Mesenchymal stem cells-derived extracellular vesicle-incorporated H19 attenuates cardiac remodeling in rats with heart failure.

Cardiac remodeling is manifested by hypertrophy and apoptosis of cardiomyocytes, resulting in the progression of cardiovascular diseases. Long noncoding RNAs (lncRNAs) serve as modifiers of cardiac remodeling. In this study, we aimed to explore the molecular mechanism of H19 shuttled by mesenchymal stem cells (MSC)-derived extracellular vesicles (EV) in cardiac remodeling upon heart failure (HF). Using the GEO database, H19, microRNA (miR)-29b-3p, and CDC42 were screened out as differentially expressed biomolecules in HF. H19 and CDC42 were elevated, and miR-29b-3p was decreased after MSC-EV treatment in rats subjected to ligation of the coronary artery. MSC-EV alleviated myocardial injury in rats with HF. H19 downregulation exacerbated myocardial injury, while miR-29b-3p inhibitor alleviated myocardial injury. By contrast, CDC42 downregulation aggravated the myocardial injury again. PI3K/AKT pathway was activated by MSC-EV. These findings provide insights into how H19 shuttled by EV mitigates cardiac remodeling through a competitive endogenous RNA network regarding miR-29b-3p and CDC42.

The small peptide VISP1 acts as a selective autophagy receptor regulating plant-virus interactions.

Selective macroautophagy/autophagy is tightly regulated by cargo receptors that recruit specific substrates to the ATG8-family proteins for autophagic degradation. Therefore, identification of selective receptors and their new cargoes will improve our understanding of selective autophagy functions in plant development and stress responses. We have recently demonstrated that the small peptide VISP1 acts as a selective autophagy receptor to mediate degradation of suppressors of RNA silencing (VSRs) of several RNA and DNA viruses. Moreover, VISP1 induces symptom recovery through fine-tuning the balance of plant immunity and virus pathogenicity. Our findings provide new insights into the double-edged sword roles of selective autophagy in plant-virus interactions.

Deficiency of astrocyte CysLT1R ameliorates depression-like behaviors in mice by modulating glutamate synaptic transmission.

Our previous study suggests that hippocampal cysteinyl leukotriene receptor 1 (CysLT1R) could be involved in depression. Herein we hypothesize that CysLT1R may regulate depression by affecting synaptic glutamate cycling based on existence of CysLT1R in the astrocytes that participate in occurrence of depression. We found that CysLT1R expression was significantly increased in the astrocyte of chronic unpredictable mild stress (CUMS)-induced depression-like mice, CysLT1R astrocyte-specific conditional knockout (AcKO) significantly improved depression-like behaviors, as indicated by decreased immobility time in the forced swimming test and tail suspension test and increased sucrose preference in the sucrose preference test, and knockdown of CysLT1R in the astrocyte of dentate gyrus (DG), the region with the most significant increase of CysLT1R in the astrocyte of depression-like mice, produced similar effects. Correspondingly, overexpression of CysLT1R in the astrocyte of DG induced depression-like behaviors in mice. The further study showed that CysLT1R AcKO ameliorated synaptic plasticity impairment, as reflected by increased synapse, LTP and PSD95, and promoted glutamate transporter 1 (GLT-1) expression by inhibiting NF-κB p65 nuclear translocation mediated by ß-arestin2 and clatrhin, subsequently decreased glutamate in synaptic cleft and GluN2B on postsynaptic membrane in depression-like mice. The present study also showed that GLT-1 agonist or NF-κB inhibitor ameliorated depressive-like behaviors induced by overexpression of the astrocyte CysLT1R of DG. Our study demonstrated that astrocyte CysLT1R regulated depression by modulating glutamate synaptic transmission, suggesting that CysLT1R could be a potential target for developing novel drugs of anti-depression.

Interpretation of ischiofemoral impingement via a clinical test using hip triaxial dynamic magnetic resonance imaging.

