Chronic inflammation triggered by the NLRP3 inflammasome in myeloid cells promotes growth plate dysplasia by mesenchymal cells

AbstractSkeletal complications are common features of neonatal-onset multisystem inflammatory disease (NOMID), a disorder caused by NLRP3-activating mutations. NOMID mice in which NLRP3 is activated globally exhibit several characteristics of the human disease, including systemic inflammation and cartilage dysplasia, but the mechanisms of skeletal manifestations remain unknown. In this study, we find that activation of NLRP3 in myeloid cells, but not mesenchymal cells triggers chronic inflammation, which ultimately, causes growth plate and epiphyseal dysplasia in mice. These responses are IL-1 signaling-dependent, but independent of PARP1, which also functions downstream of NLRP3 and regulates skeletal homeostasis. Mechanistically, inflammation causes severe anemia and hypoxia in the bone environment, yet down-regulates the HIF-1α pathway in chondrocytes, thereby promoting the demise of these cells. Thus, activation of NLRP3 in hematopoietic cells initiates IL-1β-driven paracrine cascades, which promote abnormal growth plate development in NOMID mice.</jats:p

Global thyroid cancer incidence trend and age-period-cohort model analysis based on Global Burden of Disease Study from 1990 to 2019

BackgroundIn view of the rapid increase in the incidence of thyroid cancer (TC) and the spread of overdiagnosis around the world, the quantitative evaluation of the effect of age, period and birth cohort on the incidence of TC, and the analysis of the role of different factors in the incidence trend can provide scientific basis and data support for the national health departments to formulate reasonable prevention and treatment policies.MethodsThe study collated the global burden disease study data of TC incidence from 1990 to 2019, and used APC model to analyze the contribution of age, period and birth cohort to the incidence trend of TC.ResultsThere was an obvious unfavorable upward trend in terms of age and cohort effect all over the world. Since 2007, the growth rate of risk slowed down and the risk in female even decreased since 2012, which mainly contributed to the developed countries. In all SDI countries, 2002 is the dividing point of risk between male and female. In 2019, The global age-standardized incidence rate (ASIR) of TC in the 5 SDI countries all showed a significant upward trend, with the largest upward trend in the middle SDI countries.ConclusionThe trend of rapid increase in the incidence of TC has begun to slow down, but the global incidence of TC has obvious gender and regional/national heterogeneity. Policy makers should tailor specific local strategies to the risk factors of each country to further reduce the burden of TC

Alterations of Serum Levels of BDNF-Related miRNAs in Patients with Depression

Depression is a serious and potentially life-threatening mental disorder with unknown etiology. Emerging evidence shows that brain-derived neurotrophic factor (BDNF) and microRNAs (miRNAs) play critical roles in the etiology of depression. Here this study was aimed to identify and characterize the roles of BDNF and its putative regulatory miRNAs in depression. First, we identified that miR-182 may be a putative miRNA that regulates BDNF levels by bioinformatic studies, and characterized the effects of miR-182 on the BDNF levels using cell-based studies, side by side with miR-132 (a known miRNA that regulates BDNF expression). We showed that treatment of miR-132 and miR-182 respectively decreased the BDNF protein levels in a human neuronal cell model, supporting the regulatory roles of miR-132 and miR-182 on the BDNF expression. Furthermore, we explored the roles of miR-132 and miR-182 on the BDNF levels in depression using human subjects by assessing their serum levels. Compared with the healthy controls, patients with depression showed lower serum BDNF levels (via the enzyme-linked immunosorbent assays) and higher serum miR-132 and miR-182 levels (via the real-time PCR). Finally, the Pearson’s (or Spearman’s) correlation coefficient was calculated to study whether there was a relationship among the Self-Rating Depression Scale score, the serum BDNF levels, and serum BDNF-related miRNA levels. Our results revealed that there was a significant negative correlation between the SDS scores and the serum BDNF levels, and a positive correlation between the SDS scores and miR-132 levels. In addition, we found a reverse relationship between the serum BDNF levels and the miR-132/miR-182 levels in depression. Collectively, we provided evidence supporting that miR-182 is a putative BDNF-regulatory miRNA, and suggested that the serum BDNF and its related miRNAs may be utilized as important biomarkers in the diagnosis or as therapeutic targets of depression