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1.
Artigo em Inglês | MEDLINE | ID: mdl-34505945

RESUMO

PURPOSE: Obtaining tumour-free margins is critical for avoiding re-excision and reducing local recurrence following breast-conserving surgery; however, it remains challenging. Imaging-guided surgery provides precise detection of residual lesions and assists surgical resection. Herein, we described water-soluble melanin nanoparticles (MNPs) conjugated with cyclic Arg-Gly-Asp (cRGD) peptides for breast cancer photoacoustic imaging (PAI) and surgical navigation. METHODS: The cRGD-MNPs were synthesised and characterized for morphology, photoacoustic characteristics and stability. Tumour targeting and toxicity of cRGD-MNPs were determined by using either breast cancer cells, MDA-MB-231 tumour-bearing mice or the FVB/N-Tg (MMTV-PyVT) 634Mul/J mice model. PAI was used to locate the tumour and guide surgical resection in MDA-MB-231 tumour-bearing mice. RESULTS: The cRGD-MNPs exhibited excellent in vitro and in vivo tumour targeting with low toxicity. Intravenous administration of cRGD-MNPs to MDA-MB-231 tumour-bearing mice showed an approximately 2.1-fold enhancement in photoacoustic (PA) intensity at 2 h, and the ratio of the PA intensity at the tumour site to that in the surrounding normal tissue was 3.2 ± 0.1, which was higher than that using MNPs (1.7 ± 0.3). Similarly, the PA signal in the spontaneous breast cancer increased ~ 2.5-fold at 2 h post-injection of cRGD-MNPs in MMTV-PyVT transgenic mice. Preoperative PAI assessed tumour volume and offered three-dimensional (3D) reconstruction images for accurate surgical planning. Surgical resection following real-time PAI showed high consistency with histopathological analysis. CONCLUSION: These results highlight that cRGD-MNP-mediated PAI provide a powerful tool for breast cancer imaging and precise tumour resection. cRGD-MNPs with fine PA properties have great potential for clinical translation.

2.
J Bone Miner Metab ; 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34392464

RESUMO

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is not only a biomarker of kidney injury but also a bone-derived factor involved in metabolism. We aimed to explore relationships between plasma NGAL and chronic kidney disease-mineral bone disorder (CKD-MBD) parameters in maintenance hemodialysis (MHD) patients. MATERIALS AND METHODS: First, a cross sectional observational study, including 105 MHD patients, was conducted to explore relationships between plasma NGAL levels and CKD-MBD parameters. Second, impact of parathyroidectomy and auto-transplantation (PTX + AT) on plasma NGAL was investigated in 12 MHD patients with severe secondary hyperparathyroidism (SHPT). RESULTS: According to Spearman correlation analysis, plasma NGAL levels were positively correlated with female (r = 0.243, P = 0.012), vintage (r = 0.290, P = 0.003), Klotho (r = 0.234, P = 0.016), calcium(Ca) (r = 0.332, P = 0.001), alkaline phosphatase (ALP) (r = 0.401, P < 0.001) and intact parathyroid hormone (iPTH) (r = 0.256, P = 0.008); while inversely correlated with albumin(Alb) (r = - 0.201, P = 0.039). After adjusting for age, sex, vintage, Alb and all parameters of CKD-MBD(Ca, P, lg(ALP), lg(iPTH), Klotho and fibroblast growth factor 23(FGF23)), lg(NGAL) were positively correlated with Ca (r = 0.481, P < 0.001), P (r = 0.336, P = 0.037), lg(ALP) (r = 0.646, P < 0.001) in Partial correlation analysis; further multiple linear regression analysis showed same positive associations between lg(NGAL) and Ca (ß = 0.330, P = 0.002), P (ß = 0.218, P = 0.037), lg(ALP) (ß = 0.671, P < 0.001). During the 4-7 days after PTX + AT, plasma NGAL decreased from 715.84 (578.73, 988.14) to 688.42 (660.00, 760.26) ng/mL (P = 0.071), Klotho increased from 496.45 (341.73, 848.30) to 1138.25 (593.87, 2009.27) pg/mL (P = 0.099). CONCLUSION: Plasma NGAL levels were positively associated with ALP in MHD patients; and downtrends were shown after PTX + AT in patients with severe SHPT. These findings suggest that NGAL is a participant in CKD-MBD under MHD condition.

