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1.
Stem Cell Res Ther ; 11(1): 125, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32192530

RESUMO

OBJECTIVES: Mesenchymal stem cells (MSCs) have been intensively investigated as to their therapeutic potentials. However, the full chemical-defined medium supporting the isolation and expansion of human MSCs has not been developed yet. MATERIALS AND METHODS: Here, we developed the full chemical-defined medium, NBVbe medium, via RNA sequencing, bioinformatic analysis, and growth factor screening. RESULTS: The NBVbe medium contains N2B27 medium with the BSA (bovine serum albumin) replaced by the recombinant human albumin, bFGF (basic fibroblast growth factor), vitamin C, and EGF (epidermal growth factor). The NBVbe medium could support the isolation and expansion of human MSCs from the umbilical cords. CONCLUSIONS: The full chemical-defined medium supporting the isolation and expansion of human MSCs has been developed. This would be helpful for further optimization of the MSC medium, their clinical applications, and molecular characterization.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32153511

RESUMO

Purpose: To increase knowledge for the early differential diagnosis and accurate therapeutic strategies for pediatric patients with sellar or suprasellar region (SSR) lesions who initially present with central diabetes insipidus (CDI). Methods: This is a retrospective review of 55 pediatric patients (≤14 years old) with identified lesions in the SSR who initially presented with CDI at a large pituitary center between 2012 and 2018. The following data were summarized: demographic, clinical, endocrine, and neuroimaging data, intraoperative findings, histopathological findings, treatments, and prognosis. Results: In our group, the etiologies of the SSR lesions included germ cell tumors (GCTs, 74.5%), Langerhans cell histiocytosis (LCH, 18.2%), and craniopharyngioma (CP, 7.3%). Almost all patients (50/55, 90.9%) showed anterior pituitary dysfunction [multiple axes dysfunction (38), and isolated axis dysfunction (14)], while the GH/IGF-I axis was the most affected. Most GCT patients presented with various clinical manifestations besides CDI and had elevated ß-HCG, whereas LCH and CP patients mostly presented few non-specific symptoms besides CDI and most had normal level tumor markers. Sellar MRI demonstrated that posterior pituitary bright spot disappearance occurred in all patients, and pituitary stalk thickening was observed in 96.7% of patients. Treatment varied due to the different etiologies of the SSR lesions. After follow-up for 35.4 ± 20.2 months, the proportions of patients who needed AVP (arginine vasopressin) for GCT, LCH, and CP were 86.5, 100, and 75%, respectively, and the proportions of patients who needed HRT were 89.2, 50, and 75%, respectively. Conclusion: For pediatric SSR lesions that first manifest as CDI, we should comprehensively consider clinical characteristics and imaging features to aid in their early differential diagnosis. Tumor markers and surgical histopathology are also great complements for the differential diagnosis. Additionally, various treatment strategies should be adopted according to different causes to improve the child's prognosis and quality of life.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31950846

RESUMO

Aims: Obesity-induced excessive visceral fat (VF) accumulation is associated with insulin resistance (IR), systemic oxidative stress, and chronic inflammation. As toll-like receptor 4 (TLR4) plays an important role in innate immunity, we herein investigate the effect of TLR4 knockout (T4KO) in a high-fat high-sucrose diet (HFD)-induced obesity mouse model. Results: C57BL6 wild-type (WT) and T4KO mice were fed with either control diet (CD) or HFD for 12 months, rendering four experimental groups: WT+CD, WT+HFD, T4KO+CD, and T4KO+HFD. Compared with WT+CD, WT+HFD demonstrated significant increase in VF accumulation, oxidative damage, M1/M2 macrophage ratio, chronic inflammation, and development of IR. Compared with WT+HFD, T4KO+HFD presented increased BW and body fat with higher subcutaneous fat (SF)/VF ratio, but lower body temperature, as well as decreased oxidative damage, M1/M2 macrophage ratio, chronic inflammation, and IR. Unlike WT+HFD, T4KO+HFD exhibited an increase in mitochondrial electron transport chain activity but a decrease of uncoupling protein 2 (UCP2) level. While T4KO hindered HFD-induced increasing mitochondrial oxygen consumption rate, a shift toward a higher extracellular acidification rate in VF was observed. Notably, T4KO inhibits HFD-induced mitochondrial translocation of nuclear factor of activated T cells 2 (NFATC2), which contributed to mitochondrial metabolic reprogramming. Both fat distribution shifting from VF to SF and mitochondrial metabolic reprogramming may alleviate systemic oxidative stress and chronic inflammation. Innovation and Conclusion: Abrogation of TLR4 contributes to reduction of oxidative stress through metabolic reprogramming of mitochondria in VF, mitigating obesity-induced IR. The study provides critical insight into associating innate immunity-mitochondria interplay with prevention of diabetes.

