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Bone morphogenetic protein (BMP) 9 is a potent inducer of osteogenic differentiation from mesenchymal stem cells, but the mediators of BMP9-induced osteogenesis remain elusive. Here, the authors show that inhibition of Notch1 signaling effectively diminishes BMP9-induced osteogenesis. Genetic disruption of Notch pathway severely impairs BMP9-induced bone formation. Thus, these results demonstrate that Notch signaling may play an essential role in coordinating osteogenic differentiation.
In this study, the authors show that overexpression of hypoxia-inducible factor(HIF)-1α by ERK1/2, Akt and NF-κB activation contributes to melphalan-resistance in multiple myeloma (MM) cells. Additionally, inhibition of HIF-1α resensitizes melphalan-resistant MM cells to melphalan. Therefore, HIF-1α inhibitors may be therapeutically useful as anti-multidrug resistance protein agents in MM.
The cytoskeletal GTPase SEPT6 is elevated during hepatic stellate cell (HSC) activation and in liver fibrosis. SEPT6 promotes HSC activation, proliferation, cell cycle progression, survival and migration through the TGF-β1/Smad, MAPK and PI3K/AKT signaling pathways. Adenovirus-mediated SEPT6 inhibition attenuates thioacetamide-induced liver fibrosis.
Mitochondrial pyruvate carrier1 (MPC1) is a key factor that controls pyruvate transportation in mitochondria. Renal cell carcinoma (RCC) patients with higher MPC1 expression in tumors exhibit longer overall survival rate than those with lower MPC1. This study shows that MPC1 is a novel prognostic biomarker to predict patient.
A poorly developed placental capillary network is associated with early onset fetal growth restriction (FGR) and pre-eclampsia (PE). First trimester placental endothelial cells from pregnancies at increased risk of developing early onset FGR/PE were more sensitive to apoptotic stimuli and this was functionally linked to the synthesis of NO. This may contribute to the poor placental vascular development seen in ongoing pregnancies.
Using a novel slingshot 1 phosphatase (SSH1) knock-out mouse model, the authors demonstrate that loss of the actin-binding protein potentiates angiotensin II-induced medial thickening and fibrosis due to altered TGFβ1 signaling, resulting in increased expression of fibronectin and osteopontin.
Defective thermogenic response to calorie overload contributes to obesity and, in foz/foz mice, to nonalcoholic steatohepatitis (NASH). Activation of brown adipose tissue function by b3AR-agonists together with moderate calorie restriction improves the obese phenotype and resolves NASH pathology. This identifies the brown adipose tissue as a target for adjuvant therapy for NASH.
The underlying immunopathogenic mechanisms of autoimmune hepatitis (AIH) have not been well elucidated. Kruppel-like factors 14 (KLF14) may regulate Treg differentiation, but the biological functions remain unclear. In this study, the authors reveal that KLF14 plays an as yet unrecognized role in immune- mediated hepatitis via induced Treg differentiation and inflammatory cytokine suppression. These findings indicate the possibility of KLF14 as a therapeutic target in AIH patients.
Bronchial epithelium is now believed to participate in the pathophysiology of bronchial asthma. In this report, the authors show that the ΔNp63 transcription factor, expressed in the basal layer of bronchus, modulates distinctive survival and immune-related bronchial epithelial responses. These results suggest functional significance of the epithelial shedding found in the pathology of bronchial asthma.
This study was designed to investigate the role of polymerase delta interacting protein 2 (Poldip2) in vascular smooth muscle proliferation and neointimal formation. Neointimal formation and proliferating cell nuclear antigen expression were inhibited in Poldip2+/- mice, in part due to induction of the cell cycle inhibitor p21.
Cellular senescence induced by replication and an AKT inhibitor in ex-vivo spheroid leiomyomas was examined in this work. Several dysregulated genes in the ROS, hypoxic and AKT pathways were identified, including WIPI1 and SLITKR4. Induced senescence in spheroids can be reversed by ABT263, a BH3 mimetic, which may be therapeutic modality for treatment of leiomyoma.
S3I-201, a chemical inhibitor of the transcription factor STAT3, suppresses liver fibrogenesis and angiogenesis through multiple mechanisms both in vitro and in vivo. Moreover, S3I-201 and sorafenib, an FDA-approved multikinase inhibitor, function synergistically in suppressing fibrogenesis and angiogenesis of human hepatic stellate cells, indicating high potential for liver fibrosis treatment.
This study outlines the trends in human-genomic deposits in the gene expression omnibus (GEO). The authors found that there were significant increases in the use of high-throughput sequencing, protein array and multiple-platforms, and in the proportion of North-American deposits. Unclassified diseases, cancer and immunological diseases dominated GEO deposits. There was also geographic disparity in the trends of GEO deposit characteristics.
In this study, a novel epidermal growth factor receptor (EGFR)-targeted, human β-defensin 1-tailored fusion protein, Ec-LDP-DF, and its enediyne-integrated analogue, Ec-LDP(AE)-DF, have been prepared by genetic engineering and molecular reconstitution. The fusion protein Ec-LDP(AE)-DF displays extremely potent cytotoxicity and might be highly effective for non-small cell lung cancer therapy and useful for other EGFR-targeted therapeutics.
Applying histological/histomorphometrical analyses on femora and/or lumbar vertebrae, as well as spectrometric and molecular methodologies on bone-marrow mesenchymal stem cells form APOE knock out and wild-type mice, the authors demonstrate that APOE deficient mice fed a Western-type diet have remarkably augmented bone-marrow adiposity and significantly reduced bone mass due to enhanced osteoclastic and impaired osteoblastic function.
Vitamin D insufficiency is associated with the severity of oxidative stress in vitiligo patients. This study provides new insights into the mechanism of vitamin D as a treatment for vitiligo; it protects melanocytes against oxidative stress by activating Wnt/β-catenin signaling. Targeting this signaling could be a useful approach to improve treatment for vitiligo.
This study shows excellent reproducibility among 3 different digital image (DIA) analysis platforms in Ki67 scoring. An outstanding concordance was found among four operators using the same calibrated DIA platform suggesting a highly reproducible Ki67 scoring method. Finally, the authors also found that all three DIA platforms were essentially indistinguishable with respect to prediction of breast cancer patient outcome.
DNA ligase I (LIG1), an essential enzyme implicated in DNA recombination and DNA repair, is modulated by the oncoprotein SRSF1. In non-small cell lung cancer (NSCLC) cells, LIG1 inhibition is associated with reduced proliferation and increased apoptosis. LIG1 expression is therefore a poor prognosis factor in NSCLC.
Wnt/β-catenin signaling pathway activation is frequent event in the development of neoplasms. In this study, the authors defined an immunohistochemical approach to dissect CTNNB1 (β-catenin) mutations in formalin-fixed and paraffin-embedded primary neoplasms. They validated an immunohistochemical mutation detection algorithm in colon adenomas, carcinomas and various non-colonic Wnt pathway activated tumors.
Tumor cell-endothelial adhesion is one of the key steps for invasion and metastasis. The authors show that Gal-3 promotes cancer cell adhesion to vascular endothelial cells by increasing the expression of N-cadherin and CD44 via an increase of β-catenin nuclear accumulation. This new molecular mechanism of Gal-3-mediated cell adhesion may aid in the development of new strategies to prevent metastasis.