3.
Aging (Albany NY) ; 13(16): 20629-20650, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34428745

RESUMO

Human osteoblasts are multifunctional bone cells, which play essential roles in bone formation, angiogenesis regulation, as well as maintenance of hematopoiesis. However, the categorization of primary osteoblast subtypes in vivo in humans has not yet been achieved. Here, we used single-cell RNA sequencing (scRNA-seq) to perform a systematic cellular taxonomy dissection of freshly isolated human osteoblasts from one 31-year-old male with osteoarthritis and osteopenia after hip replacement. Based on the gene expression patterns and cell lineage reconstruction, we identified three distinct cell clusters including preosteoblasts, mature osteoblasts, and an undetermined rare osteoblast subpopulation. This novel subtype was found to be the major source of the nuclear receptor subfamily 4 group A member 1 and 2 (NR4A1 and NR4A2) in primary osteoblasts, and the expression of NR4A1 was confirmed by immunofluorescence staining on mouse osteoblasts in vivo. Trajectory inference analysis suggested that the undetermined cluster, together with the preosteoblasts, are involved in the regulation of osteoblastogenesis and also give rise to mature osteoblasts. Investigation of the biological processes and signaling pathways enriched in each subpopulation revealed that in addition to bone formation, preosteoblasts and undetermined osteoblasts may also regulate both angiogenesis and hemopoiesis. Finally, we demonstrated that there are systematic differences between the transcriptional profiles of human and mouse osteoblasts, highlighting the necessity for studying bone physiological processes in humans rather than solely relying on mouse models. Our findings provide novel insights into the cellular heterogeneity and potential biological functions of human primary osteoblasts at the single-cell level.

4.
Aging (Albany NY) ; 13(11): 15595-15619, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34111027

RESUMO

The homeostasis of bone metabolism depends on the coupling and precise regulation of various types of cells in bone tissue. However, the communication and interaction between bone tissue cells at the single-cell level remains poorly understood. Thus, we performed single-cell RNA sequencing (scRNA-seq) on the primary human femoral head tissue cells (FHTCs). Nine cell types were identified in 26,574 primary human FHTCs, including granulocytes, T cells, monocytes, B cells, red blood cells, osteoblastic lineage cells, endothelial cells, endothelial progenitor cells (EPCs) and plasmacytoid dendritic cells. We identified serine protease 23 (PRSS23) and matrix remodeling associated protein 8 (MXRA8) as novel bone metabolism-related genes. Additionally, we found that several subtypes of monocytes, T cells and B cells were related to bone metabolism. Cell-cell communication analysis showed that collagen, chemokine, transforming growth factor and their ligands have significant roles in the crosstalks between FHTCs. In particular, EPCs communicated with osteoblastic lineage cells closely via the "COL2A1-ITGB1" interaction pair. Collectively, this study provided an initial characterization of the cellular composition of the human FHTCs and the complex crosstalks between them at the single-cell level. It is a unique starting resource for in-depth insights into bone metabolism.


Assuntos
Cabeça do Fêmur/metabolismo , Análise de Sequência de RNA , Análise de Célula Única , Linfócitos B/metabolismo , Linhagem da Célula/genética , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Monócitos/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Linfócitos T/metabolismo
5.
Toxicol Lett ; 350: 81-90, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34153405

RESUMO

BACKGROUND: Pulmonary fibrosis is a fatal lung disease with limited treatment options. Icaritin is the active ingredient derived from the traditional Chinese medical plant Epimedium and possesses many biomedical activities. This study aimed to investigate the effects and molecular mechanisms of icaritin on bleomycin-induced pulmonary fibrosis in mice. METHODS: To assess its preventative effects, bleomycin treated mice received 0, 0.04, 0.2, and 1 mg/kg of icaritin from day 1 onwards. To assess its therapeutic effects, bleomycin treated mice received 0 and 1 mg/kg of icaritin from day 15 onwards. Mice were sacrificed on day 21 and lung tissues were collected, stained with HE, Masson and immunohistochemistry. Q-PCR was used to measure Collagen I and Collagen III expression, western blotting was used to quantify α-SMA, Collagen I expression. Hydroxyproline content was measured using a biochemical method. NIH3T3 and HLF-1 cells were treated with TGF-ß1with or without icaritin, and α-SMA, Collagen I were tested. PPARγ antagonist GW9662 and PPARγ-targeted siRNA were used to investigate the mechanism of icaritin in inhibiting myofibroblast differentiation. RESULTS: Both preventative and therapeutic administration of icaritin improved the histopathological changes, decreased Collagen and α-SMA, lowered hydroxyproline content in bleomycin-treated lung tissues. Icaritin decreased α-SMA and Collagen I expression in TGF-ß1-stimulated NIH3T3 and HLF-1 cells. However, its effect in reducing α-SMA and Collagen I expression was suppressed when expression or activity of PPARγ was inhibited. CONCLUSIONS: Icaritin has therapeutic potential against pulmonary fibrosis via the inhibition of myofibroblast differentiation, which may be mediated by PPARγ.


