Exosome-packaged miR-1246 contributes to bystander DNA damage by targeting LIG4.

BACKGROUND: An increasing number of studies have recently reported that microRNAs packaged in exosomes contribute to multiple biological processes such as cancer progression; however, little is known about their role in the development of radiation-induced bystander effects. METHODS: The exosomes were isolated from the culture medium of BEP2D cells with or without γ-ray irradiation by ultracentrifugation. To monitor DNA damage and repair efficiency, the DNA double-strand break biomarker 53BP1 foci, comet, micronuclei, expression of DNA repair genes and NHEJ repair activity were detected. The miR-1246 targeting sequence of the DNA ligase 4 (LIG4) mRNA 3'UTR was assessed by luciferase reporter vectors. RESULTS: miR-1246 was increased in exosomes secreted from 2 Gy-irradiated BEP2D cells and inhibited the proliferation of nonirradiated cells. The miR-1246 mimic, exosomes from irradiated cells, and radiation-conditioned cell culture medium increased the yields of 53BP1 foci, comet tail and micronuclei in nonirradiated cells, and decreased NHEJ efficiency. miR-1246 downregulated LIG4 expression by directly targeting its 3'UTR. CONCLUSIONS: Our findings demonstrate that miR-1246 packaged in exosomes could act as a transfer messenger and contribute to DNA damage by directly repressing the LIG4 gene. Exosomal miR-1246 may be a critical predictor of and player in radiation-induced bystander DNA damage.

Bone morphogenetic protein 4 is involved in cadmium-associated bone damage.

Cadmium (Cd) is a well-characterized bone toxic agent and can induce bone damage via inhibiting osteogenic differentiation. Bone morphogenetic protein (BMP)/SMAD signaling pathway can mediate osteogenic differentiation, but the association between Cd and BMP/SMAD signaling pathway is yet to be illuminated. To understand what elements of BMPs and SMADs are affected by Cd to influence osteogenic differentiation and if BMPs can be the biomarkers of which Cd-induced osteoporosis, human bone marrow mesenchymal stem cells (hBMSCs) were treated with cadmium chloride (CdCl2) in vitro to detect the expression of BMPs and SMADs, and 134 subjects were enrolled to explore if the BMPs can be potential biomarkers of Cd-associated bone damage. Our results showed that Cd exposure significantly promoted the adipogenic differentiation of hBMSCs and inhibited its osteogenic differentiation by inhibiting the expression of BMP-2/4, SMAD4, and p-SMAD1/5/9 complex. And mediation analyses yielded that BMP-4 mediated 39.32% (95% confidence interval 7.47, 85.00) of the total association between the Cd and the risk of Cd-associated bone damage. Moreover, during differentiation, BMP-4 had the potential to enhance mineralization compared with CdCl2 only group. These results reveal that BMP-4 can be a diagnostic biomarker and therapeutic target for Cd-associated bone damage.

[Analysis of Gene Deficiency Types of Thalassemia in Lingui District of Guilin City].

OBJECTIVE: To analyze the gene defect types and distribution characteristics of α- and ß-thalassemia in Lingui District of Guilin City, Guangxi, so as to provide scientific basis for genetic consultation and prevention measures. METHODS: A total of 6 496 suspected cases for screening the thalassemia during physical examination, premarital examination, pregnancy examination and hospitalization in the Second Affiliated Hospital of Guilin Medical University from May 2016 to October 2019 were analyzed. Gap-PCR, PCR-RDB and DNA sequencing techniques were used to detect the types and constituent ratios of gene defects in α- and ß-thalassemia positive cases. RESULTS: Among 6 496 suspected patients, 1 363 were thalassemia carriers, the total positive rate was 20.98%. There were 677 cases of single-gene deletion and 26 cases of double-gene detetion on the deletional α-thalassemia, 115 cases of non-deletion α-thalassemia mutation and 4 cases of deletion plus mutation. The positive rate of α-thalassemia was 12.66%. There were 11 gene abnormalities for α-thalassemia, of which --SEA/αα (50.36%) was the most common, followed by -α3.7/αα (23.84%); the main α-gene mutation was ααCS (6.93%). There were 514 ß-thalassemia gene carriers, with a positive rate of 7.93%. In 12 types of ß-gene mutations, CD41-42 (-TTCT) (55.64%) was the most common, followed by CD17 (A→T) (20.23%). There were 25 cases of double heterozygous α and ß thalassemia (0.39%), of which -α3.7/ßCD17 (24%) and --SEA/ß41-42 (16%) were numerically dominant. Two of rare thalassemia genotypes were identified by sequencing, which were heterozygous mutations of Chinese Hong Kong type α thalassemia (HKαα/αα or HKαα/-α3.7) and ß gene mutations IVS-I (-2) or codon30 (A→G) ß0, respectively. CONCLUSION: Lingui district of Guilin city is a high incidence area of thalassemia. The mutation rate of α-thalassemia --SEA/αα type deletion is relatively high, followed by that of the right deletion type (-α3.7/αα). CD41-42 (-TTCT) has the highest mutation rate in ß-thalassemia, followed by CD17(A→T). The results of this study provide reference data for the regional screening, diagnosis and treatment of thalassemia and eugenics.

Altered mean platelet volume in children with Henoch-Schonlein purpura and its association with disease activity.

Background Henoch-Schonlein purpura is a systemic small-vessel vasculitis that occurs mainly in children. A review of the literature has suggested a correlation between mean platelet volume and several inflammatory disorders. However, to the best of our knowledge, any potential correlation between mean platelet volume and Henoch-Schonlein purpura has not been reported in the literature. Therefore, our study aimed to evaluate the role of mean platelet volume concentrations in patients with Henoch-Schonlein purpura. Methods This study included 97 children with Henoch-Schonlein purpura and 120 healthy individuals as controls. Results Mean platelet volume concentrations were found to be significantly lower in Henoch-Schonlein purpura patients compared with healthy controls (8.1 ± 0.86 vs. 9.4 ± 0.81, P < 0.001). Similarly, significant negative correlations were observed between mean platelet volume and neutrophil count, platelet count and erythrocyte sedimentation rate in patients with Henoch-Schonlein purpura (r=-0.327, P = 0.001; r=-0.419, P < 0.001; r=-0.255, P = 0.012). Interestingly, mean platelet volume was significantly lower in the acute phase compared with the convalescent phase of Henoch-Schonlein purpura patients (7.8 ± 0.86 vs. 8.3 ± 0.77, P = 0.002). A cut-off value for mean platelet volume was 7.85 with area under the curve of 0.726 to identify acute phase vs. convalescent phase in patients with Henoch-Schonlein purpura. Mean platelet volume was independently associated with Henoch-Schonlein purpura in logistic regression analysis (odds ratio = 0.114, 95% confidence interval = 0.053-0.243, P < 0.001). Conclusions Our results suggest that mean platelet volume is inversely associated with disease in patients with Henoch-Schonlein purpura, and mean platelet volume may be a useful marker to identify active disease in Henoch-Schonlein purpura patients.