METTL14 regulates M6A methylation-modified primary miR-19a to promote cardiovascular endothelial cell proliferation and invasion.

OBJECTIVE: Increasing evidence indicated that N6-methyl-adenosine (M6A) played a key role in a variety of pathophysiological processes. Methylases could promote the processing of mature mi-RNA in a M6A-dependent manner, thereby participating in the pathological cells' occurrence and development. However, the regulatory mechanism of M6A in atherosclerosis (AS) was still unclear. PATIENTS AND METHODS: Quantificational Real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression levels of M6A, methyltransferase, demethylase transferase, miR-19a and other mi-RNA in atherosclerotic vascular endothelial cells (ASVEC). Cell Counting Kit (CCK8) was used to detect cell proliferation, the expression of PCNA was measured by Western Blot (WB) and qRT-PCR. Transwell assays were used to detect the invasion ability of ASVEC. Co-immunoprecipitation (Co-IP) was used to detect the binding of METTL14 to DGCR8. RNA Immunoprecipitation (RIP) was used to detect the binding of METTL14 to miR-19a. RESULTS: M6A modification levels and METTL14 methylation transferase were significantly overexpressed in ASVEC. Silencing METTL14 inhibited the proliferation and invasion of ASVEC. Low expression of METTL14 suppressed the binding of methylated RNA and RNA splicing related protein DGCR8. Moreover, silencing METTL14 significantly inhibited the expression of miR-19a while promoted the expression of primary pre-miR-19a. However, high expression of METTL14 obviously increased the expression of DGCR8 and methylated m6A. Furthermore, silencing miR-19a inhibited the proliferation and invasion of ASVEC. CONCLUSIONS: METTL14 increased the M6A modification of pri-miR-19a and promoted the processing of mature miR-19a, thus promoting the proliferation and invasion of ASVEC. These results suggested that METTL14/ M6A/ miR-19a signaling pathway may be a new target for atherosclerosis treatment.

A peculiar low-luminosity short gamma-ray burst from a double neutron star merger progenitor.

Double neutron star (DNS) merger events are promising candidates of short gamma-ray burst (sGRB) progenitors as well as high-frequency gravitational wave (GW) emitters. On August 17, 2017, such a coinciding event was detected by both the LIGO-Virgo gravitational wave detector network as GW170817 and Gamma-Ray Monitor on board NASA's Fermi Space Telescope as GRB 170817A. Here, we show that the fluence and spectral peak energy of this sGRB fall into the lower portion of the distributions of known sGRBs. Its peak isotropic luminosity is abnormally low. The estimated event rate density above this luminosity is at least [Formula: see text] Gpc-3 yr-1, which is close to but still below the DNS merger event rate density. This event likely originates from a structured jet viewed from a large viewing angle. There are similar faint soft GRBs in the Fermi archival data, a small fraction of which might belong to this new population of nearby, low-luminosity sGRBs.

Lack of estrogen down-regulates CXCR4 expression on Treg cells and reduces Treg cell population in bone marrow in OVX mice.

Postmenopausal osteoporosis (PMO) is the most common metabolic bone disease in women after menopausal. Recent works focused on cross—talk between immune regulation and bone metabolism pathways and suggested Treg cells suppressed bone resorption and osteoclasts (OC) differentiation in bone marrow via cell—cell contact interaction and/or secreting of IL—10 and TGF—beta. In this study, we investigated the impact of estrogen on regulatory T cells (Treg cells) trafficking and staying in bone marrow and we found that a significant reduction of Treg cell population in bone marrow in estrogen deficiency ovariectomied (OVX) mice. We then studied the expressions of chemokines CXCL12/CXCR4 axes, which were critical to Treg cells migration and our data show the expression of CXCR4 on Treg cells was relative with oestrogen in vivo, however, the expression of CXCL12 was not. Furthermore, the loss of trafficking ability of Treg cells in OVX mice was recoverable in our system. These findings may mechanistically explain why Treg cells lose their suppressive functions on the regulation of OC cells and demonstrate a previously unappreciated role for estrogen, which may be critical to the novel therapy in clinical practice of PMO patients.

Morphological classification for prediction of malignant transformation in multiple exostoses.

