ALBERT

Description: ABSTRACT Osteoblasts are essential for maintaining skeletal architecture and modulating bone microenvironment homeostasis. From numerous associated investigations, the BMP-2 pathway has been well-defined as a vital positive modulator of bone homeostasis. Gremlin2 (Grem2) is a bone morphogenetic protein (BMP) antagonists. However, the effect of Grem2 on the BMP-2-induced osteogenesis of human bone marrow-derived mesenchymal stem cells (hBMSCs) remains ambiguous. This study aimed to analyze the procedure in vitro and in vivo. The differentiation of hBMSCs was assessed by determining the expression levels of several osteoblastic genes, as well as the enzymatic activity and calcification of alkaline phosphatase. We found that Grem2 expression was upregulated by BMP-2 within the range of 0–1 µg/mL, and significant increases were evident at 48, 72, and 96 h after BMP-2 treatment. Si-Grem2 increased the BMP-2-induced osteogenic differentiation of hBMSCs, whereas over-expression of Grem2 had the opposite trend. The result was confirmed using a defective femur model. We also discovered that the BMP-2/Smad/Runx2 pathway played an important role in the process. This study showed that si-Grem2 increased the BMP-2-induced osteogenic differentiation of hBMSCs via the BMP-2/Smad/Runx2 pathway. This article is protected by copyright. All rights reserved

Description: ABSTRACT It was found that the expression level of miR-147a was significantly increased and the pathway of PI3K/AKT was dramatically inhibited after radiation. In view of the relationship between miRNA and target genes, we put forward the question, what is the relationship between PI3K /AKT and miR-147a? In order to find the answer to the question, we used bioinformatics techniques to analyze the relationship between miR-147 (a or b) and PI3K/AKT signaling pathway. miR-147a overexpression plasmid and PDPK1 3'UTR luciferase reporter gene plasmid were constructed. Dual luciferase reporter gene system validation experiments were carried out on miR-147a and PDPK1 relationship. The verification experiments were also carried out. Bioinformatics analysis showed that there is a miR-147a binding site in the non-coding region (3'UTR) of PDPK1. In the experimental groups transfected with wild type PDPK1 gene of 3'UTR plasmid, the luciferase activity decreased (or increased) significantly in miR-147a(or inhibitor) group compared with miR-NC(or anti-miR-NC); There was no significant difference between the miR-147a group(or inhibitor) and the miR-NC group(or anti-miR-NC) in the transfection of PDPK1-3'UTR-Mut gene vector. PDPK1 was a target gene for direct regulation of miR-147a downstream. Verifying test results showed that the expression of PDPK1 mRNA and protein was reduced after overexpression of miR-147a, which was up-regulated after silencing miR-147a in TC and V79 cells. These results suggest that miR-147a could be involved in the regulation of PDPK1 transcription by binding to the target site in PDPK1 mRNA 3'UTR, and then regulated AKT. This article is protected by copyright. All rights reserved

Description: ABSTRACT This study explored Cisplatin resistance effect of microRNA-21 (miR-21) antisense oligonucleotide (AS-ODN) in human melanoma A375 cell. AS-ODN was transfected in melanoma A375 cells and Cisplatin-resistant cell line A375/CDDP, and divided into the AS-ODN, nonsense oligonucleotide (NS-ODN) and normal groups. Cell ultrastructure changes were observed through transmission electron microscope. MiR-21 AS-ODN could be tested cell growth effect in different time periods by trypan blue exclusion. MiR-21 mRNA expression change was detected by quantitative fluorescence PCR. Cell apoptosis, cycle distribution and miR-21 AS-ODN effect on proliferation and Cisplatin sensitivity were tested by flow cytometry, MTT assay, TUNEL, and Clonogenic assay. Cell apoptosis was observed after transfection 24 h with the AS-ODN group, while the NS-ODN and normal group cells had no apoptotic symptoms; Compared with the normal group, the AS-ODN group began to show obvious cell growth inhibition effect after transfection 24 h lasting 72 h (all P  〈 0.05), but the NS-ODN group had no significant difference ( P  〉 0.05). miR-21 mRNA expression in the AS-ODN group was obviously decreased with rising apoptosis rate (all P  〈 0.05) and there was no significant difference in the NS-ODN group ( P  〉 0.05). MiR-21 AS-ODN could remarkably increase A375 cell and A375/CDDP cell sensitivity to Cisplatin ( P  〈 0.05), while A375 cell sensitivity to Cisplatin between the NS-ODN group and the normal group had no difference. MiR-21 AS-ODN decreased IC 50 and increased Cisplatin sensitivity for A375 cells and A375/CDDP cells, which would be a new target of melanoma treatment. This article is protected by copyright. All rights reserved

