Postprandial triglyceride-rich lipoproteins promote the adipogenic differentiation of adipose-derived mesenchymal stem cells via the LRP1/caveolin-1/AKT1 pathway.

Diet-induced obesity (OB) is usually accompanied by hypertriglyceridemia, which is characterized by the accumulation of triglyceride (TG)-rich lipoprotein (TRL) particles in the circulation. We previously found that postprandial TRL combined with insulin induced the adipogenic differentiation of 3T3-L1 preadipocytes, which may represent a key mechanism underlying obesity. However, the specific mechanism and signaling pathway involved in this process remain to be fully elucidated. In this study, we found that, in the postprandial state, patients with obesity had significantly higher levels of TG and remnant cholesterol (RC) than normal-weight controls. In vitro, we found that postprandial TRL, together with insulin, promoted the adipogenic differentiation of adipose-derived mesenchymal stem cells (AMSCs), as evidenced by the increased expression of lipogenesis-related genes and their protein products, including low-density lipoprotein related protein 1 (LRP1). Besides, caveolin-1 (Cav-1) expression was also significantly upregulated under this condition. Cav-1 and LRP1 were observed to interact, and then led to the activation of the PI3K/AKT1 signaling pathway. Meanwhile, the inhibition of LRP1 or Cav-1 significantly attenuated the adipogenic differentiation of AMSCs and downregulated AKT1 phosphorylation levels. Moreover, treatment with a selective AKT1 inhibitor significantly suppressed postprandial TRL and insulin-induced adipogenesis in AMSCs. Combined, our results demonstrated that, in association with insulin, postprandial TRL can promote the adipogenic differentiation of AMSCs in a manner that is dependent on the LRP1/Cav-1-mediated activation of the PI3K/AKT1 signaling pathway. Our findings indicated that a postprandial increase in TRL content is a critical factor in the pathogenesis of hypertriglyceridemia and diet-induced obesity.

Myocardial Damage in a Highly Suspected Case With Paraneoplastic Pemphigus: A Case Report and Literature Review.

Paraneoplastic pemphigus (PNP) is a rare mucocutaneous autoimmune disease. It has multiple clinical accompanied symptoms by affecting various types of epithelia, including the gastrointestinal and respiratory tract. However, an extensive review of the literature found no cases of PNP associated with myocardial damage. Here, we present a 56-year-old male patient with clinically and histopathologically typical paraneoplastic pemphigus (PNP), who had sustained myocardial injury due to non-cardiac disease involvement. Therefore, we suppose that, when persistent cardiac necrosis markers are elevated in patients with paraneoplastic pemphigus (PNP), the possibility of concomitant myocardial damage should get more attention from clinicians to obtain quick diagnosis and treatment.

Postprandial triglyceride-rich lipoproteins-induced premature senescence of adipose-derived mesenchymal stem cells via the SIRT1/p53/Ac-p53/p21 axis through oxidative mechanism.

The accumulation of senescent adipose-derived mesenchymal stem cells (AMSCs) in subcutaneous white adipose tissue (WAT) is the main cause for the deterioration of WAT and the subsequent age-related disorders in obesity. The number of AMSCs staining positively for senescence-associated-ß-galactosidase (SA-ß-Gal) increased significantly after incubation with postprandial triglyceride-rich lipoproteins (TRL), accompanied by an impaired cell proliferation capacity and increased expression of inflammatory factors. Besides, the expression of anti-aging protein, silent mating-type information regulation 2 homolog 1 (SIRT1), was downregulated significantly, while those of acetylated p53 (Ac-p53), total p53, and p21 proteins were upregulated significantly during postprandial TRL-induced premature senescence of AMSCs. Furthermore, the production of intracellular reactive oxygen species (ROS) in the TRL group increased significantly, while pretreatment with the ROS scavenger N-acetyl-L-cysteine effectively attenuated the premature senescence of AMSCs by decreasing ROS production and upregulating SIRT1 level. Thus, postprandial TRL induced premature senescence of AMSCs through the SIRT1/p53/Ac-p53/p21 axis, partly through increased oxidative stress.

MicroRNAs as a novel cellular senescence regulator.

Cellular senescence is a program activated in normal cells in response to various types of stresses and is manifested by permanent arrest of cell cycle. Cellular senescence is closely related to tumor suppression, and may contribute to the ageing of organisms. The complex senescence cell phenotype has many different mechanisms. Recent studies have provided important insights regarding the role played by miRNAs during cellular senescence as a novel molecular mechanism. In this article, we will review the latest advances in the identification and validation of senescence-regulatory miRNAs and the possible mechanisms.

Remnant-like particles accelerate endothelial progenitor cells senescence and induce cellular dysfunction via an oxidative mechanism.