5.
Sleep Med ; 67: 164-170, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31935618

RESUMO

OBJECTIVE: To elucidate the sleep quality characteristics and factors related to either good or poor sleep quality in acromegaly patients before surgery and to explore sleep quality changes after transsphenoidal surgery and the factors related to these changes. METHODS: We prospectively enrolled 39 acromegaly patients and 78 patients with nonfunctioning pituitary adenomas. Scales for anxiety, depression, disease stigma and nasal condition were evaluated. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was administered before surgery as well as one month and three months after surgery. RESULTS: A higher percentage of acromegaly patients had poor sleep quality compared to controls (35.9% vs. 5.1%, p < 0.001). In addition, acromegaly patients experienced worse subjective sleep quality, extended sleep latency, increased sleep disturbance and decreased daytime functioning. Higher scores for anxiety, disease stigma and sinonasal outcomes were correlated with worse sleep quality in acromegaly patients. At one month after transsphenoidal surgery, we found worse subjective sleep quality, extended sleep latency, shortened sleep duration, impaired sleep efficiency and increased sleep disturbance in acromegaly patients. At three months postoperatively, most impaired PSQI domains in acromegaly patients recovered to preoperative levels. The use of soluble gauze was related to decreased sleep quality at one month after surgery and severe anxiety and depression were related to improved sleep quality at three months after surgery. CONCLUSIONS: Sleep quality was reduced in acromegaly patients. Moreover, sleep quality initially worsened after surgery but later recovered. Emotional problems and the use of soluble gauze were related factors. CLINICAL TRIAL REGISTRATION: None.

6.
J Vasc Surg ; 71(1): 141-148, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31327613

RESUMO

OBJECTIVE: The purpose of this study was to examine the efficacy and safety of catheter-directed thrombolysis (CDT) for first-line treatment of popliteal and infrapopliteal acute limb ischemia. METHODS: A total of 28 consecutive patients (30 limbs) who underwent CDT for treatment of popliteal and infrapopliteal acute limb ischemia of thromboembolic origin between March 2012 and December 2017 were enrolled in this study. Per the Society for Vascular Surgery, limbs were classified into three runoff score groups: <5, good; 5 to 10, compromised; and >10, poor. The primary end points were primary patency and limb salvage assessed by Kaplan-Meier survival analysis. Secondary end points were technical success and clinical success. The Society for Vascular Surgery-recommended scale for gauging changes in clinical status was used to assess clinical success. Safety of the procedure was evaluated on the basis of periprocedural complications according to the Society of Interventional Radiology classification system. RESULTS: Technical success was achieved in 25 (83.33%) treated limbs. Improved clinical status (grade +3/+2) was achieved in 93.33% of limbs. Primary patency and limb salvage for the entire cohort were 76.67% and 90% at 6 months and 60.0% and 76.67% at 12 months, respectively. The patency rate at 6 months and 12 months was 91.67% and 83.33% for the good runoff group, 80% and 60% for the compromised runoff group, and 50% and 25% for the poor runoff group, respectively. The patency rate of the good runoff group was significantly higher compared with that of the poor runoff group (P = .004). Major amputation rate and mortality rate were 16.67% and 7.14%, respectively, at 12 months. The reintervention rate was 3.57% at 6 months and 21.42% at 12 months. CONCLUSIONS: CDT is safe and effective for revascularization of smaller vessel acute arterial thromboembolism as a primary therapy. However, more studies with a larger sample are warranted.

