Background/Objectives: The polyphenol resveratrol (Rev) has been found to exhibit various beneficial effects including prevention of pulmonary arterial hypertension (PAH). The present study was designed to investigate the action and potential mechanism of Rev on PAH, focusing on the role of SIRT1 (Silent Information Regulator 1) in apoptosis of pulmonary artery smooth muscle cells (PASMCs). Methods: PAH rats were established by exposure to hypoxia for 21 days. Rev and SRT1720 (a selective SIRT1 activator) were used to reverse PAH by gavaging rats. PASMCs were confronted with hypoxia for 24 h or 48 h and were then treated with Rev or SRT1720 in vitro. Western blot was performed to detect the protein expression of SIRT1. CCK-8 and scratch wound experiments were carried out to verify cell proliferation. In addition, the TUNEL positive assay and flow cytometry assay were used to measure PASMC apoptosis. Mitochondrial permeability transition (mPT) was identified by confocal microscopy. Right ventricular systolic pressure (RVSP) was determined with a Gould pressure transducer, and right ventricular hypertrophy (RVH) was determined by weighing the cardiac muscle. Results: We demonstrated that Rev could reverse the remodelling of the pulmonary vasculature, thus contributing to alleviating the severity of PAH. Down-regulation of SIRT1 was observed in PAH, but administration of Rev had no obvious effect on the protein expression of SIRT1. In addition, Rev could induce mitochondrial swelling and nuclear pyknosis, leading to small, dense, and dysmorphic mitochondria in rats exposed to hypoxia alone. Rev treatment inhibited PASMC proliferation in a dose-dependent manner in vitro. Incubation with SRT1720, a specific activator of SIRT1, significantly retarded PASMC proliferation and promoted PASMC apoptosis in vitro. The mechanism could be associated with inducing mPT damage in PASMCs. Rev and SRT1720 treatment mitigated RVSP and reduced RVH. Conclusion: Rev produced a beneficial effect partially by enhancing the activation of SIRT1, thus improving RVSP and reducing RVH. SIRT1 activation increased PASMC apoptosis by inducing mPT dysfunction, which might be a novel future strategy for the treatment of PAH.

No abstract

Background/Aims: Atherosclerosis (AS) is one of the major leading causes of death globally, which is highly correlated with metabolic abnormalities. Resveratrol (REV) exerts beneficial effects on atherosclerosis. Our aim is to clarify the involvement of liver metabolic reprogramming and the atheroprotective effects of REV.Methods: ApoE-deficient mice were administered with normal diet (N), high-fat diet (H), or HFD with REV (HR). Twenty-four weeks after treatment, Oil Red O staining was used to assess the severity of AS. Non-targeted metabolomics was employed to obtain metabolic signatures of the liver from different groups.Results: High-fat diet–induced AS was alleviated by REV, with less lipid accumulation in the lesions. The metabolic profiles of liver tissues from N, H, and HR groups were analyzed. A total of 1,146 and 765 differentially expressed features were identified between N and H groups, and H and HR groups, respectively. KEGG enrichment analysis uncovered several metabolism-related pathways, which are potential pathogenesis mechanisms and therapeutic targets including “primary bile acid biosynthesis,” “phenylalanine metabolism,” and “glycerophospholipid metabolism.” We further conducted trend analysis using 555 metabolites with one-way ANOVA, where p < 0.05 and PLS-DA VIP >1. We found that REV could reverse the detrimental effect of high-fat diet–induced atherosclerosis. These metabolites were enriched in pathways including “biosynthesis of unsaturated fatty acids” and “intestinal immune network for IgA production.” The metabolites involved in these pathways could be the potential biomarkers for AS-related liver metabolic reprogramming and the mechanism of REV treatment.Conclusions: REV exerted atheroprotective effects partially by modulating the liver metabolism.