BACKGROUND: The present study aimed to use magnetic resonance (MR) to explore the dynamic changes of the ischiofemoral space (IFS) under the triaxial motion of the hip joint and verify the clinical test mechanism for ischiofemoral impingement (IFI). METHODS: A prospective design was used to screen 37 patients with clinically confirmed IFI, which included a total of 67 lateral hips, and 39 healthy controls with a total of 69 lateral hips. A dynamic MR examination was performed in positions designed by a simulated IFI test (adduction, adduction with 30° external rotation, 30° internal rotation, supine with 30° flexion, and prone with 30° backward extension). The IFS (mm) and quadratus femoris space (QFS, mm) were measured in different positions. All the data were evaluated independently by three musculoskeletal radiologists. The differences between the two groups were compared using the two-tailed t-test. RESULTS: The IFS and QFS in the case group were smaller than those in the control group. The IFS and QFS were significantly reduced in the prone with backward extension and adduction with external rotation positions of the hip. The correlation coefficients of the IFI test and long-stride walking (LSW) test were -0.621 and -0.715 for IFS and -0.653 and -0.696 for QFS, respectively. CONCLUSIONS: In this study, the mechanism of the IFI-specific clinical examination (IFI and LSW tests) was verified by triaxial dynamic MR imaging of the hip joint, which provided a dynamic imaging basis for the clinical application of the IFI-specific impingement test. The IFI impingement test can be used as a specific clinical test for IFI screening.

Hippocampal CysLT1R overexpression or activation accelerates memory deficits, synaptic dysfunction, and amyloidogenesis in young APP/PS1 transgenic mice.

BACKGROUND: Our previous studies demonstrated that cysteinyl leukotrienes receptor 1 (CysLT1R) knockout, pharmacological blockade, or hippocampus knockdown produced beneficial effects against Alzheimer's disease (AD); however, whether CysLT1R upregulation has deleterious effects on AD remains elusive. METHODS: In this study, we investigated the changes in behaviors, hippocampal amyloidogenesis, and synapse plasticity after CysLT1R overexpression by microinfusion of the lentiviral vector, containing its coding sequence of mouse (LV-CysLT1R), into the bilateral dentate gyri (DG) of the hippocampus or CysLT1R activation by repeated systemic administration of its agonist YM-17690 (0.1 mg/kg, once a day, i.p., for 28 d). RESULTS: The behavior data showed that overexpression of CysLT1R in hippocampal DG or administration of YM-17690 deteriorated behavioral performance in Morris water maze (MWM), Y-maze tests, and novel object recognition (NOR) in young APP/PS1 mice. The further studies showed that these treatments significantly destroyed synaptic function, as evidenced by impaired hippocampal long-term potentiation (LTP), decreased spine density, low number of synapses, and decreased postsynaptic protein (PSD95), and promoted the generation of amyloid ß (Aß) through increased expression of BACE1 and PS1 in the hippocampus of young APP/PS1 mice. CONCLUSIONS: Together, our results indicate that CysLT1R upregulation accelerates memory impairment in young APP/PS1 mice, which is associated with promoting synaptic dysfunction and amyloidogenesis in the hippocampus.

A small peptide inhibits siRNA amplification in plants by mediating autophagic degradation of SGS3/RDR6 bodies.

Selective autophagy mediates specific degradation of unwanted cytoplasmic components to maintain cellular homeostasis. The suppressor of gene silencing 3 (SGS3) and RNA-dependent RNA polymerase 6 (RDR6)-formed bodies (SGS3/RDR6 bodies) are essential for siRNA amplification in planta. However, whether autophagy receptors regulate selective turnover of SGS3/RDR6 bodies is unknown. By analyzing the transcriptomic response to virus infection in Arabidopsis, we identified a virus-induced small peptide 1 (VISP1) composed of 71 amino acids, which harbor a ubiquitin-interacting motif that mediates interaction with autophagy-related protein 8. Overexpression of VISP1 induced selective autophagy and compromised antiviral immunity by inhibiting SGS3/RDR6-dependent viral siRNA amplification, whereas visp1 mutants exhibited opposite effects. Biochemistry assays demonstrate that VISP1 interacted with SGS3 and mediated autophagic degradation of SGS3/RDR6 bodies. Further analyses revealed that overexpression of VISP1, mimicking the sgs3 mutant, impaired biogenesis of endogenous trans-acting siRNAs and up-regulated their targets. Collectively, we propose that VISP1 is a small peptide receptor functioning in the crosstalk between selective autophagy and RNA silencing.

