Promoter DNA Methylation of Oncostatin M receptor-β as a Novel Diagnostic and Therapeutic Marker in Colon Cancer

In addition to genetic changes, the occurrence of epigenetic alterations is associated with accumulation of both genetic and epigenetic events that promote the development and progression of human cancer. Previously, we reported a set of candidate genes that comprise part of the emerging “cancer methylome”. In the present study, we first tested 23 candidate genes for promoter methylation in a small number of primary colon tumor tissues and controls. Based on these results, we then examined the methylation frequency of Oncostatin M receptor-β (OSMR) in a larger number of tissue and stool DNA samples collected from colon cancer patients and controls. We found that OSMR was frequently methylated in primary colon cancer tissues (80%, 80/100), but not in normal tissues (4%, 4/100). Methylation of OSMR was also detected in stool DNA from colorectal cancer patients (38%, 26/69) (cut-off in TaqMan-MSP, 4). Detection of other methylated markers in stool DNA improved sensitivity with little effect on specificity. Promoter methylation mediated silencing of OSMR in cell lines, and CRC cells with low OSMR expression were resistant to growth inhibition by Oncostatin M. Our data provide a biologic rationale for silencing of OSMR in colon cancer progression and highlight a new therapeutic target in this disease. Moreover, detection and quantification of OSMR promoter methylation in fecal DNA is a highly specific diagnostic biomarker for CRC

Regulation of large conductance calcium-activated potassium channel by protein tyrosine phosphorylation and SNARE protein syntaxin 1A

Bibliography: p. 184-24

METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/β-Catenin Axis

Epithelial ovarian cancer (EOC) ranks third in the incidence of gynecological malignancies. m6A methylation as RNA modification plays a crucial role in the evolution, migration, and invasion of various tumors. However, the role of m6A methylation in ovarian cancer (OC) only recently has begun to be appreciated. Therefore, we used various bioinformatic methods to screen the public GEO datasets of epithelial ovarian cancer (EOC) for m6A methylation-related regulators. We identified methyltransferase 16 (METTL16) that was dramatically downregulated in EOC as such a regulator. We also identified metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a known target lncRNA of METTL16, in these five GEO datasets. RT-qPCR and immunohistochemical staining confirmed that compared with the normal ovarian tissues and cells, METTL16 was significantly downregulated, while lncRNA MALAT1 was significantly upregulated, in 30 EOC tissues of our own validation cohorts and EOC cell lines, revealing a negative correlation between METTL16 and lncRNA MALAT1. Moreover, our analysis unveiled a correlation between downregulated METTL16 and the known adverse prognostic factors of EOC patients in our own cohorts. The CCK-8, EdU, scratch wound healing, and transwell invasion assays revealed that METTL16 significantly suppressed the proliferating, migrating, and invading abilities of OC cells. The inhibitory effects of METTL16 on the in vivo tumor growth of EOC cells were measured by subcutaneous tumor formation assay in mice. Furthermore, the RIP, RNA stability assay, western blotting, and cytoimmunofluorescence staining showed that METTL16 hindered the growth of EOC cells through promoting the degradation of MALAT1 by binding that, in turn, upregulates β-catenin protein and promotes nuclear transport of β-catenin protein in EOC cells. This study suggests that METTL16 acts as a tumor suppressor gene of EOC by achieving its inhibitory function on the malignant progression of EOC through the METTL16/MALAT1/β-catenin axis that are new targets for EOC diagnosis and therapy

Different radius of curvature at the talus trochlea from northern Chinese population measured using 3D model