Remnant-like particles (RLPs) are closely associated with coronary heart disease and can induce endothelial dysfunction through oxidative mechanisms. Many risk factors accelerate the onset of endothelial progenitor cells (EPCs) senescence via increased oxidative stress. In this study, we investigated the effect of RLPs on EPCs senescence and function. RLPs were isolated from postprandial plasma of hypertriglyceridemic patients by use of the immunoaffinity gel mixture of anti-apoA-1 and anti-apoB-100 monoclonal antibodies. Our results show that EPCs became senescent as determined by senescence-associated acidic beta-galactosidase (SA-beta-Gal) staining after ex vivo cultivation without any stimulation. Co-incubation with RLPs accelerated the increase in SA-beta-Gal-positive EPCs. The acceleration of RLPs-induced EPCs senescence occurred dose-dependently with a maximal effect when EPCs were treated with RLPs at 0.10 mg cholesterol/mL (P<0.01). Moreover, RLPs decreased adhesion, migration and proliferation capacities of EPCs as assessed by adherence to fibronectin, modified Boyden chamber technique and MTT assay (P<0.01), respectively. RLPs increased nitrotyrosine staining in EPCs. However, RLPs-induced EPCs senescence and dysfunction were significantly inhibited by pre-treatment of superoxide dismutase (50 U/mL) (P<0.05). Our results provide evidence that RLPs accelerate the onset of EPC senescence via increased oxidative stress, accompanying with the impairment of adhesion, migration and proliferation capacities.

[The relationship between apolipoprotein E genotype and hypertriglyceridemia-associated recurrent acute pancreatitis].

OBJECTIVE: To explore the relationship of apolipoprotein E (ApoE) genotype with hypertriglyceridemia-associated recurrent acute pancreatitis. METHODS: Taking the fasting serum triglyceride (TG) level > or = 2.3 mmol/L as hypertriglyceridemia, ApoE genotypes in 115 patients with hypertriglyceridemia-associated recurrent acute pancreatitis were assessed by polymerase chain reaction. According to the fasting serum TG level, all patients were divided into 3 groups: TG mild elevation group (2.3 mmol/L < or = TG < 5.5 mmol/L, Group A), TG moderate elevation group (5.5 mmol/L < or = TG < 11.3 mmol/L, Group B), and TG severe elevation group (TG > or = 11.3 mmol/L, Group C). RESULTS: Group C had significantly fewer patients with biliary tract disease, improper diet and heavy alcohol consumption, and significantly more patients with passed history of moderate-severe hypertriglyceridemia than Group A and B (P < 0.05). The proportion of patients with E3/4, E3/2, E2/4 and E2/2 genotypes and gene frequency for epsilon 2 and epsilon 4 alleles are significantly higher in Group C than in Group A and B(P < 0.05). Group B had significantly more patients with E3/2 genotype and higher gene frequency for epsilon 2 allele than Group A (P < 0.05). CONCLUSIONS: Apo epsilon 2 and epsilon 4 alleles are closely related to moderate-severe hypertriglyceridemia-associated recurrent acute pancreatitis.

Postprandial hypertriglyceridemia associated with inflammatory response and procoagulant state after a high-fat meal in hypertensive patients.

OBJECTIVE: To investigate the changes of inflammatory factors and hemostatic variable in plasma after a high-fat meal in normocholesterolemic patients with essential hypertension. METHODS: A total of 60 hypertensive patients were randomly assigned to accept a single high-fat meal (group 1, n=40) or not (group 2, n=20) in the morning after an overnight fast, and 20 healthy participants (group 3) consumed a single high-fat meal on the same day. Plasma lipid profiles, high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNFalpha), soluble P-selectin and plasminogen activator inhibitor type 1 (PAI-1) antigen levels were measured at fasting and 4 h after meal ingestion. RESULTS: Postprandial triglyceride levels increased significantly in groups 1 and 3 (P<0.01), whereas levels were higher in group 1 (P<0.001). Postprandial plasma TNFalpha, hsCRP, soluble P-selectin and PAI-1 antigen levels increased in group 1 (P<0.001) but not in group 3. Postprandial plasma triglyceride level was correlated with log(hsCRP) (P<0.001), TNFalpha (P<0.001), soluble P-selectin (P<0.01) and PAI-1 antigen (P<0.05) levels, respectively. Both postprandial plasma level of soluble P-selectin and that of PAI-1 antigen were positively and significantly correlated with those of log(hsCRP) (P<0.01) and TNFalpha (P<0.001), respectively. CONCLUSION: Postprandial hypertriglyceridemia in hypertensive patients is associated with inflammatory response and procoagulant state.

AICAR induces astroglial differentiation of neural stem cells via activating the JAK/STAT3 pathway independently of AMP-activated protein kinase.

Neural stem cell differentiation and the determination of lineage decision between neuronal and glial fates have important implications in the study of developmental, pathological, and regenerative processes. Although small molecule chemicals with the ability to control neural stem cell fate are considered extremely useful tools in this field, few were reported. AICAR is an adenosine analog and extensively used to activate AMP-activated protein kinase (AMPK), a metabolic "fuel gauge" of the biological system. In the present study, we found an unrecognized astrogliogenic activity of AICAR on not only immortalized neural stem cell line C17.2 (C17.2-NSC), but also primary neural stem cells (NSCs) derived from post-natal (P0) rat hippocampus (P0-NSC) and embryonic day 14 (E14) rat embryonic cortex (E14-NSC). However, another AMPK activator, Metformin, did not alter either the C17.2-NSC or E14-NSC undifferentiated state although both Metformin and AICAR can activate the AMPK pathway in NSC. Furthermore, overexpression of dominant-negative mutants of AMPK in C17.2-NSC was unable to block the gliogenic effects of AICAR. We also found AICAR could activate the Janus kinase (JAK) STAT3 pathway in both C17.2-NSC and E14-NSC but Metformin fails. JAK inhibitor I abolished the gliogenic effects of AICAR. Taken together, these results suggest that the astroglial differentiation effect of AICAR on neural stem cells was acting independently of AMPK and that the JAK-STAT3 pathway is essential for the gliogenic effect of AICAR.