AIM: To explore the value of morphological classification in predicting malignant transformation in multiple exostoses (ME). PATIENTS AND METHODS: The imaging data of 116 patients (totally 190 tumors) with ME were retrospectively analyzed. All the tumors were pathology confirmed after surgical resection, including 175 exostoses from 101 patients, and 15 exostotic chondrosarcomas in 15 cases. Based on the ratio of diameter between tumor tip and tumor base (R1), tumors were classified into two types: cauliflower-like tumor (R1 ≥ 1.0) and non-cauliflower-like tumor (R1 < 1.0). In addition, non-cauliflower-like tumors were further classified into two subtypes according to the ratio of tumor height to tumor base diameter: sessile type (R2 < 1.0) and pedunculated type (R2 ≥ 1.0). The relationship between tumor shape and malignant transformation was studied. RESULTS: Of all the 175 exostoses from 101 patients, 27 were cauliflower-like tumors and 148 were non-cauliflower-like tumors. Of all the 15 exostotic chondrosarcomas in 15 cases, most tumors were cauliflower-like (c2 = 38.0075, p < 0.05). Cauliflower-like tumor for the prediction of exostotic chondrosarcoma, the sensibility, specificity, positive predictive value, negative predictive value were 86.7%, 84.6%, 32.5%, 98.7%, respectively. CONCLUSIONS: Tumor malignant transformation was more common in cauliflower-like tumors than in non-cauliflower-like tumors. The morphological classification and preventive resection of cauliflower-like tumors maybe helpful in preventing the malignant transformation of ME.

Specific thalamic nuclei function as novel 'nociceptive discriminators' in the endogenous control of nociception in rats.

Recently, we hypothesized that supraspinal structures may have important functions in discriminating between noxious mechanically and heat mediated nociception through distinct functions: facilitation and inhibition. In this study, conducted in conscious rats, we explored the role of different thalamic nuclei: the mediodorsal (MD) nucleus, the central medial (CM) nucleus, the submedius (SM) nucleus, the ventralmedial (VM) nucleus and the ventral posterolateral (VPL) nucleus, in the descending control of secondary and contralateral mechanical hyperalgesia and heat hypoalgesia occurring in intramuscularly hypertonic (HT, 5.8%) saline-induced muscle nociception. We found that the MD nuclei participated in the descending facilitation of mechanical hyperalgesia, and that the VM nuclei were specifically involved in the descending inhibition of heat hypoalgesia. Neither descending facilitation nor descending inhibition was affected after electrolytic lesion of the thalamic CM, SM, and VPL nuclei. This descending facilitatory and inhibitory modulation of nociception was strengthened by glutamate, and weakened by GABA, microinjected into the thalamic MD and VM nuclei. It is suggested that (1) thalamic MD nucleus and VM nucleus form two distinct endogenous systems in the control of noxious mechanically and heat evoked responses, and (2) the strengthening of descending inhibition and the weakening of descending facilitation by means of up regulation and down regulation of appropriate receptor expression in the VM and MD nuclei may provide a new strategic policy in treating pathological pain.

Chronic morphine treatment and withdrawal induce up-regulation of c-Jun N-terminal kinase 3 gene expression in rat brain.

Chronic opiate applications produce long-term impacts on many functions of the brain and induce tolerance, dependence, and addiction. It has been demonstrated that opioid drugs are capable to induce apoptosis of neuronal cells, but the mechanism is not clear. c-Jun N-terminal kinase 3 (JNK3), specifically expressed in brain, has been proved to mediate neuronal apoptosis and is involved in opiate-induced cell apoptosis in vitro. The present study investigated the effect of opioid administration on expression of JNK3, an important mediator involved in apoptosis of neurons, in rat brain. Our results showed that single or chronic injection of morphine resulted in a 45-50% increase in the level of JNK3 mRNA in frontal cortex, while no significant change was detected in other brain regions such as thalamus, hippocampus and locus coeruleus. Similar to what was observed after the acute or chronic morphine administration, no significant change in JNK3 expression was detected in locus coeruleus following cessation of the chronic morphine administration. However, interestingly, sustained elevation of JNK3 expression peaked on day 14 after cessation of morphine treatment was observed in the brain regions such as hippocampus and thalamus, where acute or chronic morphine treatment did not cause any significant change in JNK3 gene expression. The increased JNK3 mRNA in these brain areas returned to the control levels in 28 days following cessation of chronic morphine treatment. Taken together, these results demonstrated for the first time that the expression of JNK3 gene is regulated by opioids and that chronic opioid administration and withdrawal could induce sustained elevation of JNK3 mRNA in many important brain areas. The changes in JNK3 gene expression in brain induced by chronic opioid treatment may play a role in opioid-induced apoptosis and neurotoxicity.