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Tumour necrosis factor (TNF) superfamily member 11 (TNFSF11), also known as RANKL, plays a crucial role in regulating several physiological and pathological activities. Additionally, it is a vital factor in bone physiology, and the sex hormone progesterone regulates the expansion of stem cells and the proliferation of mammary epithelial cells. It is essential for animal growth and reproductive physiological processes. This study aimed to evaluate the tissue-specific expression characteristics and promoter activity of the TNFSF11 gene in pigs. As a result, the study examined the presence of TNFSF11 expression in the tissues of Xiangsu pigs at 0.6 and 12 months of age. Moreover, the core promoter region of TNFSF11 was also identified by utilizing a combination of bioinformatic prediction and dual-luciferase activity tests. Finally, the effect of transcription factors on the transcriptional activity of the core promoter region was determined using site-directed mutagenesis. TNFSF11 was uniformly expressed in all tissues; however, its expression in muscles was comparatively low. The core promoter region of TNFSF11 was located in the −555 to −1 region. The prediction of the transcription start site of TNFSF11 gene-2000 ∼ + 500bp showed that there was a CpG site in 17 ∼ + 487bp. Analysis of mutations in the transcription factor binding sites revealed that mutations in the Stat5b , Myog , Trl , and EN1 binding sites had significant effects on the transcriptional activity of the TNFSF11 gene, particularly following the EN1 binding site mutation (P < 0.001). This study provides insights into both the tissue-specific expression patterns of TNFSF11 in the tissues of Xiangsu pigs and the potential regulatory effects of transcription factors on its promoter activity. These results may be helpful for future research aimed at clarifying the expression and role of the porcine TNFSF11 gene. [ABSTRACT FROM AUTHOR]

Background. MicroRNAs (miRNAs) play an important role in the pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH). However, the potential correlation between miRNA expression and the severity of CTEPH remains unclear. Our previous study indicated that miRNAs hsa-let-7b-3p, hsa-miR-17-5p, hsa-miR-106b-5p, hsa-miR-3202, hsa-miR-665, and hsa-miR-93-5p are closely involved in CTEPH. This study assessed the associations between the expression levels of these miRNAs and clinical parameters in CTEPH patients. Methods. A total of eight CTEPH patients and eight healthy adults as a reference group were included, and clinical data including total protein (TP), albumin (Alb), lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), uric acid (UA), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were collected. Right heart catheterization was conducted to obtain hemodynamic data including cardiac index (CI). The expression levels of let-7b-3p, miR-17-5p, miR-106b-5p, miR-3202, miR-665, and miR-93-5p were measured by quantitative real-time PCR (qPCR). Correlation analysis was applied to estimate the associations between miRNA expression levels and clinical parameters in CTEPH patients. Results. Serum TP and Alb levels were decreased, while LDH, HBDH, and UA levels were increased in CTEPH patients compared with the reference group (P < 0.05). miR-3202 and miR-665 were upregulated, whereas let-7b-3p, miR-17-5p, miR-106b-5p, and miR-93-5p were downregulated in CTEPH patients relative to the reference group (P < 0.05). miR-93-5p expression was positively correlated with NT-proBNP level and negatively correlated with CI (P < 0.05). Moreover, let-7b-3p tended to be positively correlated with mean pulmonary arterial pressure. Conclusions. miR-93-5p expression was associated with the severity of CTEPH and could act as a potential predictor of high-risk CTEPH. [ABSTRACT FROM AUTHOR]