Assuntos
Flavonoides/metabolismo , Flavonoides/uso terapêutico , PPAR gama/genética , PPAR gama/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Animais , Bleomicina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Epimedium/química , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Fibrose Pulmonar/induzido quimicamente
6.
Aging (Albany NY) ; 13(7): 10619-10658, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33835050

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of genetic loci for type 2 diabetes (T2D) and birth weight (BW); however, a large proportion of the total trait heritability remains unexplained. The previous studies were generally focused on individual traits and largely failed to identify the majority of the variants that play key functional roles in the etiology of the disease. Here, we aim to identify novel functional loci for T2D, BW and the pleiotropic variants shared between them by performing a targeted conditional false discovery rate (cFDR) analysis that integrates two independent GWASs with summary statistics for T2D (n = 26,676 cases and 132,532 controls) and BW (n = 153,781) which entails greater statistical power than individual trait analyses. In this analysis, we considered CpG-SNPs, which are SNPs that may influence DNA methylation status, and are therefore considered to be functionally important. We identified 103 novel CpG-SNPs for T2D, 182 novel CpG-SNPs for BW (cFDR < 0.05), and 52 novel pleiotropic loci for both (conjunction cFDR [ccFDR] < 0.05). Among the identified novel CpG-SNPs, 33 were annotated as methylation quantitative trait loci (meQTLs) in whole blood, and 145 displayed at least some effects on meQTL, metabolic QTL (metaQTL), and/or expression QTL (eQTL). These findings may provide further insights into the shared biological mechanisms and functional genetic determinants that overlap between T2D and BW, thereby providing novel potential targets for treatment/intervention development.


Assuntos
Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Recém-Nascido de Baixo Peso , Polimorfismo de Nucleotídeo Único/genética , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
7.
J Cell Mol Med ; 25(6): 2851-2860, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33599396

RESUMO

Although previous studies have explored the gene expression profiles of human oocytes and granulosa cells by single-cell RNA sequencing (scRNA-seq), the dynamic regulatory network at a single-cell resolution during folliculogenesis remains largely unknown. We identified 10 functional modules by WGCNA, four of which were significantly correlated with primary/antral oocyte and antral/pre-ovulatory granulosa cells. Functional enrichment analysis showed that the brown module, which was correlated with antral oocyte, was enriched in oocyte differentiation, and two core subnetworks identified by MCODE were involved in cell cycle (blue subnetwork) and oogenesis (red subnetwork). The cell-specific network (CSN) analysis demonstrated a distinct gene network structure associated with the antral follicular stage, which was notably different from other developmental stages. To our knowledge, this is the first study to explore gene functions during folliculogenesis at single-cell network level. We uncovered two potential gene subnetworks, which may play an important role in oocyte function beginning at the antral stage, and further established their rewiring process at intra-network/whole transcriptome level. The findings provide crucial insights from a novel network perspective to be further explored in functional mechanistic studies.


Assuntos
Oócitos/citologia , Oócitos/metabolismo , Oogênese , Folículo Ovariano/citologia , Folículo Ovariano/crescimento & desenvolvimento , Algoritmos , Biomarcadores , Comunicação Celular , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Humanos , Oogênese/genética , Mapas de Interação de Proteínas , Proteoma , Proteômica/métodos , Transcriptoma
8.
Theranostics ; 11(5): 2247-2262, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500723

