Abstract:
:Bone loss in postmenopausal osteoporosis is induced chiefly by an imbalance of bone-forming osteoblasts and bone-resorbing osteoclasts. Salubrinal is a synthetic compound that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Phosphorylation of eIF2α alleviates endoplasmic reticulum (ER) stress, which may activate autophagy. We hypothesized that eIF2α signaling regulates bone homeostasis by promoting autophagy in osteoblasts and inhibiting osteoclast development. To test the hypothesis, we employed salubrinal to elevate the phosphorylation of eIF2α in an ovariectomized (OVX) mouse model and cell cultures. In the OVX model, salubrinal prevented abnormal expansion of rough ER and decreased the number of acidic vesiculars. It regulated ER stress-associated signaling molecules such as Bip, p-eIF2α, ATF4 and CHOP, and promoted autophagy of osteoblasts via regulation of eIF2α, Atg7, LC3, and p62. Salubrinal markedly alleviated OVX-induced symptoms such as reduction of bone mineral density and bone volume fraction. In primary bone-marrow-derived cells, salubrinal increased the differentiation of osteoblasts, and decreased the formation of osteoclasts by inhibiting nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Live cell imaging and RNA interference demonstrated that suppression of osteoclastogenesis is in part mediated by Rac1 GTPase. Collectively, this study demonstrates that ER stress-autophagy axis plays an important role in OVX mice. Bone-forming osteoblasts are restored by maintaining phosphorylation of eIF2α, and bone-resorbing osteoclasts are regulated by inhibiting NFATc1 and Rac1 GTPase.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Li J,Li X,Liu D,Hamamura K,Wan Q,Na S,Yokota H,Zhang Pdoi
10.1038/s41419-019-2159-zsubject
Has Abstractpub_date
2019-12-04 00:00:00pages
921issue
12issn
2041-4889pii
10.1038/s41419-019-2159-zjournal_volume
10pub_type
杂志文章abstract::Nilotinib is a second-generation tyrosine kinase inhibitor, designed to specifically inhibit break-point cluster region (BCR)-Abelson (ABL) and developed to treat chronic myeloid leukemia (CML) in patients showing a resistance to imatinib. We previously demonstrated that nilotinib-induced apoptosis was reduced by stem...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.309
更新日期:2013-10-03 00:00:00
abstract::Therapy resistance is a major roadblock in oncology. Exacerbation of molecular dysfunctions typical of cancer cells have proven effective in twisting oncogenic mechanisms to lethal conditions, thus offering new therapeutic avenues for cancer treatment. Here, we demonstrate that selective agonists of Transient Receptor...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03256-5
更新日期:2020-12-07 00:00:00
abstract::Neuronal apoptosis and survival are tightly controlled processes that regulate cell fate during the development of the central nervous system and its homeostasis throughout adulthood. A new study in primary cultures of cerebellar granule neurons identified common transcriptional cascades during rescue from apoptosis b...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2015.309
更新日期:2015-11-05 00:00:00
abstract::The role of autophagy in cancer onset and progression appears still controversial. On one hand, autophagy allows cancer cell to survive in unfavorable environmental conditions, on the other hand, once internal energy resources are exhausted, it leads to cell death. In addition, autophagy interpheres with cell cycle pr...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0864-7
更新日期:2018-08-06 00:00:00
abstract::Immune surveillance through Foxp3+ regulatory T cells plays a crucial role in bone homeostasis. Scurfy, the mouse model of autoimmune IPEX syndrome, bears a loss-of-function mutation in Foxp3 that leads to multi-organ inflammation. Herein, we report that scurfy mice exhibit severe bone loss mediated by accelerated ost...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2015.87
更新日期:2015-04-16 00:00:00
abstract::Although targeting of the death receptors (DRs) DR4 and DR5 still appears a suitable antitumoral strategy, the limited clinical responses to recombinant soluble TNF-related apoptosis inducing ligand (TRAIL) necessitate novel reagents with improved apoptotic activity/tumor selectivity. Apoptosis induction by a single-c...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2012.29
更新日期:2012-04-12 00:00:00
abstract::Enhanced SNHG1 (small nucleolar RNA host gene 1) expression has been found to play a critical role in the initiation and progression of hepatocellular carcinoma (HCC) with its detailed mechanism largely unknown. In this study, we show that SNHG1 promotes the HCC progression through epigenetically silencing CDKN1A and ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03031-6
更新日期:2020-10-02 00:00:00
