ther ; 10: 3991-4005, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28860807

RESUMO

PURPOSE: Long noncoding RNAs (lncRNAs) are known to function as regulators in the development and occurrence of various tumors. MALAT1 is a highly conserved lncRNA and has vital functions in diverse tumors, including pancreatic cancer (PC). However, the underlying molecular regulatory mechanism involved in the occurrence and development of PC remains largely unknown. Thus, it is important to explore MALAT1 in PC and elucidate its function, which might offer a new perspective for clinical diagnosis and therapy. METHODS: First, we used the Gene Expression Omnibus, Oncomine, and The Cancer Genome Atlas databases to determine the clinical diagnostic and prognostic values of MALAT1. We next used our own GeneChip and The Cancer Genome Atlas database to collect the possible target genes of MALAT1 and further utilized a bioinformatics analysis to explore the underlying significant pathways that might be crucial in PC. Finally, we identified several key target genes of MALAT1 and hope to offer references for future research. RESULTS: We found that the expression of MALAT1 was significantly elevated in patients with PC. A receiver operating characteristics curve analysis showed a moderate diagnostic value (area under the curve =0.75, sensitivity =0.66, specificity =0.72). A total of 224 important overlapping genes were collected, and six hub genes (CCND1, MAPK8, VEGFA, FOS, CDH1, and HSP90AA1) were identified, of which CCND1, MAPK8, and VEGFA, are important genes in PC. Several pathways, including the mTOR signaling pathway, pathways in cancer, and the MAPK signaling pathway, were suggested to be the vital MALAT1 pathways in PC. CONCLUSION: MALAT1 is suggested to be a promising diagnostic biomarker in PC. Six hub genes (CCND1, MAPK8, VEGFA, FOS, CDH1, and HSP90AA1), and specifically CCND1, MAPK8, and VEGFA, might be key MALAT1 target genes in PC. Due to their possible clinical significance in PC, several pathways, such as the mTOR signaling pathway, pathways in cancer, and the MAPK signaling pathway, are worthy of further study.

20.
Biomarkers ; 20(6-7): 487-94, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26616150

RESUMO

Breast cancer is currently the second most common cancer worldwide and the most frequent malignant tumor among women. However, the exact contribution of various allelic alterations remains unclear. This meta-analysis was conducted to evaluate the association of the transforming growth factor ß receptor I 6A/9A (TßR-I 6A/9A) gene polymorphism with breast cancer risk. Relevant studies were identified from PubMed and Cochrane Library on 1 October 2013, and eligible reports were recruited and synthesized. Eleven reports that included a total of 12 studies were recruited into this meta-analysis for the association of the TßR-I 6A/9A gene polymorphism and breast cancer risk. The results indicated that overall the TßR-I 6A allele was associated with breast cancer risk (OR = 1.33, 95% CI: 1.02-1.73, p = 0.04). However, the TßR-I 6A/6A and 9A/9A genotypes were not associated with an increased risk of developing breast cancer (6A/6A: OR = 1.71, 95% CI: 0.95-3.08, p = 0.07; 9A/9A: OR = 0.82, 95% CI: 0.66-1.02, p = 0.08). In the Caucasian population, no such association could be established. In conclusion, the TßR-I 6A allele might represent a risk factor for breast cancer risk, but significantly larger data sets from a larger number of studies, including studies that allow ethnicity, subgroup analysis and environmental impact evaluation, are required to maximize statistical significance and meta-analysis robustness.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Razão de Chances , Receptor do Fator de Crescimento Transformador beta Tipo I , Medição de Risco , Fatores de Risco
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