RESUMO

RATIONALE: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of regulators in these processes remain largely elusive. Evidence has suggested that the glutamate/N-methyl-D-aspartic acid receptor (NMDAR) axis contributes to acute lung injury, pulmonary arterial hypertension, and diabetes, but the specific metabolic contribution of the glutamate/NMDAR axis is not clear. Here we provide data at the animal, cellular, and molecular levels to support the role of the glutamate/NMDAR axis as a therapeutic target for metabolic syndrome in obesity. Methods: We examined the glutamate level in the obese mouse induced by a high-fat diet (HFD) for 12 weeks. To assess the role of NMDAR in insulin sensitivity and lipid metabolism, we tested the effects of Memantine (an NMDAR antagonist) and NMDA (an NMDAR agonist) on mice fed with HFD or standard chow diet. The in vitros NMDAR roles were analyzed in hepatocytes and potential mechanisms involved in regulating lipid metabolism were investigated. Results: Glutamate was increased in the serum of HFD-treated mice. The NMDAR blockade by Memantine decreased the susceptibility to insulin resistance and hepatic steatosis in obese mice. NMDA treatment for 6 months induced obesity in mice, characterized by hyperglycemia, hyperlipidemia, insulin resistance, and pathological changes in the liver. We provided in vitro evidence demonstrating that NMDAR activation facilitated metabolic syndrome in obesity through promoting lipid accumulation. NMDAR inhibition attenuated lipid accumulation induced by palmitic acid. Mechanistically, NMDAR activation impaired fatty acid oxidation by reducing PPARα phosphorylation and activity. The PPARα activity reduction induced by NMDAR activation was reversibly mediated by ERK1/2 signaling. Conclusion: These findings revealed that targeting NMDAR might be a promising therapeutic strategy for metabolic syndrome in obesity.


Assuntos
Fígado Gorduroso/prevenção & controle , Intolerância à Glucose/prevenção & controle , Resistência à Insulina , Metabolismo dos Lipídeos , Memantina/farmacologia , Obesidade/complicações , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Dieta Hiperlipídica , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fosforilação , Transdução de Sinais
9.
Cancer Manag Res ; 12: 10163-10172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116871

RESUMO

Background: Clinical tolerance to trastuzumab greatly affects the therapeutic effect in breast cancer (BC). Long-chain non-coding RNA (lncRNA) plays an important role in the development of trastuzumab resistance, in which SNHG7 can promote the epithelial mesenchymal transformation (EMT) of breast cancer cells into, while EMT is related to trastuzumab resistance of breast cancer cells. Objective: To investigate whether lncRNA-SNHG7 can enhance chemotherapy resistance and cell viability of BC cells by regulating miR-186. Methods: SK-BR-3 and SNHG7 of HER2+BC cells were induced to enhance the resistance of BC cells to trastuzumab by regulating miR-186, and to regulate the expression levels of SNHG7 and miR-186. The sensitivity of drug-resistant cells to trastuzumab and the changes of cell proliferation, migration, apoptosis, and EMT were measured and verified by tumorigenesis in vivo. The effects of miR-186 on SNHG7 were investigated through rescue experiments; the regulatory relationship between the expression of SNHG7 and miR-186 was verified by the double luciferase reporter (DLR) and the mechanism of SNHG7 was explored. Results: Down-regulation of SNHG7 or up-regulation of miR-186 could increase the sensitivity of BC cells to trastuzumab, inhibit the proliferation, migration and EMT, and promote apoptosis. Compared with the down-regulation of SNHG7 or miR-186 alone, simultaneous down-regulation of SNHG7 and miR-186 on drug-resistant cells brought notably lower sensitivity to trastuzumab and apoptosis rate, and higher proliferation and apoptosis ability. The DLR showed that miR-186 could specifically inhibit the expression of SNHG7. The results of tumorigenesis in vivo revealed that down-regulation of SNHG7 or up-regulation of miR-186 could improve the therapeutic effect of trastuzumab and reduce the tumor volume, and miR-186 could also antagonize the effect of SNHG7. Conclusion: Down-regulation of SNHG7-targeted miR-186 can reverse trastuzumab resistance of BC cells, inhibit the proliferation, migration, and EMT levels of BC cells, and promote apoptosis.

10.
Mol Genet Genomics ; 295(5): 1173-1185, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32474671

RESUMO

Genome-wide association studies (GWASs) have identified more than 20 genetic loci as risk predictors associated with stroke. However, these studies were generally performed for single-trait and failed to consider the pleiotropic effects of these risk genes among the multiple risk factors for stroke. In this study, we applied a novel metaCCA method followed by gene-based VEGAS2 analysis to identify the risk genes for stroke that may overlap between seven correlated risk factors (including atrial fibrillation, hypertension, coronary artery disease, heart failure, diabetes, body mass index, and total cholesterol level) by integrating seven corresponding GWAS data. We detected 20 potential pleiotropic genes that may be associated with multiple risk factors of stroke. Furthermore, using gene-to-trait pathway analysis, we suggested six potential risk genes (FUT8, GMIP, PLA2G6, PDE3A, SMARCA4, SKAPT) that may affect ischemic or hemorrhage stroke through multiple intermediate factors such as MAPK family. These findings provide novel insight into the genetic determinants contributing to the concurrent development of biological conditions that may influence stroke susceptibility, and also indicate some potential therapeutic targets that can be further studied for the prevention of cerebrovascular disease.