Description: ABSTRACT This network meta-analysis (NMA) was conducted to compare the predictive value of 14 SNPs in 8 DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). These included ERCC1 (rs11615, rs3212986, rs3212948), XRCC1 (rs25487, rs25489, rs1799782), XPD (rs13181, rs1799793), XPG (rs1047768, rs17655), XPA (rs1800975), XRCC3 (rs861539), APE1 (rs3136820) and RRM1 (rs1042858). The PubMed and Cochrane library databases were reviewed from their inception to February 2017 and studies which met our inclusion criteria were included in our investigation. This network meta-analysis combines direct and indirect evidence to assess the predictive value of 14 SNPs in 8 DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC. We evaluated the predictive value through the use of the odd ratios (OR) and drawing surface under the cumulative ranking curves (SUCRA). A total of 26 eligible cohort studies were enrolled in this NMA. The pairwise meta-analysis indicated that in terms of overall response ratio (ORR), ERCC1 (rs11615), XRCC1 (rs25487, rs1799782) and XPD (rs13181) polymorphisms are associated with the efficacy of platinum-based chemotherapy in NSCLC. The result of this NMA suggests that there is no significant difference in predictive value of 8 DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC patients. The rank of SUCRA values of the 14 SNPs in the 8 DNA repair genes were: XPD (rs1799793) ERCC1 (rs3212986) XPA (rs1800975) ERCC1 (rs3212948) XRCC1 (rs25487) XRCC3 (rs861539) APE1 (rs3136820) ERCC1 (rs11615) XRCC1 (rs1799782) RRM1 (rs1042858) XPD (rs13181) XPG (rs1047768) XPG (rs17655) XRCC1 (rs25489). ERCC1 (rs11615), XRCC1 (rs25487, rs1799782) and XPD (rs13181) polymorph isms were better predictors in evaluating the efficacy of platinum-based chemotherapy in NSCLC patients. This article is protected by copyright. All rights reserved

Description: Preeclampsia is a kind of disease that severely harms the health of pregnant women and infants. To better understand the molecular mechanisms involved in preeclampsia, we used liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) to construct a comparative peptidomic profiling of human serum between normal and preeclamptic pregnancies. A total of 201 peptides were confidently identified, with 21 up-regulated and 3 down-regulated. Further analysis indicated that these differentially expressed peptides correlate with enzyme regulator activity, biological regulation, and coagulation cascades occurring during pathological changes of preeclampsia. The identification of key peptides in serum may serve not only as a basis for better understanding and further exploring the etiology and pathogenesis of PE, but also as potential biomarkers and in providing targets for future therapy in PE, especially in early-onset severe PE (sPE). This article is protected by copyright. All rights reserved

Description: mTORC1 signaling has been shown to promote limb skeletal growth through stimulation of protein synthesis in chondrocytes. However, potential roles of mTORC1 in prechondrogenic mesenchyme have not been explored. In this study, we first deleted Raptor , a unique and essential component of mTORC1, in prechondrogenic limb mesenchymal cells. Deletion of Raptor reduced the size of limb bud cells, resulting in overall diminution of the limb bud without affecting skeletal patterning. We then examined the potential role of mTORC1 in chondrogenic differentiation in vitro. Both pharmacological and genetic disruption of mTORC1 significantly suppressed the number and size of cartilage nodules in micromass cultures of limb bud mesenchymal cells. Similarly, inhibition of mTORC1 signaling in chondrogenic ATDC5 cells greatly impaired cartilage nodule formation, and decreased the expression of the master transcriptional factor Sox9 , along with the cartilage matrix genes Acan and Col2a1 . Thus, we have identified an important role for mTORC1 signaling in promoting limb mesenchymal cell growth and chondrogenesis during embryonic development. This article is protected by copyright. All rights reserved

Description: ABSTRACT A network meta-analysis was performed in order compare the efficacy and safety of single-drug or double-drug antidiabetic regimens in the treatment of type 2 diabetes mellitus (T2DM). PubMed and Cochrane Library searches were conducted since inception to February 2017. Randomized controlled trials (RCTs) of different antidiabetic regimens in the treatment of T2DM were included in this study. Direct and indirect evidences were combined to calculate the odds ratio (OR) or weighted mean difference (WMD) and its 95% confidence interval (95% CI), and in order to draw the surface under the cumulative ranking curves (SUCRA). A total of 19 RCTs meeting our inclusion criteria were finally incorporated into our network meta-analysis, including nineteen single-drug or double-drug antidiabetic regimens. The network meta-analysis showed that the anti-hyperglycemic effects of Sitagliptin + Metformin, Empagliflozin + Metformin, Exenatide + Metformin, Vildagliptin + Metformin, Taspoglutide + Metformin and Pioglitazone + Metformin were better than individual Metformin regimens. Dulaglutide + Metformin and Taspoglutide + Metformin regimens were comparatively less safe than individual Metformin regimens. The cluster ranking analysis based on SUCRA values suggested that Taspoglutide + Metformin regimens had best efficacy and worst safety among the different therapy regimens. Our data confirmed previous observations and suggested that Taspoglutide + Metformin regimen may have better efficacy for the treatment of T2DM among nineteen therapy regimens, while its incidence of adverse events was relatively higher. This article is protected by copyright. All rights reserved