Background Oocytes have a lot of maternal RNAs and proteins, which are used by the early embryo before zygotic genome activation. Transducin‐like enhancer of split 6 (TLE6) is a component of a subcortical maternal complex which plays a critical role in early embryonic development. Methods The patient had been diagnosed with primary infertility for 6 years and had undergone multiple failed in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Genomic DNA samples were extracted from her parents’ peripheral blood as well as hers. Whole‐exome sequencing and Sanger validation were performed to identify candidate variants. Results We identified a novel transducin‐like enhancer of split 6 (TLE6) gene mutations in the female patient with recurrent IVF/ICSI failure. The patient carried a homozygous mutation (NM_001143986.1(TLE6): c.541+1G>A) and had viable but low‐quality embryos. Her parents both had heterozygous mutations at this locus. Conclusion Our study expands the mutational and phenotypic spectrum of TLE6 and suggests the important role of TLE6 during embryonic development. Our findings have implications for the genetic diagnosis of female infertility with recurrent IVF/ICSI failure.

Against the background of economic globalization, the strategies for constructing college students' entrepreneurial value judgment are explored, providing college graduates with more employment options and thereby keeping up with the trend of the times. The documentary analysis and questionnaire survey methods are adopted to investigate contemporary college students' entrepreneurial value judgments, and the investigation results are organized. According to documentary materials, the discovered problems are analyzed to put forward strategies for constructing college students' entrepreneurial value judgments based on educational psychology. Results show that only 14.1% of college graduates choose to start a business; 48.7% do not understand or recognize the entrepreneurial values; 14.8% believe teaching activities on constructing entrepreneurial value judgments are insufficient, and the entrepreneurial atmosphere is lacking. Regarding the above investigation results, strategies for constructing college students' entrepreneurial value judgments are proposed, involving the construction environment, construction system, construction method, and construction mechanism. Hence, considering contemporary college students' entrepreneurial values, the proposed strategies for constructing college students' entrepreneurial judgments are suitable and valuable, providing a practical reference for enriching and perfecting the college innovation and entrepreneurship education systems.

Although female genital tuberculosis may lead to infertility, pregnancy is still possible, especially through in vitro fertilization (IVF). In this eventuality, even latent tuberculosis (TB) infection is prone to reactivate. Because some of the symptoms of TB overlap with those of pregnancy, diagnosis and treatment may be delayed. We report the case of a 30-year-old infertile woman with repeated genital tuberculosis (GTB) who underwent two laparoscopic surgeries and anti-TB treatments. The woman conceived through IVF and, unfortunately, a cervical pregnancy was diagnosed, together with a third recurrence of GTB. When the condition became stable after anti-TB treatment, the pregnancy was terminated using oral mifepristone in combination with an ultrasound-guided local injection of methotrexate. The gestational sac was expelled 4 days later with minimal blood loss. In view of the reciprocal influence and interconnection between IVF, pregnancy, and TB, we conducted a literature review to provide valuable information for early diagnosis and treatment, as well as for routine screening before IVF of TB in infertile patients.

Background Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. Methods Apolipoprotein E deficiency (ApoE−/−) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA–protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. Results The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. Conclusion These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.

BACKGROUD: Previous in vitro studies have indicated that pyrimidinergic receptor P2Y6 (P2RY6, P2Y6 receptor) may function as a cancer-promoting factor in lung adenocarcinoma (LUAD). However, the prognostic significance of P2RY6 expression in LUAD has not been investigated. OBJECTIVE: This study aimed to assess the impact of P2RY6 expression on the survival of patients with LUAD. METHODS: First, we assessed P2RY6 mRNA and protein expression in LUAD and non-cancerous lung tissues using the online bioinformatics analysis tool GEPIA, fresh LUAD tissues, and LUAD tissue microarrays (TMAs). Second, we investigated the correlation between P2RY6 expression and clinicopathological parameters of LUAD patients based on data from The Cancer Genome Atlas (TCGA) database and TMAs. Finally, we analyzed the prognostic significance of P2RY6 expression in LUAD using the online survival analysis tool Kaplan-Meier Plotter and data from TMAs. RESULTS: We demonstrated that P2RY6 mRNA and protein expression levels in LUAD tissues were significantly higher than those in non-cancerous lung tissues. The expression of P2RY6 in LUAD was positively correlated with poor differentiation, more lymph node metastasis, and more advanced clinical stage. Higher P2RY6 expression level was correlated with shorter survival of the LUAD patients. Univariate and multivariate Cox regression analyses indicated that higher P2RY6 tumor expression was an independent unfavorable prognostic factor for LUAD patients. CONCLUSIONS: P2RY6 expression was elevated in LUAD and correlated with poor prognosis.