Assuntos
Biologia Computacional/métodos , Redes Reguladoras de Genes , Acidente Vascular Cerebral/genética , Algoritmos , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
Clin Lab ; 66(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32538054

RESUMO

BACKGROUND: The current study aims to investigate the expression and significance of lncRNA PANDAR in the serum of patients with type II diabetes mellitus (T2DM) and diabetic nephropathy (DN). METHODS: The expression of PANDAR in 77 T2DM patients, 60 DN patients, and 60 healthy controls was detected by RT-PCR. Pearson's correlation assay was carried out to analyze the correlation between serum lncRNA PANDAR and clinical indicators. Receiver operator characteristic (ROC) analysis was carried out to analyze the diagnostic value of PANDAR in T2DM and DN patients. RESULTS: The expression of PANDAR in T2DM and DN patients was significantly higher than that in the control group. Moreover, the expression of PANDAR in DN patients with massive proteinuria was significantly higher than that in DN patients with microalbuminuria. Further study showed that the expression of PANDAR was positively correlated with the level of proteinuria (r = 0.690, p < 0.001), and negatively correlated with the glomerular filtration rate (r = -0.780, p < 0.001). In T2DM and DN patients, the area under ROC curve (AUC) of PANDAR as serum marker was 0.861 (95% CI: 0.786 - 0.935, p < 0.001), between DN patients and T2DM patients, while the AUC of PANDAR as a marker in diabetic nephropathy was 0.914 (95% CI: 0.828 - 0.980, p < 0.001) between DN patients and healthy controls. CONCLUSIONS: In summary, the high expression of PANDAR is related to the development of DN in T2DM patients, and it is expected to be a biomarker for predicting the prognosis of DN patients.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , RNA Longo não Codificante/sangue , Biomarcadores/sangue , Correlação de Dados , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/urina , Feminino , Perfilação da Expressão Gênica/métodos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Proteinúria/diagnóstico , Proteinúria/etiologia , Curva ROC
12.
Polymers (Basel) ; 12(3)2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32143509

RESUMO

Adsorption and desorption of proteins on biomaterial surfaces play a critical role in numerous biomedical applications. Spherical diblock polymer brushes (polystyrene with photoiniferter (PSV) as the core) with different block sequence, poly(acrylic acid)-b-poly(N-(2-hydroxyethyl) acrylamide) (PSV@PAA-b-PHEAA) and poly(N-(2-hydroxyethyl) acrylamide)-b-poly(acrylic acid) (PSV@PHEAA-b-PAA) were prepared via surface-initiated photoiniferter-mediated polymerization (SI-PIMP) and confirmed by a series of characterizations including TEM, Fourier transform infrared (FTIR) and elemental analysis. Both diblock polymer brushes show typical pH-dependent properties measured by dynamic light scattering (DLS) and Zeta potential. It is interesting to find out that conformation of PSV@PAA-b-PHEAA uniquely change with pH values, which is due to cooperation of electrostatic repulsion and steric hindrance. High-resolution turbidimetric titration was applied to explore the behavior of bovine serum albumin (BSA) binding to diblock polymer brushes, and the protein adsorption could be tuned by the existence of PHEAA as well as apparent PAA density. These studies laid a theoretical foundation for design of diblock polymer brushes and a possible application in biomedical fields.