Comparison of three treatment methods for simple bone cyst in children.

BACKGROUND: The unicameral bone cyst (UBC) is a kind of benign tumor whose clinical treatments and efficacy are controversial. The purpose of this study was to evaluate the efficacy of the elastic stable intramedullary nail (ESIN), the injection of autologous bone marrow (ABM), and the combination of ESIN and ABM in the treatment of bone cyst in children. METHODS: Eighty-three cases with simple bone cyst were analyzed retrospectively. Twenty-eight cases were treated with ABM. Twenty-eight cases were treated with ESIN. Twenty-seven cases were treated with ABM and ESIN. All cases were diagnosed through X-ray, CT, or MRI scans. For the suspicious ones, the pathological biopsy was performed for an accurate diagnosis. X-ray examinations were carried out for the postoperative follow-up. Capanna criteria for bone cyst was used for postoperative evaluation of three methods. RESULTS: All cases accomplished the follow-up. The effective rate of the ABM + ESIN group was significantly higher than that of the ABM group (P < 0.05), and the cure rates of the ESIN group and the ABM + ESIN group were higher than that of the ABM group (P < 0.05, respectively). The cure time in the ESIN group was lower than that of the other two groups (P < 0.05, respectively). The times for admission were 2.0 ± 0.0 in the ESIN group, 5.7 ± 1.9 in the ABM group, and 4.7 ± 2.4 in the ABM + ESIN group (P < 0.05 when compared with each other). CONCLUSIONS: The method of ABM combined with ESIN for children's bone cyst has the highest effective rate and curative rate. For the individual method, ESIN has a higher effective rate and curative rate than that of ABM. Meanwhile, it has the fewest time of hospitalization.

Personal exposure to PM2.5 associated with heavy metals in four travel modes of Tianjin during the summer season.

Personal exposure to PM2.5 associated with heavy metals were investigated at and around the same road by cycling, walking, taxi and bus in Tianjin, China. One trip on each mode was undertaken during 4 h of both morning and evening peak hours. Results of one-way analysis of variance (ANOVA) to compare mean concentrations of PM2.5 and each metal measured by four modes, the enrichment level of heavy metals in four modes and the carcinogenic, non-carcinogenic risk and probabilistic estimation of health risks of metals (Cr, Ni, Cu, Zn and Pb). Arithmetic means of PM2.5 personal exposure were 323.66, 313.37, 214.84 and 160.71 µg/m3 for cycling, walking, bus and taxi, which resulted from the difference of source (vehicle exhaust and road dust) of exposure to PM2.5. Na has the highest concentration, followed by Al, Ca, K, Fe, Mg, Zn, Ni, Pb, Cu and Cr. The higher Na concentrations were observed in Tianjin in light of its major sea salt influence. The concentrations of Ca, Mg, Fe and Zn in four modes followed different orders, while other metals have no significant difference between four modes. Enrichment factors of metals in PM2.5 showed that some metals are enriched, ranging from contaminated to extremely contaminated, for example, Ni, Cu, Zn, Pb, Na and Cr. Others are barely enriched such as Ca, K, Mg and Fe. It illustrated the former is mainly effected by anthropogenic activates and the source of latter comes from crust. From the results of non-carcinogenic and carcinogenic risks of metals, the intake of metals with inhalation for 4 h by four modes did not pose a significant potential chronic-toxic risk and was an acceptable or tolerable risk at present. But uncertainty analysis of health risks showed there were 4.05 and 6.87% probability that make carcinogenic risk values to exceed 10-4 when male choose walking/cycling to work. Commuters' rush hour exposures were significantly influenced by mode of transport. We suggest that future work should focus on further research between heavy metals in PM2.5 exposure and its specific epidemiology effects.