The aim of this study was to understand the importance of chronic thromboembolic pulmonary hypertension- (CTEPH-) associated microRNAs (miRNAs). miRNAs differentially expressed in CTEPH samples compared with control samples were identified, and the target genes were predicted. The target genes of the key differentially expressed miRNAs were analyzed, and functional enrichment analyses were carried out. Finally, the miRNAs were detected using RT-PCR. Among the downregulated miRNAs, MiR-3148 regulated the most target genes and was significantly enriched in pathways in cancer, glioma, and ErbB signaling pathway. Furthermore, the number of target genes coregulated by miR-3148 and other miRNAs was the most. AR (androgen receptor), a target gene of hsa-miR-3148, was enriched in pathways in cancer. PRKCA (Protein Kinase C Alpha), also a target gene of hsa-miR-3148, was enriched in 15 of 16 KEGG pathways, such as pathways in cancer, glioma, and ErbB signaling pathway. In addition, the RT-PCR results showed that the expression of hsa-miR-3148 in CTEPH samples was significantly lower than that in control samples (P<0.01). MiR-3148 may play an important role in the development of CTEPH. The key mechanisms for this miRNA may be hsa-miR-3148-AR-pathways in cancer or hsa-miR-3148-PRKCA-pathways in cancer/glioma/ErbB signaling pathway. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurodegenerative disease. Majority of PD cases are sporadic, resulting from interaction of genetic and environmental factors. Accumulating evidence indicates that autophagy, which delivers alpha-synuclein to lysosomes for degradation, is involved in the PD pathogenesis. Some lysosomal hydrolases, such as glucocerebrosidase gene and ATP13A2, a lysosomal ATPase gene, have been implicated in PD. We have previously screened the activities of a group of lysosomal hydrolases in sporadic PD patients and found that alpha-galactosidase A (GLA) activities are significantly decreased. In this study, we analyzed GLA gene in sporadic PD patients by sequencing its promoter and exon regions. One single-nucleotide polymorphism (SNP) in the promoter region, rs3027580 (NG_007119.1:g.4292G>C), and two SNPs in the GLA 5′-untranslated region, rs2071225 (NM_000169.2:c.−10C>T) and rs3027585 (NM_000169.2:c.−12G>A), were identified with similar frequencies in sporadic PD patients and healthy controls. A novel variant (NG_007119.1:g.4488C>G) within the promoter region, at the −573 site upstream of the translation start codon (ATG), was found in one male PD patient, but not in female PD patients or healthy controls. Our data suggest that the sequence variant may affect GLA gene expression by altering transcription factor binding sites, contributing to the pathogenesis of sporadic PD. [ABSTRACT FROM AUTHOR]

Abstract: Parkinson''s disease (PD) is a progressive neurodegenerative disease caused by interaction of genetic and environmental factors. To date, genetic genes and variants causing PD remain largely unknown. Autophagy is a conserved cellular process including three subtypes, macroautophagy (hereafter referred to as autophagy), microautophagy and chaperone-mediated autophagy (CMA). Although reduced CMA and induced autophagy are observed in human PD brain samples, cell and animal PD models, CMA and autophagy have not been systemically studied in sporadic PD patients. In the peripheral leukocytes of sporadic PD patients, we examined gene expression levels of lysosome-associated membrane 2 (LAMP-2), a CMA receptor and a limiting step, and microtubule-associated protein 1 light chain 3 (LC3), product of which is sequentially cleaved and lipidated to form LC3-II as an autophagosome marker. Compared to age- and sex-matched healthy controls, LAMP-2 gene expression and protein levels in sporadic PD patients were significantly decreased, which may lead to reduced CMA activity and impaired fusion of autophagosome and lysosome. LC3 gene expression and LC3-II protein levels were significantly increased in sporadic PD patients, suggesting that autophagosomes are accumulated. Our findings, decreased LAMP-2 gene expression and increased LC3 gene expression, are consistent to the previous studies with dopaminergic neuronal cells in vitro and in vivo, which may contribute to the pathogenesis of sporadic PD by altering CMA and autophagy activities. The genetic causes leading to decreased LAMP-2 gene expression need further investigation and genetic or pharmacological restoration of LAMP-2 might be a novel strategy for treating PD patients. [Copyright &y& Elsevier]

Abstract: Bone marrow stromal stem cells (MSCs), which normally differentiate into mesenchymal derivatives, have recently reported to trans-differentiate into neurons. However, the findings from different groups and interpretations have been challenged. The purpose of this paper is to re-evaluate the phenomenon of neuronal trans-differentiation of MSCs and compare the expression levels of neurotrophins in rMSCs and neuronal-like phenotypes derived from rMSCs. We put rMSCs in 2-mercaptoethanol and 2% dimethylsulfoxide for 5h. Then, the cells were transferred to neuronal induction media composed of DMEM+10%FBS, 10ug/L basic fibroblast growth factor, 10ug/L human epidermal growth factor, 1mmol dibutyryl cyclicn AMP and 0.5mmol isobutylmethylxanthine for 7 days and 14 days. The study demonstrated that the level of BDNF, NGF, NT3, CNTF and GDNF of rMSCs is remarkably higher in rMSCs than the neuronal-like phenotypes, especially CNTF. The expression level of these neurotrophins did not change significantly after enduring induction. We believed that rMSCs can trans-differentiate into neuronal-like phenotype under certain conditions. The non-induced rMSCs has a dynamic expression profile of neurotrophins and may serves as a better tool than the trans-differentiated rMSCs for transplant therapy. [Copyright &y& Elsevier]