Human mesenchymal stem cells-derived conditioned medium inhibits hypoxia-induced death of neonatal porcine islets by inducing autophagy.

BACKGROUND: The dysfunction of islet grafts is generally attributed to hypoxia-induced damage. Mesenchymal stem cells (MSCs) are currently thought to effectively protect cells from various risk factors via regulating autophagy. In our study, we investigated if human umbilical cord-derived MSCs could ameliorate hypoxia-induced apoptosis in porcine islets by modulating autophagy, and we explored the underlying mechanisms. METHODS: Neonatal porcine islet cell clusters (NICCs) were cultured with human umbilical cord-derived MSC conditioned medium (huc-MSC-CM) and RPMI-1640 medium (control) under hypoxic conditions (1% O2 ) in vitro. NICCs were treated with 3-methyladenine (3-MA) and chloroquine (CQ) to examine the role of huc-MSC-CM in regulating autophagy. Finally, the levels of several cytokines secreted by huc-MSCs were detected by ELISAs, and the corresponding inhibitors were applied to investigate which cytokine mediates the protective effects of huc-MSC-CM. The effects of huc-MSC-CM on NICCs viability and autophagy were examined using AO/PI staining, flow cytometry analysis, transmission electron microscopy (TEM) and confocal fluorescence microscopy analysis. The insulin secretion of NICCs was tested with an insulin immunoradiometric assay kit. RESULTS: Compared to the control, the huc-MSC-CM treatment improved the viability of NICCs, inhibited apoptosis, increased autophagic activity and the levels of PI3K class III and phosphorylated Akt, while the ratio of phosphorylated mTOR/mTOR was reduced. These changes were reversed by CQ and 3-MA treatments. High concentrations of IL-6 were detected in hu-MSC-CM. Furthermore, recombinant IL-6 pre-treatment exerted similar effects as huc-MSC-CM, and these effects were reversed by a specific inhibitor of IL-6 (Sarilumab). CONCLUSIONS: Our results demonstrated that huc-MSC-CM improved islet viability and function by increasing autophagy through the PI3K/Akt/mTOR pathway under hypoxic conditions. Additionally, IL-6 plays an important role in the function of huc-MSC-CM.

Replication of previous genome-wide association studies of HKDC1, BACE2, SLC16A11 and TMEM163 SNPs in a gestational diabetes mellitus case-control sample from Han Chinese population.

Background: Four novel glucose metabolism risk loci (HKDC1 rs4746822, BACE2 rs6517656, SLC16A11 rs13342232 and TMEM163 rs998451) were identified in recent genome-wide association studies (GWAS) of Afro-Caribbean, European, Hispanic, Thai, Mexican, Latin American and Indian populations. None of the abovementioned SNPs has been reported in a Han Chinese population. Aim: To replicate the relationships between HKDC1 rs4746822, BACE2 rs6517656, SLC16A11 rs13342232 and TMEM163 rs998451 with gestational diabetes mellitus (GDM) in a Han Chinese population. Methods: This was a case-control study which enrolled 334 pregnant women with GDM and 367 pregnant women with normal glucose tolerance. The linear regression and logistic regression were used to estimate the association between SNPs with the risk of GDM, HOMA-IR and fasting insulin levels. The fasting insulin concentration and HOMA-IR were log10 transformed before analysis. Results: No significant differences in the alleles and genotypes of SLC16A11 rs13342232, HKDC1 rs4746822 and BACE2 rs6517656 were observed between cases and controls. After adjusting the weekly BMI growth, pre-pregnancy BMI and maternal age, under the additive model, SLC16A11 rs13342232 was associated with log10fasting serum insulin (Beta=0.046, p=0.016), log10HOMA-IR level (Beta=0.061, p=0.003) and fasting plasma glucose level (Beta=0.164, p=0.011); HKDC1 rs4746822 was associated with OGTT 2-hr plasma glucose level (Beta=0.239, p=0.016); and BACE2 rs6517656 was associated with log10fasting serum insulin (Beta=-0.053, p=0.044) and log10HOMA-IR level (Beta=-0.060, p=0.048). After correction for multiple testing, the associations of SLC16A11 and HKDC1 with glucose metabolism remained statistically significant. The A allele of TMEM163 rs998451 was not detected in this population. Conclusion: HKDC1 rs4746822, BACE2 rs6517656 and SLC16A11 rs13342232 are associated with glucose metabolism in pregnant women of Han Chinese.

Mesenchymal stem cells alleviate hypoxia-induced oxidative stress and enhance the pro-survival pathways in porcine islets.

IMPACT STATEMENT: The utilization of mesenchymal stem cells (MSCs) is a promising approach to serve as adjuvant therapy for islet transplantation. But the inability to translate promising preclinical results into sound therapeutic effects in human subjects indicates a lack of key knowledge of MSC-islet interactions that warrant further research. Hypoxia and oxidative stress are critical factors which lead to a tremendous loss of islet grafts. However, previous studies mainly focused on other aspects of MSC protection such as inducing revascularization, enhancing insulin secretion, and reducing islet apoptosis. In this study, we aim to investigate whether MSC can protect islet cells from hypoxic damage by inhibiting ROS production and the potential underlying pathways involved. We also explore the effects of MSC-derived exosomes and IL-6 on hypoxia-injured islets. Our data provide new molecular targets for developing MSC applications, and this may ultimately promote the efficiency of clinical islet transplantation.

[Application of CT-based radiomics in differentiating primary gastric lymphoma from Borrmann type IV gastric cancer].

OBJECTIVE: To explore the feasibility of CT-based image radiomics signature in identification of primary gastric lymphoma and Borrmann type IV gastric cancer.
 Methods: A retrospective analysis of 71 patients with primary gastric lymphoma or Borrmann type IV gastric cancer confirmed by pathology in our Hospital from January 2009 to April 2017 was performed. There were 28 patients with primary gastric lymphoma and 43 patients with Borrmann type IV gastric cancer. The feature extraction algorithm based on Matlab 2017a software was used to extract the features of image, and the logistic regression model was used to screen the features to establish radiomics signature. The CT sign diagnosis model was established, which included the periplasmic fat infiltration, softness of the stomach wall, abdominal lymph node and peripheral organ metastasis, ascites, mucosal white line sign and lesion thickness. The classification of the two models was evaluated by receiver operating characteristic curve.
 Results: A total of 32 3D features were extracted from CT image for each patients. Two features were found to be the most important differential diagnosis factors, and the radiomics signature was established. The CT sign diagnosis model consisted of ascites, periplasmic fat infiltration, stomach wall softness and mucosal white line. For the radiomics signature and the CT subjective finding model, the AUCs were 0.964 and 0.867 with the accuracy at 94.4% and 80.2%, the sensitivity at 93.0% and 74.4%, the specificity at 96.4% and 89.3%, respectively. After Delong test, the diagnostic efficacy of the radiomics signature was higher than the CT sign diagnosis model (P<0.001).
 Conclusion: CT-based image radiomics signature can accurately identify primary gastric lymphoma and Borrmann type IV gastric cancer, and can potentially provide important assistance in clinical diagnosis for the two diseases.