[Advances in the research of pharmacogenomics of tamoxifen].

Tamoxifen (TAM) is the most common nonsteroidal antiestrogen agent, which has been widely used in the prevention of recurrence of estrogen or progesterone receptor-positive breast cancer in patients. It is metabolized by cytochrome P450 oxidases to its active metabolite (4-hydroxytamoxifen, 4-OH-TAM) and endoxifen (EDF), which played a critical role in the therapy. 4-OH-TAM and EDF have 30- to 100-fold more potency than TAM in the suppression of estrogen-dependent breast cancer cell proliferation. CYP3A4 and CYP2D6, as the key drug-metabolizing enzymes in those metabolic actions, are known to have several alleles. Genetic polymorphisms of CYP2D6 and CYP3A4 will influence the plasma concentrations of active TAM metabolites and clinical outcomes for breast cancer patients treated with TAM. The genetic polymorphisms of drug transporters, involved in the disposition of active TAM metabolites, also have the potential to influence the plasma concentrations of active TAM metabolites and clinical outcome for the treatment of breast cancer. In this review, we summarized the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the metabolism and disposition of TAM with the metabolite concentration, efficacy and adverse effects of TAM, which provides a fundamental reference for further pharmacogenomic study and clinical use of TAM.

[BRCA1 selectively regulates the expression of progesterone receptor A in sporadic invasive ductal breast carcinoma].

OBJECTIVE: To investigate the expression level of BRCA1, progesterone receptor A (PRA) and B (PRB) in tissue of sporadic invasive ductal breast carcinoma and further statistically analyze the BRCA1 effects on the expression rates of PRA and PRB. METHODS: Sixty-eight cases of adenosis of breast and sporadic invasive ductal breast carcinoma were selected. The corresponding paraffin-embodied tissues were collected from the archive of Department of Pathology, Nanfang Hospital. The expressions level of BRCA1, PRA and PRB were detected by immunohistochemistry. Wilcoxon two-sample test was used to analyze the differential expression of BRCA1 between adenosis and sporadic invasive ductal breast carcinoma. Chi-square test was used to analyze the effects of BRCA1 on the PRA or PRB expression rate. P value < 0.05 was considered statistically significant. RESULTS: (1) In invasive sporadic ductal breast carcinoma, the positive rate of BRCA1 expression of 60.29% (41/68) was lower than the positive rate of BRCA1 expression at 85.30% (58/68) in adenosis of breast. And the difference of BRCA1 expression between two groups was statistically significant (P < 0.01); (2) In invasive sporadic ductal breast carcinoma, the positive rate of PRA expression for negative BRCA1 expression samples was 81.48% (22/27) and it was higher than the positive rate of PRA expression at 53.66% (22/47) for positive BRCA1 expression samples. And the difference of PRA expression rates between two groups was statistically significant (P < 0.05). It indicated that the expression of BRCA1 affected the expression rate of PRA; In invasive sporadic ductal breast carcinoma, the PRB expression rates between positive and negative BRCA1 expression samples were not statistically significant (P > 0.05). It indicated that BRCA1 had no effect upon the expression rate of PRB. CONCLUSION: In sporadic breast carcinoma, a negative expression of BRCA1 is selectively associated with a higher expression rate of PRA rather than PRB. Thus BRCA1 selectively regulates the expression of PRA in sporadic breast carcinoma.

[Progesterone promotes the proliferation and migration of cultured breast cancer cells].

OBJECTIVE: To investigate the effects of progesterone on the growth and migration of breast cancer cells. METHODS: MCF-7 and T-47D cells were cultured in DMEM and stimulated with 100 nmol/L progesterone for 48 h, and the cell proliferation was evaluated by MTT assay, cell migration by wound-healing assay and E-catherin expression by Western blotting. RESULTS: Progesterone stimulated the cell proliferation and migration and down-regulated the expression of E-catherin in both MCF-7 and T-47D cells. CONCLUSIONS: Progesterone stimulates the cell proliferation and migration of cultured breast cancer cells, suggesting the clinical significance of anti-progesterone therapy in breast cancer.