Abstract Background To analyze the curvature characteristics of the talus trochlea in people from northern China in different sex and age groups. Methods Computed tomography scanning data of talus from 61 specimens were collected and constructed as a three-dimensional model by Materialise’s Interactive Medical Image Control System(MIMICS) software, anteromedial(AM), posteromedial(PM), anterolateral(AL), and posterolateral(PL) edge, anterior edge of medial trochlea, posterior edge of medial trochlea and anterior edge of lateral trochlea were defined according to the anatomical landmarks on trochlear surface. The curvature radii for different areas were measured using the fitting radius and measure module. Results There were significant differences among the talus curvatures in the six areas (F = 54.905, P = 0.000), and more trends in the analytical results were as follows: PM > PL > MP > AL > MA > AM. The average PL radius from specimens aged > 38 years old was larger than that from specimens aged < = 38 years (t=-2.303, P = 0.038). The talus curvature of the AM for males was significantly larger than that for females (t = 4.25, P = 0.000), and the curvature of the AL for males was larger than that for females (t = 2.629, P = 0.010). For observers aged < = 38 years, the AM curvature of the right talus in the male group was significantly larger than that in the female group (P < 0.01). In age < = 38years group, the MA curvature of right talus in male was significantly larger than in female group(P < 0.01), fitting radius of talus for male (21.90 ± 1.97 mm) was significantly greater than female of this(19.57 ± 1.26 mm)(t = 6.894, P = 000). The average radius of the talus in the male population was larger than that in the female population. Conclusion There was no significant relationship between age and talus curvature for males and females. The radius of curvature in the posterior area was significantly larger than that in the anterior area. We recommend that this characteristic of the talus trochlea should be considered when designing the talus component in total ankle replacement (TAR)

Chemical genomic analysis of GPR35 signaling

GPR35, a family A orphan G protein-coupled receptor, has been implicated in inflammatory, neurological, and cardiovascular diseases. However, not much is known about the signaling and functions of GPR35. We performed a label-free kinome short hairpin RNA screen and identified a putative signaling network of GPR35 in HT-29 cells, some of which was validated using gene expression, biochemical and cellular assays. The results showed that GPR35 induced hypoxia-inducible factor 1 alpha, and was involved in synaptic transmission, sensory perception, the immune system, and morphogenetic processes. Collectively, our data suggest that GPR35 may play an important role in response to hypoxic stress and be a potential target for the treatment of inflammatory, cardiovascular, and neurological disorders

Discovery of Natural Phenols as G Protein-Coupled Receptor-35 (GPR35) Agonists

We report the discovery and characterization of natural phenols as G protein-coupled receptor-35 (GPR35) agonists. Pharmacological characterization using label-free dynamic mass redistribution and Tango β-arrestin translocation assays revealed that GPR35-active natural phenols are divergent in their biased agonism

Health-related quality of life in patients with Kashin–Beck disease is lower than in those with osteoarthritis: a cross-sectional study

Abstract Background Kashin–Beck disease (KBD) is an endemic deformable bone and joint disease, which affects the quality of life (QOL) of patients. We conducted a cross-sectional study of the QOL of KBD patients by a new KBD quality of life (KBDQOL) questionnaire. Methods A total of 252 KBD patients and 248 OA patients came from Northwest China, and 260 healthy people living in the same area as KBD and osteoarthritis (OA) patients served as the controls. KBDQOL questionnaire was used to evaluate the QOL of all objects. Results The average scores for physical functions, activity limitations, support of society, mental health and general health were significantly lower in KBD patients than that in OA patients and healthy people except for economics. Monofactor analysis showed that age, height, weight status, education level and grade of KBD had a significant effect on KBDQOL score. Multivariate analysis showed that grade of KBD was the influencing factor of physical function score; gender, age, height, grade of KBD and duration of symptoms were the influencing factors of activity restriction score; age and grade of KBD were factors affecting the general health score. Conclusion The QOL of KBD patients was significantly lower than that of OA patients and healthy people. The KBDQOL questionnaire may be a promising tool for assessing the QOL of KBD patients

TREM2 Alleviates Subarachnoid Hemorrhage-Induced Brain Injury through Attenuating Neuroinflammation and Programmed Cell Death in Vivo and in Vitro