abstract::Our recent study identified a list of differentially expressed microRNAs (miRNAs) in human prostate cancer (PCa) tissues compared to adjacent benign prostate tissues. In the current study, to identify the crucial miRNA-mRNA regulatory biomodule involved into prostate carcinogenesis based on the previous miRNA expressi...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0293-7
更新日期:2018-02-21 00:00:00
abstract::MicroRNAs (miRNAs) have been demonstrated to affect the biological processes of cancers and showed great potential for prognostic biomarkers. In this study, we screened differentially expressed miRNAs in ccRCC based on three dimensions of metastasis, prognosis, and differential expression compared to normal tissue usi...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03306-y
更新日期:2021-01-04 00:00:00
abstract::Hepatocellular carcinoma (HCC) is one of the greatest life threats for Chinese people, and the prognosis of this malignancy is poor due to the strong chemotherapy resistance in patients. Notch pathway components mediate cell survival and epithelial-mesenchymal transition (EMT), and also participate in the induction of...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0804-6
更新日期:2018-07-03 00:00:00
abstract::The voltage-gated K+ channel has key roles in the vasculature and in atrial excitability and contributes to apoptosis in various tissues. In this study, we have explored its regulation by carbon monoxide (CO), a product of the cytoprotective heme oxygenase enzymes, and a recognized toxin. CO inhibited recombinant Kv1....
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.568
更新日期:2017-11-02 00:00:00
abstract::Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Dry AMD is characterized by a progressive macular degeneration of the retinal pigment epithelium (RPE) and photoreceptors, and the RPE oxidative damage/dystrophy is at the core of the disease. Recent population/patients-based stud...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2216-7
更新日期:2020-01-13 00:00:00
abstract::Abdominal Aortic aneurysm (AAA) is associated with chronic inflammation, cells apoptosis, and impairment of autophagy. BP-1-102, a novel potent STAT3 inhibitor, has been recently reported to significantly block inflammation-related signaling pathways of JAK2/STAT3 and NF-κB, as well as regulate autophagy. However, its...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-2326-2
更新日期:2020-02-18 00:00:00
abstract::Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating cancer cell proliferation, and invasion, but how the premalignant stromal fibroblasts trigger epithelial changes remain unclear. We demonstrate that atypical ductal hyperplasia-associated fibroblasts (AHFs) are one kind of activated fibroblasts ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-017-0133-1
更新日期:2018-01-26 00:00:00
abstract::ELABELA (ELA), a 32-residue hormone peptide abundantly expressed in adult kidneys, has been identified as a novel endogenous ligand for APJ/Apelin receptor. The aim of this study was to investigate the role of ELA in deoxycorticosterone acetate (DOCA)/salt-induced hypertension and further explore the underlying mechan...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-02912-0
更新日期:2020-08-22 00:00:00
abstract::Impaired synaptic plasticity and neuron loss are hallmarks of Alzheimer's disease and vascular dementia. Here, we found that chronic brain hypoperfusion (CBH) by bilateral common carotid artery occlusion (2VO) decreased the total length, numbers and crossings of dendrites and caused neuron death in rat hippocampi and ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.243
更新日期:2017-06-01 00:00:00
abstract::The vascular leakage in diabetic retinopathy leads to macular edema and vision loss. Although astrocyte play an important role in regulating blood-brain barrier integrity in the brain, the precise role of astrocyte in blood-retinal barrier was yet to be elucidated. This study aimed to investigate the role of angiopoie...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2015.347
更新日期:2016-02-18 00:00:00
abstract::PTPL1 is a non-receptor protein tyrosine phosphatase involved in apoptosis regulation, although controversial findings have been reported in different cancer types. We report here a proapoptotic role for PTPL1 in PC3 and LNCaP prostate cancer cells, as its absence induces apoptosis resistance upon treatment with diffe...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.90
更新日期:2013-04-04 00:00:00
abstract::Following publication of this article, it was brought to our attention that there was a typo in the References (reference number 43) whereby the first author's name was misspelled. The correct citation is provided below. We apologize for the inconvenience. ...
