Lysimachia christinae polysaccharide attenuates diet-induced hyperlipidemia via modulating gut microbes-mediated FXR-FGF15 signaling pathway.

Polysaccharides are one of the most abundant and active components of Lysimachia christinae (L. christinae), which is widely adopted for attenuating abnormal cholesterol metabolism; however, its mechanism of action remains unclear. Therefore, we fed a natural polysaccharide (NP) purified from L. christinae to high-fat diet mice. These mice showed an altered gut microbiota and bile acid pool, which was characterized by significantly increased Lactobacillus murinus and unconjugated bile acids in the ileum. Oral administration of the NP reduced cholesterol and triglyceride levels and enhanced bile acid synthesis via cholesterol 7α-hydroxylase. Additionally, the effects of NP are microbiota-dependent, which was reconfirmed by fecal microbiota transplantation (FMT). Altered gut microbiota reshaped bile acid metabolism by modulating bile salt hydrolase (BSH) activity. Therefore, bsh genes were genetically engineered into Brevibacillus choshinensis, which was gavaged into mice to verify BSH function in vivo. Finally, adeno-associated-virus-2-mediated overexpression or inhibition of fibroblast growth factor 15 (FGF15) was used to explore the farnesoid X receptor-fibroblast growth factor 15 pathway in hyperlipidemic mice. We identified that the NP relieves hyperlipidemia by altering the gut microbiota, which is accompanied by the active conversion of cholesterol to bile acids.

Mitochondrial gene COX2 methylation and downregulation is a biomarker of aging in heart mesenchymal stem cells.

The mitochondria have been proven to be involved in processes of aging; however, the mechansims through which mitoepigenetics affect the cytological behaviors of cardiomyocytes during the aging process are not yet fully understood. In the present study, two senescence models were constructed, replicative senescence (RS) and stress­induced premature senescence (SIPS), using human heart mesenchymal stem cells (HMSCs). First, the differences in age­related gene expression levels and telomere length were compared between the HMSCs in the RS and SIPS models by PCR. Subsequently, protein expression and the mitochondrial DNA (mtDNA) methylation status of cytochrome c oxidase subunit II (COX2) was measured by western blot analysis and bisulfite genomic sequencing (BSP). Finally, the value of the DNA methyltransferase (Dnmt) inhibitor, 5­aza­2'­deoxycytidine (AdC), in delaying the senescence of HMSCs was evaluated. It was found that the p16, p27 and p53 mRNA expression levels increased in the senescent cells, whereas p21 mRNA expression did not. It was also found that telomere shortening only occurred in the RS model, but not in the SIPS model. Along with the senescence of HMSCs, COX2 gene methylation increased and its protein expression level significantly decreased. It was demonstrated that AdC inhibited COX2 methylation and downregulated COX2 expression. The addition of exogenous COX2 or the administration of AdC promoted cell proliferation and delayed cell aging. On the whole, the present study demonstrates that COX2 methylation and downregulation are biomarkers of HMSC senescence. Thus, COX2 may have potential for use as a therapeutic target of cardiovascular diseases and this warrants further investigation.

Large Animal Models for the Clinical Application of Human Induced Pluripotent Stem Cells.

Induced pluripotent stem cell (iPSC) technology offers a practically infinite and ethically acceptable source to obtain a variety of somatic cells. Coupled with the biotechnologies of cell therapy or tissue engineering, iPSC technology will enormously contribute to human regenerative medicine. Before clinical application, such human iPSC (hiPSC)-based therapies should be assessed using large animal models that more closely match biological or biomechanical properties of human patients. Therefore, it is critical to generate large animal iPSCs, obtain their iPSC-derived somatic cells, and preclinically evaluate their therapeutic efficacy and safety in large animals. During the past decade, the establishment of iPSC lines of a series of large animal species has been documented, and the acquisition and preclinical evaluation of iPSC-derived somatic cells has also been reported. Despite this progress, significant obstacles, such as obtaining or preserving the bona fide pluripotency of large animal iPSCs, have been encountered. Simultaneously, studies of large animal iPSCs have been overlooked in comparison with those of mouse and hiPSCs, and this field deserves more attention and support due to its important preclinical relevance. Herein, this review will focus on the large animal models of pigs, dogs, horses, and sheep/goats, and summarize current progress, challenges, and potential future directions of research on large animal iPSCs.