7.
J Am Soc Nephrol ; 31(1): 54-65, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31604808

RESUMO

BACKGROUND: Although mesenchymal stem cells (MSCs) might offer a promising strategy for treating SLE, their immunoregulatory plasticity makes their therapeutic effects unpredictable. Whether overexpressing IL-37, an IL-1 family member with immunosuppressive activity, might enhance the therapeutic effects of these cells for SLE is unknown. METHODS: We genetically modified MSCs to overexpress IL-37 and assessed their effects on immune suppression in vitro. We also evaluated the effects of such cells versus effects of various controls after transplanting them into MRL/lpr mice (model of SLE). RESULTS: Stem cell characteristics did not appear altered in MSCs overexpressing IL-37. These cells had enhanced immunosuppression in vitro in terms of inhibiting splenocyte proliferation, reducing proinflammatory factors (IL-1ß, TNF-α, IL-17, and IL-6), and suppressing autoantibodies (anti-dsDNA and anti-ANA). Compared with animals receiving control MSCs or IL-37 treatment alone, MRL/lpr mice transplanted with IL-37-overexpressing cells displayed improved survival and reduced signs of SLE (indicated by urine protein levels, spleen weight, and renal pathologic scores); they also had significantly lower expression of proinflammatory factors, lower total antibody levels in serum and urine, lower autoantibody production, and showed reduced T cell numbers in the serum and kidney. Expression of IL-37 by MSCs can maintain higher serum levels of IL-37, and MSCs had prolonged survival after transplantation, perhaps through IL-37 suppressing the inflammatory microenvironment. CONCLUSIONS: Mutually reinforcing interaction between MSCs and IL-37 appears to underlie their additive therapeutic effects. Genetic modification to overexpress IL-37 might offer a way to enhance the stability and effectiveness of MSCs in treating SLE.

8.
Aging (Albany NY) ; 11(24): 12246-12269, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31844032

RESUMO

Glioblastoma (GBM) is the most common brain tumor with significant morbidity and mortality. Autophagy plays a vital role in GBM development and progression. We aimed to establish an autophagy-related multigene expression signature for individualized prognosis prediction in patients with GBM. Differentially expressed autophagy-related genes (DE-ATGs) in GBM and normal samples were screened using TCGA. Univariate and multivariate Cox regression analyses were performed on DE-ATGs to identify the optimal prognosis-related genes. Consequently, NRG1 (HR=1.142, P=0.008), ITGA3 (HR=1.149, P=0.043), and MAP1LC3A (HR=1.308, P=0.014) were selected to establish the prognostic risk score model and validated in the CGGA validation cohort. GSEA revealed that these genes were mainly enriched in cancer- and autophagy-related KEGG pathways. Kaplan-Meier survival analysis demonstrated that patients with high risk scores had significantly poorer overall survival (OS, log-rank P= 6.955×10-5). The autophagy signature was identified as an independent prognostic factor. Finally, a prognostic nomogram including the autophagy signature, age, pharmacotherapy, radiotherapy, and IDH mutation status was constructed, and TCGA/CGGA-based calibration plots indicated its excellent predictive performance. The autophagy-related three-gene risk score model could be a prognostic biomarker and suggest therapeutic targets for GBM. The prognostic nomogram could assist individualized survival prediction and improve treatment strategies.

9.
Int J Endocrinol ; 2019: 2102616, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781204

RESUMO

Purpose: This study analysed changes in bone mineral density (BMD) at different sites in patients with acromegaly and postoperative BMD changes and explored risk factors associated with BMD. Methods: Clinical data of 39 patients with growth hormone- (GH-) secreting pituitary adenomas and 29 patients with nonfunctioning pituitary adenomas who were newly diagnosed in neurosurgery from January 2016 to December 2018 were retrospectively analysed, including measurements of preoperative and postoperative BMD, serum GH glucose inhibition, random GH and IGF-1, and other anterior pituitary hormones. Results: The average patient age and disease duration were 43.74 (33.41-54.07) years and 72.15 (22.82-121.48) months, respectively. Compared with patients with nonfunctioning adenomas, patients with GH-secreting pituitary adenomas had significantly higher BMDs at L1, L2, femoral neck, Ward triangle, trochanter, femoral shaft, and total hip sites (p < 0.05). The BMD Z score at L1 and femoral neck sites significantly increased (p < 0.05). Thirteen patients underwent re-examination of BMD 1 year postsurgery, and the BMD Z score was reduced to normal levels at L1, L2, L3, L4, L1-L4, and L2-L4 compared with preoperative levels (p < 0.05). Postoperative BMD Z scores in the femoral neck and total hip were significantly increased (p < 0.05). Disease duration was negatively correlated with the lumbar-spine BMD Z score. IGF-1 burden was negatively correlated with the BMD Z score at L1 and L1-L4. Multiple regression analysis showed that IGF-1 burden was a risk factor for a BMD Z score decrease at L1 and L1-L4. Conclusion: BMD in patients with GH-secreting pituitary adenomas (compared with nonfunctional adenomas) increased at L1, L2, femoral neck, Ward triangle, trochanter, femoral shaft, and total hip sites. Lumbar-spine BMD Z score recovered to normal levels postsurgically when GH and IGF-1 levels were controlled. BMD Z score was negatively correlated with disease duration and IGF-1 burden in patients with GH-secreting pituitary adenomas, and IGF-1 burden was an independent risk factor for reduced lumbar-spine BMD Z score.