journal_title:Cell death & disease
pub_type: 已发布勘误
doi:10.1038/s41419-019-2029-8
更新日期:2019-10-22 00:00:00
abstract::Procaspase-3-activating compound 1 (PAC-1) induces procaspase-3 activation via zinc chelation. However, whether PAC-1 employs other mechanisms remains unknown. Here we systematically screened for potent PAC-1 targets using 29 enhanced green fluorescent protein-labeled reporter cell lines and identified hypoxia-inducib...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1038-3
更新日期:2018-10-04 00:00:00
abstract::We previously showed that mice with knockout of Cytl1, a functionally uncharacterized cytokine candidate, exhibit normal endochondral ossification and long-bone development. Here, we investigated the potential functions of CYTL1 in bone homeostasis. We found that Cytl1-/- mice exhibited higher bone mass than wild-type...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1284-4
更新日期:2019-01-18 00:00:00
abstract::Hyperoxia treatment has been known to induce neuronal and glial death in the developing central nervous system. Retinopathy of prematurity (ROP) is a devastating disease in premature infants and a major cause of childhood vision impairment. Studies indicate that, in addition to vascular injury, retinal neurons are als...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.23
更新日期:2014-02-20 00:00:00
abstract::Apoptosis has been established as a mechanism of anti-cancer defense. Members of the BCL-2 family are critical mediators of apoptotic cell death in health and disease, often found to be deregulated in cancer and believed to lead to the survival of malignant clones. However, over the years, a number of studies pointed ...
journal_title:Cell death & disease
pub_type: 杂志文章,评审
doi:10.1038/cddis.2015.20
更新日期:2015-03-05 00:00:00
abstract::The formulation of quercetin nanoliposomes (QUE-NLs) has been shown to enhance QUE antitumor activity in C6 glioma cells. At high concentrations, QUE-NLs induce necrotic cell death. In this study, we probed the molecular mechanisms of QUE-NL-induced C6 glioma cell death and examined whether QUE-NL-induced programmed c...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.242
更新日期:2013-08-01 00:00:00
abstract::Synapsin I is a phosphoprotein that coats the cytoplasmic side of synaptic vesicles and regulates their trafficking within nerve terminals. Autoantibodies against Syn I have been described in sera and cerebrospinal fluids of patients with numerous neurological diseases, including limbic encephalitis and clinically iso...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2106-z
更新日期:2019-11-14 00:00:00
abstract::Traumatic brain injury (TBI) activates multiple neuronal cell death mechanisms, leading to post-traumatic neuronal loss and neurological deficits. TBI-induced cell cycle activation (CCA) in post-mitotic neurons causes regulated cell death involving cyclin-dependent kinase (CDK) activation and initiation of an E2F tran...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1156-y
更新日期:2018-11-06 00:00:00
abstract::Interleukin-8 (IL-8) expression correlates with poor prognosis in many cancers, including head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism is poorly understood. In this study, we found that overexpression of IL-8 correlated with poor outcome in HNSCC patients. IL-8 significantly increased ce...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-2627-5
更新日期:2020-05-29 00:00:00
abstract::GATA3 has emerged as a prominent transcription factor required for maintaining mammary-gland homeostasis. GATA3 loss is associated with aggressive breast cancer development, but the mechanism by which breast cancer is affected by the loss of GATA3 function remains unclear. Here, we report that GATA3 expression is posi...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2062-7
更新日期:2019-11-04 00:00:00
abstract::Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening diseases that are associated with high mortality rates due to treatment limitations. Neutrophils play key roles in the pathogenesis of ALI/ARDS by promoting the inflammation and injury of the alveolar mic...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.365
更新日期:2016-11-10 00:00:00
abstract::In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0578-x
更新日期:2018-06-04 00:00:00