Predictive significance of serum dipeptidyl peptidase-IV in papillary thyroid carcinoma.

BACKGROUND: The significance of serum dipeptidyl peptidase-IV (DPP-IV) in papillary thyroid carcinoma (PTC) has not been elucidated. OBJECTIVE: This study aimed to assess the role of serum DPP-IV in the carcinogenesis and prognosis of PTC. METHODS: The serum DPP-IV concentration was measured in 171 male patients with PTC, 81 male patients with a benign thyroid nodule (BTN), and 52 male healthy controls (HCs). Multivariate logistic regression and Cox regression analyses were performed to evaluate the correlations between variables. Receiver operating characteristic (ROC) curves were used to calculate the diagnosis accuracy. RESULTS: The ROC curve indicated a good performance of DPP-IV for discriminating PTC from BTN, with an area under the curve (AUC) of 0.881 (95% CI, 0.840-0.922). Serum DPP-IV demonstrated a modest performance in predicting nonstructurally persistent disease/recurrent disease (NSPRD) survival, with an AUC of 0.778 (95% CI, 0.635-0.922). A serum DPP-IV level ⩾ 250 nkat/L (HR, 6.529; 95% CI, 2.090-20.398; P= 0.001) and an advanced tumor, lymph node, metastasis (TNM) stage (HR, 4.677; 95% CI, 1.498-14.605; P= 0.008) were found to be independent factors for predicting SPRD. PTC patients with a DPP-IV level ⩾ 250 nkat/L had a worse outcome than those with a DPP-IV level < 250 nkat/L (P< 0.001). CONCLUSIONS: Serum DPP-IV may be a predictive biomarker for PTC diagnosis and prognosis in Chinese male patients.

Short-Term Effect of Autologous Bone Marrow Stem Cells to Treat Acute Myocardial Infarction: A Meta-Analysis of Randomized Controlled Clinical Trials.

Bone marrow stem cells (BMSCs) have been used to treat patient with ST-segment elevation myocardial infarction (STEMI) via intracoronary route. We performed a meta-analysis to evaluate the short-term efficacy and safety of this modality. Seventeen randomized controlled trials (RCTs) of BMSC-based therapy for STEMI, delivered with 9 days of reperfusion and followed up shorter than 12 months, were identified by systematic review. Intracoronary BMSC therapy resulted in an overall significant improvement in left ventricular ejection fraction (LVEF) by 2.74 % (95 % confidence interval (CI) 2.09-3.39, P < 0.00001, I(2) = 84 %) at 3-6-month follow-up and 5.1 % (95 % CI 4.16-6.03, P < 0.00001 and I(2) = 85 %) at 12 months. The left ventricular end-systolic volume (LVESV) and wall motion score index (WMSI) were also reduced at 3-6 months. At 12 months, left ventricular end-diastolic volume (LVEDV), LVESV, and WMSI were significantly reduced in BMSC group. In conclusion, intracoronary BMSC therapy at post-STEMI is safe and effective in patient with acute STEMI.

Resveratrol attenuates the inflammatory reaction induced by ischemia/reperfusion in the rat heart.

The role of resveratrol (Res) in inflammation induced by ischemia/reperfusion is not well understood. The aim of the present study was to investigate whether Res modulates neutrophil accumulation and tumor necrosis factor-α (TNF-α) induction in an ischemia/reperfusion-injured rat heart model. The rats were randomly exposed to sham surgery, myocardial ischemia/reperfusion (MI/R) alone, MI/R + Res, MI/R + Res + L-NG-nitroarginine methyl ester (L-NAME) and MI/R + Res + methylene blue (MB). The results demonstrated that compared with MI/R, Res reduced the myocardial infarct area, myocardial myeloperoxidase levels, serum creatinine kinase and lactate dehydrogenase levels, and serum and myocardial TNF-α production. All the effects of Res demonstrated were inhibited by L-NAME (a nitric oxide (NO) synthase inhibitor) and MB [a cyclic guanosine monophosphate (cGMP) inhibitor]. Thus, Res produces cardioprotective and anti-inflammatory effects. These effects may be associated with an increase in NO production, the inhibition of neutrophil accumulation, TNF-α induction and cGMP signaling pathways in myocardium subjected to MI/R.