Expression of REGγ in atherosclerotic plaques and promotes endothelial cells apoptosis via the cyclophilin A pathway indicates functional implications in atherogenesis

REGγ is a member of the 11S regulatory particles family of proteasome activators and has been shown to promote the degradation of intact cellular proteins in a ubiquitin- and ATP-independent manner in the progression of various diseases. Our previous studies showed that REGγ-proteasome promotes Protein kinase A catalytic subunit α (PKAcα) turnover to modulate Forkhead box protein O1 (FoxO1) cellular activity in vascular endothelial cell migration and angiogenesis. We, therefore, studied the expression and novel functional implications and pathways involving REGγ in atherogenesis. We studied the expression of REGγ in atherosclerotic plaques in the ApoE-/- mouse model. Using immunohistochemistry, we showed that REGγ was highly expressed in these plaques, and the result of RNA-seq in Human umbilical vein endothelial cells (HUVECs), led us to explore and indentify that REGγ significantly promoted cyclophilin A (CyPA) expression, which is a proinflammatory and proapoptotic molecule in atherosclerosis progression. Next, we studied the regulation of REGγ in CyPA expression, and the proapoptotic effect on Endothelial cells (ECs). REGγ promoted CyPA expression via the REGγ-PKA-FoxO1-CyPA axis, and stimulated CyPA-dependent ECs apoptosis in vitro. Our data indicated that REGγ had proapoptotic effects on ECs depends on CyPA pathway in vitro and functional implications in atherogenesis in vivo.</p

MiR-217 targets WASF3 in osteosarcoma cells.

<p>(A) The sequences of miR-217 binding sites within the human WASF3 3′UTR and schematic reporter constructs, in this panel, WASF3-WT represent the reporter constructs containing the entire 3′UTR sequences of WASF3. WASF3-MUT represent the reporter constructs containing mutated nucleotides. (B) The analysis of the relative luciferase activities of WASF3-WT, WASF3-MUT in 293T cells. The error bars are derived from triplicate expriments. (C) qRT-PCR analysis of WASF3 mRNA expression in MG-63 cells after treatment with miRNA mimics or scramble or no transfection. The expression of WASF3 was normalized to GAPDH. (D) Western blot analysis of WASF3 expression in MG-63 cells transfected with miR-217 mimics or scramble or no transfection. GAPDH was also detected as a loading control. All data uses t test and is shown as mean ±SEM.</p

Restore WASF3 expression impairs miR-217-induced inhibition of proliferation and invasion in osteosarcoma cells.

<p>(A) Western blot analysis of WASF3 in MG-63 cells co-transfectedwith either miR-217 mimic or scramble and 2.0 µg pCDNA-WASF3 orpCDNA empty vector. (B) The relative WASF3 protein was showed with different combinations. The signal in each lane was quantified using ImageJ software and the ratio of WASF3 to GAPDH was determined. (C) Cell growth curves in MG-63 cells transfected with different combinations using CCK-8 analysis. (D) The relative ratio of wound closure per field with different combinations is shown. (E) Transwell analysis of MG-63 cells treated with different combinations. The invasive cells per field is shown right. (F) Wound healing assays of MG-63 cells after treatment with different combinations. (G) Western blot analysis of WASF3 expression in 8 miR-217 down-regulated osteosarcoma tissues and their pair-matched nontumor tissues. GAPDH was also detected as a loading control. All data uses t test and is shown as mean ±SEM. *p<0.05,** p<0.01,***p<0.001.</p

Overexpression of miR-217 inhibits the osteosarcoma cell line MG-63 proliferation, migration, and invasion.