Description: The mechanism of transition from chronic pressure overload-induced cardiac hypertrophy to heart failure is still unclear. Angiotensin II (Ang II) may be an important factor that mediates the transition in the end-stage of cardiac hypertrophy. In the present study, Goldblatt two-kidney one-clip (2K1C) rat model was used to simulate Ang II-induced hypertension. The elevated Ang II not only induced the concentric hypertrophy of left ventricle and cardiac fibrosis, but also increased the expression and glycosylation of CD147 in 2K1C rats. The left ventricular structure and function detected by echocardiogram showed a sign of the transition from cardiac hypertrophy to heart failure in 16 weeks of 2K1C rats. Ang II can activate N-acetylglucosamine transferase V (GnT-V), a key enzyme for CD147 glycosylation. Retinoic acid, an agonist of GnT-V, further increased glycosylated CD147 and activated matrix metalloproteinase-2/-9 (MMP-2 and MMP-9) in the hypertrophied left ventricle of 2K1C rat. Meanwhile, collagen cross-linking in the hypertrophied left ventricle significantly reduced in 2K1C rats. On the contrary, tunicamycin, an inhibitor of N-glycan biosynthesis, inhibited glycosylation of CD147 and activity of MMP-2 and MMP-9, and then maintained a stable of collagen cross-linking in the 2K1C rat hearts. The above results suggested that Ang II increased glycosylated CD147 which activated MMP-2 and MMP-9. Collagens were degraded by the activated MMPs and then reduced collagen cross-linking. Finally, the hypertrophied left ventricle was progressively dilated in chronic pressure overload due to losing the limitation of collagen cross-linking. Therefore, the compensated hypertrophy of left ventricle gradually transited to congestive heart failure. This article is protected by copyright. All rights reserved

Description: ABSTRACT Osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) is a central event in bone formation. However, oxidative stress has a deleterious impact on BM-MSC osteogenesis. In this study, we hypothesized that oxidative stress influenced BM-MSC osteogenesis differently in the early or late stages, in which silent information regulator type 1 (SIRT1) played a critical role. A continuous exposure to sublethal concentrations of hydrogen peroxide (H 2 O 2 ), ranging from 25 µM to 100 µM for 21 days, resulted in the complete inhibition of BM-MSC osteogenesis. We found that a 7-day treatment with H 2 O 2 inhibited the lineage commitment of BM-MSCs toward osteoblasts, as evidenced by a significant reduction of alkaline phosphatase activity (a typical marker for early osteogenesis). However, moderate oxidative stress did not affect late-differentiated BM-MSCs, as there were comparable levels of matrix mineralization (a typical marker for late osteogenesis). In addition, we observed a spontaneous up-regulation of SIRT1 and intracellular antioxidant enzymes such as superoxide dismutase 2, catalase, and glutathione peroxidase 1, which accounted for the enhanced resistance to oxidative stress upon osteogenic differentiation. Activation of SIRT1 by resveratrol rescued the effect of H 2 O 2 on early-differentiated BM-MSCs and inhibition of SIRT1 by nicotinamide intensified the effect of H 2 O 2 on late-differentiated BM-MSCs, indicating that the SIRT1-mediated pathway was actively involved in MSC osteogenesis and antioxidant mechanisms. Our findings uncovered the relationship between SIRT1 and resistance to H 2 O 2 -induced oxidative stress during BM-MSC osteogenesis, which could provide a new strategy for protecting MSCs from extracellular oxidative stress. This article is protected by copyright. All rights reserved

Description: We performed this network meta-analysis (NMA) to enhance the corresponding evidence of the relative efficacy and safety of different anti-platelet agents in cerebral ischemic disease. PubMed and EMBASE were searched systematically for relevant studies. Outcomes were compared using odds ratios (ORs) and 95% credible intervals ( CrI ). Each agent was ranked according to the value of surface under the cumulative ranking curve (SUCRA). Publication bias was evaluated by funnel plots while consistency between direct and indirect comparison was analyzed by node splitting and heat plots. Besides, clustering technique was used to categorize similar agents. A number of 44 eligible studies with 148578 patients were included in this NMA. In terms of efficacy (including mortality, recurrent stroke and vascular event), all six interventions were better than placebo. clopidogrel (Clop) and aspirin (ASA)+Clop were the best two interventions from SUCRA. However, the performance of ASA+Clop declined significantly when considering safety (including myocardial infarction, all-cause withdrawal and intracranial hemorrhage), especially worse in intracranial hemorrhage. In conclusion, Clop was potentially the most preferable treatment for preventing cerebral ischemic in terms of efficacy and safety. However, the addition of ASA was associated with a potential increase in intracranial hemorrhage, therefore, combination therapy of ASA and Clop should be introduced with caution despite it may be more effective than the monotherapy of ASA. This article is protected by copyright. All rights reserved