BACKGROUND:The OPG-RANKL-RANK transport system plays a crucial role in bone resorption mechanism of osteoclasts. OBJECTIVE:To observe the expression of OPG-RANKL-RANK signaling system in osteoclasts, osteoporosis, and the targeted therapy of OPG-RANKL-RANK signaling system. METHODS:We retrieved related literatures in the periodicals database with the key words of“osteoprotegerin, RANKL, RANK, osteoclasts, osteoporosis”in English and Chinese. According to the inclusion criteria, the literatures were included in this study after the evaluation of quality. RESULTS AND CONCLUSION:The mature of osteoclasts is mediated via OPG-RANKL-RANK signaling system and its associated signaling pathways. This signal pathway leads to the mechanism of osteoporosis. At the genetic and molecular levels, the targeted therapy of osteoporosis has become the focus. OPG-RANKL-RANK signaling system can provide a research platform for targeted treatment of osteoporosis, and OPG-RANKL-RANK signaling system is an important way to the regulation of osteoclasts and osteoporosis.

Objective To explore the effects of aberrant expression of DNA methyltransferase 1 (DNMT1) in cervical cancerization tissue and cervical cancer cells.Methods Cervical tissues were collected from 80 cases with a diagnosis of invasive cervix squamous cell carcinoma (SCC),53 cases with high-grade cervical intraepithelial neoplasia (CIN Ⅱ/Ⅲ),52 cases with low-grade cervical intraepithelial neoplasia (CIN Ⅰ)and 53 cases with normal cervix (NC).Meanwhile,Caski (HPV16-positive) and C33A (HPV-negative) cells selected from cervical cancer cell lines were cultured routinely in vitro.The expression of DNMT1 protein and mRNA were examined by Western blot analysis and real-time PCR (qRT-PCR) in the tissues and cells,respectively.Results The levels of DNMT1 protein were 1.33,1.84 and 2.28,and the Ct-ratios (DNMT1/β-actin) of DNMT1 mRNA were 1.27,1.27 and 1.26 in CIN Ⅰ,CIN Ⅱ/Ⅲand SCC group,respectively.Comparing with NC group,the expression of DNMT1 protein or mRNA was elevated in deficient cervical groups,with statistical significance (F =110.57,P ＜ 0.001,F =2.68,P =0.048).The expression levels of DNMT1 protein were increased steadily according to severity of the cervix lesions (x2tend =50.80,P ＜ 0.001),however,the expression of DNMT1 mRNA was not observed the same tendency (x2tend =3.63,P ＞ 0.05).The results from experiment in vitro showed that the levels of DNMT1 protein or mRNA were both higher in Caski cell than in C33A cell,especially for DNMT1 mRNA with significantly difference (t =7.134,P =0.002).Conclusion Aberrant expression of DNMT1 protein or mRNA could link with the risk of cervical cancerization by both transcriptional and posttranscriptional mechanisms.There would be a synergistic effect between overexpression of DNMT1 and HPV16 infection in the progression of cervix carcinogenesis.

Humanumbilicalveinendothelialcells(HUVECs)weretreatedwith3nmol/Lliraglutidefor10, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, and 270 minutes at the concentrations of 5. 5 or 30 mmol/L glucose. Western blot analysis was used to detected protein expression and phosphorylation of insulin receptor substrates-1 ( IRS-1 ) and endothelial nitric oxide synthase ( eNOS ) . The results showed that the baseline level of phosphorylated-eNOS/eNOS was lower in high glucose group than that in normal group(0. 239 ± 0. 016 vs 0. 400 ± 0. 02,P<0. 05). Liraglutide time-dependently increased phosphorylated-eNOS/eNOS and phosphorylated-IRS-1/IRS-1 levels at 5. 5 or 30 mmol/L glucose.

The modified early warning score (MEWS), as a rapid assessment and early warning scoring tool, has been widely used in patients in China, which can help nurses to identify potentially critical patients early, but not in all clinical fields. Through the retrieval of the relevant literature of the clinical application of the MEWS in Wanfang Medical Database from 2011 to 2018, the SWOT analysis was used in this paper [strength (S), weakness (W), opportunities (O) and threats (T)] methods, to systematically analyze the advantages, problems existence, implementation opportunities and challenges in the clinical application of the MEWS in our country. The purpose of this study was to obtain the best cut-off value of MEWS in different diseases and to formulate standard early-warning intervention measures for MEWS, which may provide reference for clinical workers to carry out relevant research.