10.
Int J Mol Sci ; 20(22)2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31752076

RESUMO

Ischemic damage aggravation of femoral head collapse is a prominent pathologic feature of osteonecrosis of the femoral head (ONFH). In this regard, S100 calcium binding protein A9 (S100A9) is known to deteriorate joint integrity, however, little is understood about which role S100A9 may play in ONFH. In this study, a proteomics analysis has revealed a decrease in the serum S100A9 level in patients with ONFH upon hyperbaric oxygen therapy. Serum S100A9 levels, along with serum vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), and tartrate-resistant acid phosphatase 5b levels were increased in patients with ONFH, whereas serum osteocalcin levels were decreased as compared to healthy controls. Serum S100A9 levels were increased with the Ficat and Arlet stages of ONFH and correlated with the patients with a history of being on glucocorticoid medication and alcohol consumption. Osteonecrotic tissue showed hypovasculature histopathology together with weak immunostaining for vessel marker CD31 and von Willrbrand factor (vWF) as compared to femoral head fracture specimens. Thrombosed vessels, fibrotic tissue, osteocytes, and inflammatory cells displayed strong S100A9 immunoreactivity in osteonecrotic lesion. In vitro, ONFH serum and S100A9 inhibited the tube formation of vessel endothelial cells and vessel outgrowth of rat aortic rings, whereas the antibody blockade of S100A9 improved angiogenic activities. Taken together, increased S100A9 levels are relevant to the development of ONFH. S100A9 appears to provoke avascular damage, ultimately accelerating femoral head deterioration through reducing angiogenesis. This study provides insight into the molecular mechanism underlying the development of ONFH. Here, analysis also highlights that serum S100A9 is a sensitive biochemical indicator of ONFH.

11.
Int J Mol Sci ; 20(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731750

RESUMO

Rotator cuff lesion with shoulder stiffness is a major cause of shoulder pain and motionlessness. Subacromial bursa fibrosis is a prominent pathological feature of the shoulder disorder. MicroRNA-29a (miR-29a) regulates fibrosis in various tissues; however, the miR-29a action to subacromial bursa fibrosis remains elusive. Here, we reveal that subacromial synovium in patients with rotator cuff tear with shoulder stiffness showed severe fibrosis, hypertrophy, and hyperangiogenesis histopathology along with significant increases in fibrotic matrices collagen (COL) 1A1, 3A1, and 4A1 and inflammatory cytokines, whereas miR-29a expression was downregulated. Supraspinatus and infraspinatus tenotomy-injured shoulders in transgenic mice overexpressing miR-29a showed mild swelling, vascularization, fibrosis, and regular gait profiles as compared to severe rotator cuff damage in wild-type mice. Treatment with miR-29a precursor compromised COL3A1 production and hypervascularization in injured shoulders. In vitro, gain of miR-29a function attenuated COL3A1 expression through binding to the 3'-untranslated region (3'-UTR) of COL3A1 in inflamed tenocytes, whereas silencing miR-29a increased the matrix expression. Taken together, miR-29a loss is correlated with subacromial bursa inflammation and fibrosis in rotator cuff tear with shoulder stiffness. miR-29a repressed subacromial bursa fibrosis through directly targeting COL3A1 mRNA, improving rotator cuff integrity and shoulder function. Collective analysis offers a new insight into the molecular mechanism underlying rotator cuff tear with shoulder stiffness. This study also highlights the remedial potential of miR-29a precursor for alleviating the shoulder disorder.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31736874