13.
Mol Genet Genomics ; 295(3): 607-619, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32162118

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) and coronary artery disease (CAD), respectively. Nevertheless, these studies were generally performed for single-trait/disease and failed to assess the pleiotropic role of the identified variants. To identify novel functional loci and the pleiotropic relationship between CAD and T2D, the targeted cFDR analysis on CpG-SNPs was performed by integrating two independent large and multi-centered GWASs with summary statistics of T2D (26,676 cases and 132,532 controls) and CAD (60,801 cases and 123,504 controls). Applying the cFDR significance threshold of 0.05, we observed a pleiotropic enrichment between T2D and CAD by incorporating pleiotropic effects into a conditional analysis framework. We identified 79 novel CpG-SNPs for T2D, 61 novel CpG-SNPs for CAD, and 18 novel pleiotropic loci for both traits. Among these novel CpG-SNPs, 33 of them were annotated as methylation quantitative trait locus (meQTL) in whole blood, and ten of them showed expression QTL (eQTL), meQTL, and metabolic QTL (metaQTL) effects simultaneously. To the best of our knowledge, we performed the first targeted cFDR analysis on CpG-SNPs, and our findings provided novel insights into the shared biological mechanisms and overlapped genetic heritability between T2D and CAD.


Assuntos
Doença da Artéria Coronariana/genética , Ilhas de CpG , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Redes Reguladoras de Genes , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Mapas de Interação de Proteínas
14.
World J Stem Cells ; 12(1): 87-99, 2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-32110277

RESUMO

BACKGROUND: Breast cancer is a common malignant tumor that seriously threatens women's health. Breast cancer stem cell (CSC)-like cell population may be the main factor for breast cancer metastasis. Therefore, targeted therapy for CSCs has great potential significance. Hypoxia-inducible factor is a transcription factor widely expressed in tumors. Studies have shown that down-regulation of the hypoxia signaling pathway inhibits tumor stem cell self-renewal and increases the sensitivity of stem cells to radiotherapy and chemotherapy mediated by hypoxia-inducible factor-2α (HIF-2α). However, the specific mechanism remains unclear and further research is necessary. AIM: To investigate the effect of HIF-2α down-regulation on stem cell markers, microsphere formation, and apoptosis in breast cancer cell line MDA-MB-231 under hypoxia and its possible mechanism. METHODS: Immunohistochemistry was used to detect the expression of HIF-2α and CD44 in triple-negative breast cancer (TNBC) and non-TNBC tissues. Double-labeling immunofluorescence was applied to detect the co-expression of HIF-2α and CD44 in MDA-MB-231 cells and MCF-7 cells. HIF-2α was silenced by RNA interference, and the expression of CD44 and transfection efficiency were detected by real-time fluorescent quantitative PCR. Further, flow cytometry, TdT-mediated X-dUTP nick end labeling, and mammosphere formation assays were used to evaluate the effect of HIF-2α on CSCs and apoptosis. The possible mechanisms were analyzed by Western blot. RESULTS: The results of immunohistochemistry showed that HIF-2α was highly expressed in both TNBC and non-TNBC, while the expression of CD44 in different molecular types of breast cancer cells was different. In in vitro experiments, it was found that HIF-2α and CD44 were expressed almost in the same cell. Compared with hypoxia + negative-sequence control, HIF-2α small interfering ribonucleic acid transfection can lower the expression of HIF-2α and CD44 mRNA(P < 0.05), increase the percentage of apoptotic cells (P < 0.05), and resulted in a reduction of CD44+/CD24- population (P < 0.05) and mammosphere formation (P < 0.05) in hypoxic MDA-MB-231 cells. Western blot analysis revealed that phosphorylated protein-serine-threonine kinase (p-AKT) and phosphorylated mammalian target of rapamycin (p-mTOR) levels in MDA-MB-231 decreased significantly after HIF-2α silencing (P < 0.05). CONCLUSION: Down-regulation of HIF-2α expression can inhibit the stemness of human breast cancer MDA-MB-231 cells and promote apoptosis, and its mechanism may be related to the CD44/phosphoinosmde-3-kinase/AKT/mTOR signaling pathway.

15.
iScience ; 23(2): 100847, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32058959

RESUMO

Osteoporosis is characterized by low bone mineral density (BMD). The advancement of high-throughput technologies and integrative approaches provided an opportunity for deciphering the mechanisms underlying osteoporosis. Here, we generated genomic, transcriptomic, methylomic, and metabolomic datasets from 119 subjects with high (n = 61) and low (n = 58) BMDs. By adopting sparse multiple discriminative canonical correlation analysis, we identified an optimal multi-omics biomarker panel with 74 differentially expressed genes (DEGs), 75 differentially methylated CpG sites (DMCs), and 23 differential metabolic products (DMPs). By linking genetic data, we identified 199 targeted BMD-associated expression/methylation/metabolite quantitative trait loci (eQTLs/meQTLs/metaQTLs). The reconstructed networks/pathways showed extensive biomarker interactions, and a substantial proportion of these biomarkers were enriched in RANK/RANKL, MAPK/TGF-ß, and WNT/ß-catenin pathways and G-protein-coupled receptor, GTP-binding/GTPase, telomere/mitochondrial activities that are essential for bone metabolism. Five biomarkers (FADS2, ADRA2A, FMN1, RABL2A, SPRY1) revealed causal effects on BMD variation. Our study provided an innovative framework and insights into the pathogenesis of osteoporosis.