<p>(A) Expression levels of miR-217 were examined by qRT-PCR after transfection of 20 nmol/L of miR-217 mimics, inhibitors or sramble or no transfection in the cell line MG-63. (B) The cells treated with miR-217 mimics, inhibitors or sramble or no transfection were measured by CCK8 assay at different time periods. (C) Wound healing assays of MG-63cells after treatment with miRNA mimics, inhibitors or scramble or no transfection; the relative ratio of wound closure per field is shown. (D) Transwell analysis of MG-63 cells after treatment withmiRNA mimics, inhibitors or scramble or no transfection; the invasive cells per field is shown below, All data uses t test and is shown as mean ±SEM. *p<0.05,** p<0.01, and ***p<0.001.</p

MicroRNA-217 Regulates WASF3 Expression and Suppresses Tumor Growth and Metastasis in Osteosarcoma

<div><p>Osteosarcoma is the most common type of primary tumor of bone which mainly affects adolescents and young adults. Osteosarcoma causes large number of deaths because of its complex pathogenesis and resistance to conventional treatment. MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs, causing translational repression or degradation. In this study, we showed that miR-217 was down-regulated in osteosarcoma cell lines and tissues in comparison to that in normal bone cells or tissues. Meanwhile, the lower level of miR-217 was associated with metastasis in clinical osteosarcoma patients. Furthermore, we found that overexpession of miR-217 markedly suppressed cell proliferation, migration, and invasion of osteosarcoma cells. Conversely, the inhibition of miR-217 expression significantly accelerated the cell proliferation, migration, and invasion. Moreover, we identified WASF3 as a novel functional downstream target of miR-217. The ectopic expression of WASF3 can partially reverse the inhibition of cell proliferation and invasion caused by miR-217. Take together, our results demonstrate that miR-217 functions as a tumor-suppressive miRNA and inhibits the osteosarcoma tumorigenesis through targeting WASF3.</p></div

DataSheet_1_Effect of thyroid dysfunction on N-terminal pro-B-type natriuretic peptide levels: A systematic review and meta-analysis.docx

PurposeThyroid hormones (THs) significantly affect the cardiovascular system. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful biomarker for diagnosing, evaluating, and predicting outcomes in heart failure (HF). This comprehensive review and meta-analysis aimed to investigate the effects of thyroid dysfunction (hypothyroidism and hyperthyroidism) on NT-proBNP levels.MethodsTwo investigators independently searched PubMed, Embase, Cochrane Library, and Web of Science databases for studies published from inception to July 31, 2022, without any restrictions on language.Results21 studies were included. In participants without HF, NT-proBNP levels may be elevated in those with overt hyperthyroidism (standardized mean difference [SMD] 2.38, 95% confidence interval [CI]:1.0-3.76). Notably, among patients with preexisting HF, significantly higher NT-proBNP levels were found in patients with overt hyperthyroidism, overt hypothyroidism, or subclinical hypothyroidism than in euthyroid subjects (SMD [95%CI] = 0.31[0.01, 0.62], 0.32[0.08, 0.56], and 0.33[0.21, 0.46], respectively). Seven trials compared NT-proBNP levels in patients with thyroid dysfunction before and after therapy, and significant drops in NT-proBNP levels were observed in patients with hyperthyroidism (SMD [95%CI] = -1.53[-2.50, -0.55]) upon achieving a euthyroid state. In contrast, increased NT-proBNP levels were observed in hypothyroid patients after treatment (SMD [95%CI] = 1.07[0.28, 1.85]).ConclusionThyroid dysfunction can significantly affect NT-proBNP levels, which may change upon achieving a euthyroid state. Notably, the effect of thyroid dysfunction on cardiac function may depend on the underlying cardiac status. Thus, timely recognition and effective treatment of cardiac symptoms in patients with thyroid dysfunction are mandatory because the prognosis of HF may be improved with appropriate treatment of thyroid dysfunction.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42022353700.</p

miR-217 is downregulated in human osteosarcoma cell lines and tissues.