RESUMO

Purpose: Abnormal glucose metabolism is one of the most frequent acromegaly complications. Improvement of glucose metabolism can be observed only in half of acromegaly patients after surgery. We aimed to investigate the risk factors for determining abnormal glucose metabolism before surgery in patients with acromegaly, and to explore the predictors of improved preoperative glucose intolerance after surgery. Methods: We retrospectively reviewed 64 patients who received transsphenoidal surgery for acromegaly. Growth hormone (GH), insulin-like growth factor-1 (IGF-1) and glucose metabolism were assessed before, immediately after, and 3 months after surgery. Glucose metabolic parameters included glycosylated hemoglobin (HbA1c), plasma glucose (PG), C-peptide (CP), insulin (INS), and the indices of ß-cell function, insulin sensitivity, and insulin resistance (IR). Results: Preoperatively, 18 patients (28.1%) had diabetes (DM), 34 (53.1%) had prediabetes (PreDM), and 12 (18.8%) had normal glucose tolerance (NGT). All the indices of pancreatic ß-cell function were significantly lower in patients with DM than those with PreDM and NGT (all P < 0.005). IGF-1 was significantly positively correlated with insulin sensitivity and IR (P < 0.05), while GH was not. Postoperatively, glucose tolerance was improved in 71.2% of patients (37/52) with preoperative glucose intolerance. Insulin sensitivity was increased, while ß-cell function and IR were decreased in most patients after surgery, regardless of whether their acromegaly achieved remission. A multivariate logistic regression analysis revealed that preoperative fasting C-peptide (FCP, OR = 2.639, P = 0.022), disposition index (DI, OR = 1.397, P = 0.043) and Predictor-2 (OR = 0.578, P = 0.035) were determined to be the predictors for improved glucose tolerance status after surgery. Afterwards, through Receiver operating characteristic (ROC) analyses, FCP >2.445 ng/ml was the best independent predictor, with an 86.6% PPV (positive predictive value) and a 74.5% NPV (negative predictive value). Conclusions: Preoperative high FCP is a promising postsurgical predictor of improved glucose tolerance in patients with acromegaly. Oral glucose tolerance testing (OGTT) and HbA1c should be monitored regularly after surgery, and diabetes management should be adjusted based on the patient's latest glucose tolerance status.

14.
Cell Death Dis ; 10(10): 741, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582745

RESUMO

Following publication of this article, the authors realized that there were 1) errors made in the author affiliations and that 2) a typo in a grant number needed to be corrected. The corrected author affiliations and grant numbers are listed below. We apologize for the inconvenience.

15.
Yonsei Med J ; 60(11): 1045-1053, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31637886

RESUMO

PURPOSE: To explore the molecular mechanism of the upregulation of multidrug resistance-associated protein 4 (MRP4) in cholestasis. MATERIALS AND METHODS: The mRNA and protein levels of MRP4 in liver samples from cholestatic patients were determined by quantitative real-time PCR and Western blot. In human hepatoma HepG2 cells, electrophoretic mobility shift assay (EMSA) was used to determine the affinity of nuclear factor-E2-related factor (Nrf2) binding to MRP4 promoter. Dual-luciferase reporter assay was used to detect the binding of tumor necrosis factor α (TNFα) to the promotor of E2F1. The bile duct ligation mouse models were established using male C57BL/6 mice. RESULTS: The mRNA and protein levels of MRP4 were significantly increased in cholestatic patients. TNFα treatment induced the expression of MRP4 and Nrf2 and enhanced cell nuclear extract binding activity to MRP4 promoter, as demonstrated by EMSA. Nrf2 knockdown reduced MRP4 mRNA levels in both HepG2 and Hep-3B cells. In addition, TNFα increased Rb phosphorylation and expression of MRP4 and Nrf2 and activated E2F1 and phosphorylated p38 in HepG2 and Hep-3B cells. These effects were markedly inhibited by pretreatment with E2F1 siRNA. Dual-luciferase reporter assay validated that TNFα induces the transcription of E2F1. Furthermore, the expression of MRP4, Nrf2, E2F1, and p-p38 proteins was improved with treatment of TNFα in a mouse model of cholestasis. E2F1 siRNA lentivirus or SB 203580 (p38 inhibitor) inhibited these positive effects. CONCLUSION: Our findings indicated that TNFα induces hepatic MRP4 expression through activation of the p38-E2F1-Nrf2 signaling pathway in human obstructive cholestasis.