Recently, ferroptosis, an iron-dependent novel type of cell death, has been characterized as an excessive accumulation of lipid peroxides and reactive oxygen species. Emerging studies demonstrate that ferroptosis not only plays an important role in the pathogenesis and progression of chronic diseases, but also functions differently in the different disease context. Notably, it is shown that activation of ferroptosis could potently inhibit tumor growth and increase sensitivity to chemotherapy and immunotherapy in various cancer settings. As a result, the development of more efficacious ferroptosis agonists remains the mainstay of ferroptosis-targeting strategy for cancer therapeutics. By contrast, in non-cancerous chronic diseases, including cardiovascular & cerebrovascular diseases and neurodegenerative diseases, ferroptosis functions as a risk factor to promote these diseases progression through triggering or accelerating tissue injury. As a matter of fact, blocking ferroptosis has been demonstrated to effectively prevent ischemia-reperfusion heart disease in preclinical animal models. Therefore, it is a promising field to develope potent ferroptosis inhibitors for preventing and treating cardiovascular & cerebrovascular diseases and neurodegenerative diseases. In this article, we summarize the most recent progress on ferroptosis in chronic diseases, and draw attention to the possible clinical impact of this recently emerged ferroptosis modalities.
Animals ; Chronic Disease ; Ferroptosis ; physiology ; Iron ; metabolism ; Reactive Oxygen Species

Iron homeostasis plays an important role for the maintenance of human health. It is known that iron metabolism is tightly regulated by several key genes, including divalent metal transport-1(), transferrin receptor 1(), transferrin receptor 2(), ferroportin(), hepcidin(), hemojuvelin() and . Recently, it is reported that DNA methylation, histone acetylation, and microRNA (miRNA) epigenetically regulated iron homeostasis. Among these epigenetic regulators, DNA hypermethylation of the promoter region of , and bone morphogenetic protein 6 () genes result in inhibitory effect on the expression of these iron-related gene. In addition, histone deacetylase (HADC) suppresses gene expression. On the contrary, HADC inhibitor upregulates gene expression. Additional reports showed that miRNA can also modulate iron absorption, transport, storage and utilization via downregulation of and other genes. It is noteworthy that some key epigenetic regulatory enzymes, such as DNA demethylase TET2 and histone lysine demethylase JmjC KDMs, require iron for the enzymatic activities. In this review, we summarize the recent progress of DNA methylation, histone acetylation and miRNA in regulating iron metabolism and also discuss the future research directions.
Epigenesis, Genetic ; Gene Expression Regulation ; genetics ; Homeostasis ; Humans ; Iron ; metabolism ; Receptors, Transferrin

Ferroptosis is defined as an iron-dependent regulated form of cell death driven by lipid peroxidation. In the past decade, it has been implicated in the pathogenesis of various diseases that together involve almost every organ of the body, including various cancers, neurodegenerative diseases, cardiovascular diseases, lung diseases, liver diseases, kidney diseases, endocrine metabolic diseases, iron-overload-related diseases, orthopedic diseases and autoimmune diseases. Understanding the underlying molecular mechanisms of ferroptosis and its regulatory pathways could provide additional strategies for the management of these disease conditions. Indeed, there are an expanding number of studies suggesting that ferroptosis serves as a bona-fide target for the prevention and treatment of these diseases in relevant pre-clinical models. In this review, we summarize the progress in the research into ferroptosis and its regulatory mechanisms in human disease, while providing evidence in support of ferroptosis as a target for the treatment of these diseases. We also discuss our perspectives on the future directions in the targeting of ferroptosis in human disease.
Humans ; Ferroptosis ; Autoimmune Diseases ; Cardiovascular Diseases ; Iron ; Musculoskeletal Diseases

Amino Acid Substitution ; Antineoplastic Agents/pharmacology* ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; Gastrointestinal Neoplasms/pathology* ; Humans ; MAP Kinase Signaling System/genetics* ; Mutation, Missense ; Receptor, ErbB-3/metabolism* ; Receptor, Fibroblast Growth Factor, Type 1/metabolism*

Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly down-regulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover, β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.