<p>(A) Relative expression of miR-217 in four human osteosarcoma cell lines (MG-63, U2OS, SOSP-9607, and SAOS-2) and one normal bone cell line (hFOB) was determined by qRT-PCR. Quantification of miR-217 was measured by qRT-PCR with specific primers for miR-217 and snRNA U6. (B) Relative expression of miR-217 in 60 primary osteosarcoma tissues compared with their pair-matched nontumor tissues. Data areshown as log10 of relative ratio change of osteosarcoma tissues relative tonormal tissues. (C) Relative miR-217expressionlevels in osteosarcoma tissues and adjacent normal regions; (D)The expression of miR-217 in the osteosarcoma tissues from the patients with metastases was lower than that in non-metastases tissues. All data uses t test and is shown as mean ±SEM.</p

Table_1_Policy analysis in the field of rare diseases in China: a combined study of content analysis and Bibliometrics analysis.docx

IntroductionThe Chinese government has made significant strides in addressing the needs of individuals affected by rare diseases in recent years. This paper aims to provide a comprehensive analysis of national rare disease policies in China from 2009 to 2022, using a mixed-methods approach.MethodsA two-dimensional analytical framework, which includes policy tools and policy themes, is introduced to analyze the rare disease policies comprehensively. Drawing on the policy tools theory proposed by Rothwell and Zegveld, this paper evaluates the tools used in rare disease policies. Co-word analyses and network analyses are employed to identify key themes in rare disease policies and collaboration among government departments.ResultsThe rare disease policy landscape in China is undergoing rapid growth, with an increasing number of government departments involved in policy formulation. However, further collaboration between departments is needed to strengthen these policies. Environment-based and supply-based tools are preferred in rare disease policies. The policy themes can be grouped into four categories: (1) Registration, Approval and Supply of Rare Disease Drugs, (2) Construction of Diagnosis and Treatment System for Rare Diseases, (3) Development and Genericization of Rare Disease Drugs, and (4) Social Security for Patients with Rare Diseases.DiscussionThe study provides valuable insights into the current state of rare disease policies in China and offers suggestions for policy improvement. The results show that the Chinese government has made efforts to address the needs of individuals affected by rare diseases, but there is still room for improvement. The collaboration between government departments needs to be strengthened to achieve better rare disease policies. The findings of this study have implications for other countries with similar healthcare systems and can contribute to a better understanding of the impact of rare disease policies on public health.</p

Additional file 1 of Identification of a novel metabolism-related gene signature associated with the survival of bladder cancer

Additional file 1: Figure S1. The KM survival curves of MAOB, FASN and LRP1 in the training, testing and validation sets. (A) The training set. (B) The testing set (C) The validation set

Head Injury as a Risk Factor for Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of 32 Observational Studies

<div><p>Background</p><p>Head injury is reported to be associated with increased risks of dementia and Alzheimer’s disease (AD) in many but not all the epidemiological studies. We conducted a systematic review and meta-analysis to estimate the relative effect of head injury on dementia and AD risks.</p><p>Methods</p><p>Relevant cohort and case-control studies published between Jan 1, 1990, and Mar 31, 2015 were searched in PubMed, Web of Science, Scopus, and ScienceDirect. We used the random-effect model in this meta-analysis to take into account heterogeneity among studies.</p><p>Results</p><p>Data from 32 studies, representing 2,013,197 individuals, 13,866 dementia events and 8,166 AD events, were included in the analysis. Overall, the pooled relative risk (RR) estimates showed that head injury significantly increased the risks of any dementia (RR = 1.63, 95% CI 1.34–1.99) and AD (RR = 1.51, 95% CI 1.26–1.80), with no evidence of publication bias. However, when considering the status of unconsciousness, head injury with loss of consciousness did not show significant association with dementia (RR = 0.92, 95% CI 0.67–1.27) and AD (RR = 1.49, 95% CI 0.91–2.43). Additionally, this positive association did not reach statistical significance in female participants.</p><p>Conclusions</p><p>The findings from this meta-analysis indicate that head injury is associated with increased risks of dementia and AD.</p></div