Assuntos
Colestase/metabolismo , Resistência a Múltiplos Medicamentos , Fator de Transcrição E2F1/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Animais , Colestase/sangue , Colestase/genética , Colestase/patologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Células Hep G2 , Humanos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Biológicos , Regiões Promotoras Genéticas , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/sangue
16.
Int J Mol Sci ; 20(20)2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31627291

RESUMO

Glucocorticoid excess escalates osteoclastic resorption, accelerating bone mass loss and microarchitecture damage, which ramps up osteoporosis development. MicroRNA-29a (miR-29a) regulates osteoblast and chondrocyte function; however, the action of miR-29a to osteoclastic activity in the glucocorticoid-induced osteoporotic bone remains elusive. In this study, we showed that transgenic mice overexpressing an miR-29a precursor driven by phosphoglycerate kinase exhibited a minor response to glucocorticoid-mediated bone mineral density loss, cortical bone porosity and overproduction of serum resorption markers C-teleopeptide of type I collagen and tartrate-resistant acid phosphatase 5b levels. miR-29a overexpression compromised trabecular bone erosion and excessive osteoclast number histopathology in glucocorticoid-treated skeletal tissue. Ex vivo, the glucocorticoid-provoked osteoblast formation and osteoclastogenic markers (NFATc1, MMP9, V-ATPase, carbonic anhydrase II and cathepsin K) along with F-actin ring development and pit formation of primary bone-marrow macrophages were downregulated in miR-29a transgenic mice. Mechanistically, tumor necrosis factor superfamily member 13b (TNFSF13b) participated in the glucocorticoid-induced osteoclast formation. miR-29a decreased the suppressor of cytokine signaling 2 (SOCS2) enrichment in the TNFSF13b promoter and downregulated the cytokine production. In vitro, forced miR-29a expression and SOCS2 knockdown attenuated the glucocorticoid-induced TNFSF13b expression in osteoblasts. miR-29a wards off glucocorticoid-mediated excessive bone resorption by repressing the TNFSF13b modulation of osteoclastic activity. This study sheds new light onto the immune-regulatory actions of miR-29a protection against glucocorticoid-mediated osteoporosis.

17.
J Orthop Surg Res ; 14(1): 328, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639015

RESUMO

BACKGROUND: Kashin-Beck disease (KBD) is an endemic osteoarthropathy, and its pathogenesis is still not entirely clear. Pathologically, many KBD changes are similar to those of osteoarthritis (OA). Therefore, this study aimed to identify changes in the levels of potential urinary biomarkers for OA, including C-telopeptide of type II collagen (uCTX-II), type II collagen cleavage neoepitope (uC2C), pyridinoline (uPYD), and uHelix-II, among adults with KBD. METHODS: Urinary samples of 83 external control (EC) subjects, 91 KBD patients, and 86 internal control (IC) subjects were tested by ELISA after the subjects completed a questionnaire and X-ray examination. RESULTS: The medians of the four markers in the KBD group were higher than those in the EC group and those in the IC group. The medians in the grade II KBD group were higher than those in the grade I group but were not statistically significant (P = 0.301, P = 0.408, P = 0.204, and P = 0.898 for uCTX-II, uC2C, uPYD, and uHelix-II, respectively). The area under the curve (AUC) of uCTX-II (0.775) was higher than that of the others (0.672, 0.639, and 0.628 for uC2C, uPYD, and uHelix-II, respectively). CONCLUSION: The levels of uCTX-II, uC2C, uPYD, and uHelix-II were elevated in adults with KBD and showed an increasing trend as the severity of KBD increased. The prediction accuracy of uCTX-II was more useful than that of the others for assisting in the diagnosis of KBD.