Background: Apoptosis and pyroptosis are two types of programmed cell death related to the neuroinflammatory reaction after subarachnoid hemorrhage (SAH). Research indicates that triggering receptor expressed on myeloid cells 2 (TREM2) can regulate the SAH-induced inflammatory response. However, whether TREM2 regulates programmed cell death (apoptosis and pyroptosis) remains to be clarified. The purpose of the present study was to investigate the effects of TREM2 on cell death in SAH. Methods: SAH was induced in adult male C57BL/6J mice by endovascular perforation. An in-vitro cellular model of SAH was established by treating cocultured BV2 microglia and HT22 neuronal cells with oxyhemoglobin. TREM2 overexpression or knockdown was carried out by intraventricular lentivirus injection at 7 d before SAH induction in mice or lentiviral transfection, respectively. Neurobehavioral tests as well as western blot, reverse transcription–quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, Evans blue (EB) staining, Nissl staining, and flow cytometry assays were performed to investigate the neuroprotective role of TREM2 after SAH. Results: After SAH, the TREM2 mRNA and protein levels were elevated in SAH mice, exhibiting a peak at 72 h. TREM2 overexpression improved the SAH-induced neurological deficits in mice, while TREM2 knockdown worsened them. In the brains of mice with TREM2 overexpression, less neuronal death and more neuronal survival were detected at 72 h post SAH. Meanwhile, TREM2 overexpression showed an inhibitory effect on microglial activation, neutrophil infiltration, and the expression of cell death marker proteins. Consistent results were obtained in vitro. Conclusions: Our research indicates the important role of TREM2 on cell death after SAH, suggesting that targeting TREM2 might be an effective approach for treating SAH

Integrin receptor activation triggers converging regulation of Cav1.2 calcium channels by c-Src and protein kinase A pathways.

L-type, voltage-gated Ca 2+ channels (Ca L ) play critical roles in brain and muscle cell excitability. Here we show that currents through heterologously expressed neuronal and smooth muscle Ca L channel isoforms are acutely potentiated following 5 1 integrin activation. Only the 1C pore-forming channel subunit is critical for this process. Truncation and site-directed mutagenesis strategies reveal that regulation of Cav1.2 by 5 1 integrin requires phosphorylation of 1C C-terminal residues S1901 and Y2122. These sites are known to be phosphorylated by PKA and c-Src, respectively, and are conserved between rat neuronal (Cav1.2c) and smooth muscle (Cav1.2b) isoforms. Kinase assays are consistent with phosphorylation of these two residues by PKA and c-Src. Following 5 1 integrin activation, native Ca L channels in rat arteriolar smooth muscle exhibit potentiation that is completely blocked by combined PKA and Src inhibition. Our results demonstrate that integrin-ECM interactions are a common mechanism for the acute regulation of Ca L channels in brain and muscle. These findings are consistent with the growing recognition of the importance of integrin-channel interactions in cellular responses to injury and the acute control of synaptic and blood vessel function. Voltage-gated calcium channels play critical roles in the regulation of calcium entry across the plasma membranes of excitable cells. L-type calcium channels (Ca L ), which are highly expressed in brain and muscle, are heteromeric transmembrane proteins composed of a poreforming 1C (Cav1.2) subunit along with accessory , 2 , , and sometimes subunits (1,2). The 1C subunit contains four highly-conserved repeat regions with 24 membrane-spanning domains, in addition to a variable length N-terminus and relatively long, intracellular C-terminus. The three 1C isoforms (neuronal, Cav 1.2c; smooth muscle, Cav 1.2b; cardiac, Cav 1.2a) exhibit significant sequence differences in their N-and C-termini but all are regulated by intracellular kinases in ways that uniquely determine calcium entry and cell excitability. The regulation of Ca L channels by serinethreonine kinases has been extensively investigated. PKG phosphorylates a conserved serine reside in the cytoplasmic I-II linker (3) of all three 1C isoforms, leading to inhibition of current. PKC phosphorylates N-terminal threonine residues in cardiac and smooth muscle isoforms (4-6) leading in most cases to potentiation of current. PKA phosphorylates all three 1C isoforms at a conserved C-terminal serine, (S1901 in Cav1.2c; S1928 in Cav1.2a), thereby mediating -adrenergic potentiation of calcium current in cardiac myocytes and neurons (7-9). PKA also regulates 1C in smooth muscle, but the functional consequences on calcium current are complicated by crossover activation of PKG, which is expressed at high levels in that tissue (10)