16.
Food Sci Technol Int ; 26(4): 291-299, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31779494

RESUMO

This study investigated the total viable counts, sensory and physicochemical qualities (total volatile basic nitrogen, K-value, thiobarbituric acid reactive substances value, water holding capacity and texture parameters), as well as water distribution of fresh hairtail fish during simulated cold chain. The results showed that total volatile basic nitrogen, thiobarbituric acid reactive substances and K-values increased with the increasing time, while sensory scores, water holding capacity, hardness and elasticity decreased. The transverse relaxation time T2 data detected by low-field nuclear magnetic resonance also showed that T22 (trapped water) gradually decreased with the increasing time, while T23 (free water) increased. It was observed that the quality deterioration of the fish fillets developed more quickly when the samples suffered frequent temperature fluctuations than they stored at higher but stable temperatures. The changes of T22 and T23 of both the samples stored at stable and fluctuated temperatures showed good correlations with sensory, total volatile basic nitrogen and thiobarbituric acid reactive substances values (R2 > 0.9, p < 0.05). Therefore, low-field nuclear magnetic resonance technology can be a potential tool to monitor the quality changes of hairtail fish during cold chain logistics.


Assuntos
Temperatura Baixa , Conservação de Alimentos/métodos , Armazenamento de Alimentos/métodos , Perciformes , Refrigeração , Alimentos Marinhos/análise , Água/análise , Animais , Humanos , Espectroscopia de Ressonância Magnética , Nitrogênio/análise , Temperatura
17.
Asian-Australas J Anim Sci ; 33(1): 61-68, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31480204

RESUMO

OBJECTIVE: The present study explored the effects of grape seed procyanidin extract (GSPE) on rumen fermentation, methane production and archaeal communities in vitro. METHODS: A completely randomized experiment was conducted with in vitro incubation in a control group (CON, no GSPE addition; n = 9) and the treatment group (GSPE, 1 mg/bottle GSPE, 2 g/kg dry matter; n = 9). The methane and volatile fatty acid concentrations were determined using gas chromatography. To explore methane inhibition after fermentation and the response of the ruminal microbiota to GSPE, archaeal 16S rRNA genes were sequenced by MiSeq high-throughput sequencing. RESULTS: The results showed that supplementation with GSPE could significantly inhibit gas production and methane production. In addition, GSPE treatment significantly increased the proportion of propionate, while the acetate/propionate ratio was significantly decreased. At the genus level, the relative abundance of Methanomassiliicoccus was significantly increased, while the relative abundance of Methanobrevibacter decreased significantly in the GSPE group. CONCLUSION: In conclusion, GSPE is a plant extract that can reduce methane production by affecting the structures of archaeal communities, which was achieved by a substitution of Methanobrevibacter with Methanomassiliicoccus.

18.
Aging (Albany NY) ; 13(3): 3618-3644, 2020 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-33411684

RESUMO

OBJECTIVES: Clinical and epidemiological findings indicate an association between coronary artery disease (CAD) and low birth weight (BW). However, the mechanisms underlying this relationship are largely unknown. Here, we aimed to identify novel single-nucleotide polymorphisms (SNPs) associated with CAD, BW, and their shared pleiotropic loci, and to detect the potential causal relationship between CAD and BW. METHODS: We first applied a genetic pleiotropic conditional false discovery rate (cFDR) method to two independent genome-wide association studies (GWAS) summary statistics of CAD and BW to estimate the pleiotropic enrichment between them. Then, bi-directional Mendelian randomization (MR) analyses were performed to clarify the causal association between these two traits. RESULTS: By incorporating related traits into a conditional analysis framework, we observed the significant pleiotropic enrichment between CAD and BW. By applying the cFDR level of 0.05, 109 variants were detected for CAD, 203 for BW, and 26 pleiotropic variants for both traits. We identified 11 CAD- and/or BW-associated SNPs that showed more than three of the metabolic quantitative trait loci (metaQTL), protein QTL (pQTL), methylation QTL (meQTL), or expression QTL (eQTL) effects. The pleiotropic SNP rs10774625, located at ATXN2, showed metaQTL, pQTL, meQTL, and eQTL effects simultaneously. Using the bi-directional MR approach, we found a negative association from BW to CAD (odds ratio [OR] = 0.68, 95% confidence interval [CI]: 0.59 to 0.80, p = 1.57× 10-6). CONCLUSION: We identified several pleiotropic loci between CAD and BW by leveraging GWAS results of related phenotypes and identified a potential causal relationship from BW to CAD. Our findings provide novel insights into the shared biological mechanisms and overlapping genetic heritability between CAD and BW.