18.
AJR Am J Roentgenol ; 213(6): 1213-1220, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31557054

RESUMO

OBJECTIVE. The purpose of this study was to investigate the utility of radiomics for predicting the malignancy of pulmonary nodules (PNs) of different sizes using unenhanced, thin-section CT images. MATERIALS AND METHODS. Patients with a single PN (n = 373) who underwent a preoperative chest CT were recruited retrospectively at Beijing Friendship Hospital from March 2015 to March 2018. Of the 373 PNs studied, 192 were benign and 181 were malignant. The lesions were classified into three groups (T1a, T1b, or T1c according to the 8th edition of the TNM staging system for lung cancer) on the basis of lesion diameters: T1a (diameter, 0-1 cm), T1b (1 cm < diameter ≤ 2 cm) and T1c (2 cm < diameter ≤ 3 cm). A total of 1160 radiomic features were extracted from PN segmentation on unenhanced CT images. We developed three radiomic models to predict PN malignancy in each group on the basis of the extracted radiomic features. Fivefold cross-validation was used to estimate AUC, accuracy, sensitivity, and specificity for indicating the performance of prediction models. RESULTS. The AUC, accuracy, sensitivity, and specificity for predicting PN malignancy in each group were 0.84, 0.77, 0.89, and 0.74 with the T1a model; 0.78, 0.73, 0.74, and 0.71 with the T1b model, and 0.79, 0.76, 0.77, and 0.73 with the T1c model, respectively. The most contributive radiomic features for predicting PN malignancy for groups T1a, T1b, and T1c were LoG_X_Uniformity, Intensity_Minimum, and Shape_SI9, respectively. CONCLUSION. Radiomic features based on unenhanced CT images can be used to predict the malignancy of pulmonary nodules. The radiomic T1a model showed superior prediction performance to the T1b and T1c models, and the best performance in terms of AUC and sensitivity was found for predicting the malignancy of T1a PN.

19.
Cell Death Dis ; 10(10): 705, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31543513

RESUMO

Osteoporosis deteriorates bone mass and biomechanical strength, becoming a life-threatening cause to the elderly. MicroRNA is known to regulate tissue remodeling; however, its role in the development of osteoporosis remains elusive. In this study, we uncovered that silencing miR-29a expression decreased mineralized matrix production in osteogenic cells, whereas osteoclast differentiation and pit formation were upregulated in bone marrow macrophages as co-incubated with the osteogenic cells in transwell plates. In vivo, decreased miR-29a expression occurred in ovariectomy-mediated osteoporotic skeletons. Mice overexpressing miR-29a in osteoblasts driven by osteocalcin promoter (miR-29aTg/OCN) displayed higher bone mineral density, trabecular volume and mineral acquisition than wild-type mice. The estrogen deficiency-induced loss of bone mass, trabecular morphometry, mechanical properties, mineral accretion and osteogenesis of bone marrow mesenchymal cells were compromised in miR-29aTg/OCN mice. miR-29a overexpression also attenuated the estrogen loss-mediated excessive osteoclast surface histopathology, osteoclast formation of bone marrow macrophages, receptor activator nuclear factor-κ ligand (RANKL) and C-X-C motif chemokine ligand 12 (CXCL12) expression. Treatment with miR-29a precursor improved the ovariectomy-mediated skeletal deterioration and biomechanical property loss. Mechanistically, miR-29a inhibited RANKL secretion in osteoblasts through binding to 3'-UTR of RANKL. It also suppressed the histone acetyltransferase PCAF-mediated acetylation of lysine 27 in histone 3 (H3K27ac) and decreased the H3K27ac enrichment in CXCL12 promoters. Taken together, miR-29a signaling in osteogenic cells protects bone tissue from osteoporosis through repressing osteoclast regulators RANKL and CXCL12 to reduce osteoclastogenic differentiation. Arrays of analyses shed new light on the miR-29a regulation of crosstalk between osteogenic and osteoclastogenic cells. We also highlight that increasing miR-29a function in osteoblasts is beneficial for bone anabolism to fend off estrogen deficiency-induced excessive osteoclastic resorption and osteoporosis.

20.
Cell Death Dis ; 10(8): 600, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395855

RESUMO

Oxaliplatin-based chemotherapy is recommended as the first-line therapeutic regimen for metastatic colorectal cancer. However, long-term and repeated oxaliplatin therapy leads to drug resistance and severe adverse events, which hamper its clinical application. Thus, chemosensitizers are urgently required for overcoming oxaliplatin resistance and toxicity. Here, the anticancer effects of oxaliplatin combined with piperlongumine (PL), a molecule promoting reactive oxygen species (ROS) generation, in colorectal cancer, were assessed. We demonstrated that oxaliplatin elevated cellular ROS amounts and showed synergistic anticancer effects with PL in colorectal cancer cells. These anticancer effects were mediated by mitochondrial dysfunction and endoplasmic reticulum (ER) stress apoptotic-associated networks. Meanwhile, blockage of ROS production prevented apoptosis and fully reversed mitochondrial dysfunction and ER stress associated with the oxaliplatin/PL combination. Moreover, xenograft assays in mouse models highly corroborated in vitro data. In conclusion, this study provides a novel combination therapy for colorectal cancer, and reveals that manipulating ROS production might constitute an effective tool for developing novel treatments in colorectal cancer.

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