Assuntos
Peso ao Nascer/genética , Doença da Artéria Coronariana/genética , Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Doença da Artéria Coronariana/epidemiologia , Predisposição Genética para Doença/genética , Humanos
19.
Int J Biol Sci ; 15(12): 2522-2537, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754326

RESUMO

Despite remarkable advancements in our understanding of breast cancer, it remains the leading cause of cancer deaths in women. Distant recurrence and metastasis is the main reason for death due to breast cancer. It is well recognized that the GATA binding protein 3 (GATA3), a transcription factor, is a tumor suppressor in breast cancer. To date, the mechanistic molecular details of GATA3 remain elusive, because, as a transcription factor, it is not a direct executor in physiological and pathological processes. Here, we demonstrate that GATA3 reduces the ATP level in the breast cancer microenvironment and inhibits breast cancer metastasis by up-regulating ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3). The extracellular ATP concentration is significantly higher in tumor tissues than in normal tissues and promotes the migration of cancer cells from the primary site. ENTPD3 hydrolyzes ATP in tumor microenvironment and suppresses breast cancer metastasis. Furthermore, ENTPD3 inhibits epithelial-to-mesenchymal transition, a key program responsible for the development of metastatic disease. These findings provide novel insights into the tumor suppressor activity of GATA3.


Assuntos
Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Neoplasias da Mama/metabolismo , Fator de Transcrição GATA3/fisiologia , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/fisiologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Feminino , Fator de Transcrição GATA3/metabolismo , Humanos , Hidrólise , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica , Prognóstico , Microambiente Tumoral , Regulação para Cima
20.
Theranostics ; 9(12): 3639-3652, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281503

RESUMO

Reprogramming of cellular metabolism is one of the hallmarks for cancer, in which tumor cells rewire their metabolic fluxes to generate sufficient energy and biosynthetic intermediates. Therefore, elucidating the correlation between cellular metabolism and hepatocellular carcinoma (HCC) progression may provide insights into novel approaches to cancer therapy. Methods: We assembled an integrated pathway-level metabolic profiling by mining metabolomic, transcriptomic and proteomic data of three HCC cell lines with increasing metastatic potentials. Immunohistochemical staining was performed in a tissue microarray from 185 HCC clinical specimens. Kaplan-Meier survival and Cox regression analyses were applied to test the association between gene expression and survival outcome. In vitro assays were conducted to investigate the functional role of enolase-phosphatase 1 (ENOPH1) in HCC malignant behaviors. Reversed genetics analysis was performed to determine the function of ENOPH1 in HCC metastasis. An intrahepatic mouse model further confirmed the role of ENOPH1 in metastasis. Results: We have determined that HCC cell metastasis is associated with alterations in metabolite levels and expressions of metabolic enzymes in the cysteine/methionine metabolism pathway, and show that one of metabolic enzymes, enolase-phosphatase 1 (ENOPH1), is persistently upregulated with an increase in metastatic potential. The upregulation of ENOPH1 expression was observed as an independent prognostic factor for HCC patients. ENOPH1 overexpression promoted cell migration and invasion, whereas ENOPH1 downregulation inhibited cell migration and invasion. Furthermore, an enhanced phosphorylation of AKT with ENOPH1 upregulation was observed. ENOPH1-mediated malignant capacity in HCC cells can be rescued by an AKT inhibitor. Conclusion: Taken together, our findings illustrate that ENOPH1 promotes HCC progression and could serve as a novel biomarker and therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/fisiopatologia , Neoplasias Hepáticas/fisiopatologia , Neoplasias Hepáticas/secundário , Metabolômica , Complexos Multienzimáticos/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Camundongos , Complexos Multienzimáticos/análise , Proteômica , Análise de Sobrevida
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